SEMINARS IN

PERINATOLOGY
VOL 31, NO 3 JUNE 2007

Recurring Complications of Pregnancy

JOHN C. SMULIAN, MD, MPH
Guest Editor

TABLE OF CONTENTS
Introduction John C. Smulian ............................................................................... 125
Fetal Growth Restriction and Subsequent Pregnancy Risks Wendy L. Kinzler and
Lillian Kaminsky ................................................................................................... 126
Preeclampsia Recurrence and Prevention Gary A. Dildy III, Michael A. Belfort,
and John C. Smulian ............................................................................................. 135
Recurrent Preterm Birth Shali Mazaki-Tovi, Roberto Romero, Juan Pedro Kusanovic,
Offer Erez, Beth L. Pineles, Francesca Gotsch, Pooja Mittal, Nandor Gabor Than,
Jimmy Espinoza, and Sonia S. Hassan .................................................................... 142
Postpartum Hemorrhage: A Recurring Pregnancy
Complication Michelle A. Kominiarek and Sarah J. Kilpatrick ............................... 159
Thromboembolism in Pregnancy: Recurrence and Its
Prevention Andra H. James, Chad A. Grotegut, Leo R. Brancazio,
and Haywood Brown ............................................................................................. 167
Recurrent Gestational Diabetes: Risk Factors, Diagnosis, Management, and
Implications Joseph N. Bottalico .......................................................................... 176
After Shoulder Dystocia: Managing the Subsequent Pregnancy and
Delivery Edith D. Gurewitsch, Tara L. Johnson, and Robert H. Allen ...................... 185
Epidemiologic Approaches for Studying Recurrent Pregnancy Outcomes:
Challenges and Implications for Research Cande V. Ananth ............................. 196
 SEMINARS IN
PERINATOLOGY
TOPICS FOR 2006
OPTIMIZING CARE AND OUTCOMES FOR LATE PRETERM
(NEAR-TERM) INFANTS: PART 1
Tonse N. K. Raju, MD

OPTIMIZING CARE AND OUTCOMES FOR LATE PRETERM

(NEAR-TERM) INFANTS: PART 2
Tonse N. K. Raju, MD

ADVANCES IN NEONATOLOGY: SELECTED PROCEEDINGS OF THE

INTERNATIONAL PERINATAL COLLEGIUM
William Oh, MD, and Harry Bard, MD

BPD: STATE OF THE ART

Vineet Bhandari, MD, DM

CESAREAN DELIVERY ON MATERNAL REQUEST

Catherine Y. Spong, MD, and Uma M. Reddy, MD, MPH

INHERITED RESPIRATORY DISORDERS OF THE NEONATE

Lawrence M. Nogee, MD, and Aaron Hamvas, MD

TOPICS FOR 2007

NEONATAL INFECTIONS
Robert S. Baltimore, MD, and Hal B. Jensen, MD

THE EVIDENCE BASE SUPPORTING NUTRITIONAL

PRACTICES FOR VERY LOW BIRTH WEIGHT INFANTS
Richard A. Ehrenkranz, MD, and Brenda B. Poindexter, MD, MS

RECURRING COMPLICATIONS OF PREGNANCY

John C. Smulian, MD, MPH

COAGULATION DISORDERS IN THE PERINATAL

PERIOD
Michael J. Paidas, MD

PAIN
K. J. S. Anand, MD, and Richard W. Hall, MD

ORGAN TRANSPLANTATION AND REPRODUCTION

Lloyd Ratner, MD, and Mary D’Alton, MD
Volume 31, Number 3
Introduction
. . .Whoever wishes to foresee the future must consult the past; for
human results ever resemble those of preceding times.
Niccoló Machiavelli (The Discourses, 1517)
P regnancy is associated with many unique health prob-
lems that occur at no other time in life and in no specialty
other than Obstetrics. Complications can be medical or sur-
gical and may affect the mother, the baby, or both. What is
even more unique is that we have the opportunity to follow
women through successive pregnancies, each of which is at
risk for either occurrence or recurrence of these complica-
tions. Whereas prediction of complications for nulliparous
women with no pregnancy track record is notoriously diffi-
cult, it is becoming clear that a history of a pregnancy com-
plication is the greatest predictor of a future pregnancy com-
plication. It is the role of research in complication recurrence
to grow our understanding of the heterogeneity of pregnan-
cy-associated diseases and give insight into etiologies and
risk. This will ultimately lead to better clinical prediction,
counseling, and management. As clinicians, we should not
manage these at-risk women the same as women who have
never had a pregnancy or who have had previous normal
pregnancy outcomes. We also should avoid the practice of
“anecdotal medicine,” where wide variations in clinical care
can be driven by either insufficient experience or the trauma
of a previous adverse event.
This issue of Seminars in Perinatology is organized around
the theme of recurrent pregnancy complications. There are
eight articles by recognized experts, of which seven are de-
0146-0005/07/$-see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2007.03.007
June 2007
voted to some of the most significant pregnancy complica-
tions encountered by clinicians. (There clearly are many
more pregnancy complications with a tendency to recur,
which deserve the same careful scrutiny as those reviewed
here.) Because recurrence research is complicated and re-
quires different thinking about epidemiologic and statistical
methodologies, there is included an important eighth article
that addresses challenges specific to the study of recurrent
pregnancy complications.
The selected topics covered in this issue illustrate how
important the concept of recurrence is to Obstetrics. These
articles review what is known about the epidemiology of
recurrence for each specific complication, proposed etiologic
pathways, prevention options, and management recommen-
dations for successive pregnancies. Each article also is meant
to highlight knowledge gaps and areas with a pressing need
for research. Unfortunately, our knowledge gaps about re-
currence are wide for many of these conditions.
It is my hope that this issue of Seminars in Perinatology will
provide information to directly help with the clinical care of
our highest risk women. I also hope that these articles will
stimulate further research on the recurrence of complications
in successive pregnancies and promote collaborations be-
tween epidemiologists and clinicians to advance our under-
standing of this very important area of medicine.
John C. Smulian, MD, MPH
Guest Editor
125
Fetal Growth Restriction and
Subsequent Pregnancy Risks
Wendy L. Kinzler, MD, and Lillian Kaminsky, MD

Fetal growth restriction can result from a variety of intrinsic or extrinsic insults, resulting
from maternal, fetal, and placental factors. Determining the underlying cause of poor fetal
growth can be difficult but is essential for assessing potential risks for future pregnancies.
Importantly, recurrence risks greatly depend on these underlying conditions. Understand-
ing these risks can allow more appropriate patient counseling and may influence manage-
ment strategies to optimize future pregnancies.
Semin Perinatol 31:126-134 © 2007 Elsevier Inc. All rights reserved.

KEYWORDS fetal growth restriction, recurrence risks

N ormal fetal growth is dependent on complex interac-

tions between the fetal, placental, and maternal units.
Poor fetal growth can result from a variety of intrinsic or
extrinsic insults. Determining the underlying cause can be
difficult but is essential for assessing potential risks for future
pregnancies.
Small for gestational age (SGA) infants are defined as those
born with a weight ⬍10th percentile for gestational age. Fetal
growth restriction (FGR) can be defined as an abnormal
growth trend, which is less than the genetic growth potential
of the individual fetus and which is always pathological. This
pathological FGR may affect only 3% to 5% of births. Impor-
tantly, not all SGA babies have FGR since some may be con-
stitutionally small. Conversely, a fetus still may be growth
restricted if it is above the 10th percentile in weight if it is
substantially smaller than its growth potential would predict.
It is important to accurately determine as best as possible
whether a previous pregnancy was complicated by patho-
logic FGR or merely a constitutionally SGA infant. Informa-
tion that might be helpful for establishing a diagnosis of fetal
growth restriction in a previous pregnancy is listed in Table
1. Once the diagnosis of FGR is established, an assessment of
subsequent pregnancy risk can be performed based on the
etiology of the initial case.
Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology
and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical
School, New Brunswick, NJ.
Address reprint requests to Wendy L. Kinzler, MD, Department of Obstet-
rics, Gynecology and Reproductive Sciences, Clinical Academic Build-
ing, 2nd Floor, 125 Paterson Street, New Brunswick, NJ 08901. E-mail:
kinzlewe@umdnj.edu
Etiology-Specific Risks for FGR
There are multiple factors which can adversely influence fetal
growth. In broad terms, contributing factors can be intrinsic
to the fetus, they can be specific to the uteroplacental unit, or
they may be the result of underlying maternal conditions.
Determining which of these was responsible for FGR can be
the most difficult but the most useful part of the evaluation
during a woman’s subsequent pregnancy. Prior medical
records, including prenatal labs and notes, previous ultra-
sound reports, maternal and infant hospital records, and pla-
cental pathology, should be requested and carefully re-
viewed, with particular attention being made to the following
etiologic pathways.
Fetal Causes
Chromosomal aberrations are a well-established cause of fe-
tal growth restriction and are estimated to be responsible for
up to 20% of cases.1 Early onset of growth restriction, the
presence of polyhydramnios, and the presence of structural
malformations all increase the likelihood of a chromosomal
abnormality. Triploidy is most common in severe cases of
FGR when ⬍26 weeks gestation, and Trisomy 18 is the most
common aneuploidy noted with severe FGR after 26 weeks
gestation.1 However, other trisomies, deletions/additions,
and ring chromosomes have all been associated with various
degrees of fetal growth abnormalities. Fetal aneuploidy is not
the only chromosomal abnormality to be associated with
poor fetal growth. Confined placental mosaicism is present
when the cytogenetics of the placental mass are different than
the cytogenetics of the fetus. It occurs either as the result of a
meiotic rescue of a trisomic embryo or due to a mitotic

126 0146-0005/07/$-see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2007.03.004
Fetal growth restriction
Table 1 Information Useful for Establishing a Diagnosis of
FGR in a Previous Pregnancy
● Previous birth weight and gestational age to determine
birth weight centile
● Antepartum complications (bleeding, multiple gestation,
congenital abnormalities, preeclampsia)
● Maternal pre-pregnancy BMI and weight gain during
pregnancy
● Social history (tobacco, alcohol, or illicit drug use)
● Medication exposure
● Prenatal fetal growth trends and ultrasound reports
● Medical complications (chronic hypertension, IDDM,
SLE, anemia, asthma, etc.)
● Birth weights of other pregnancies
● Maternal birth weight
● Neonatal complications (respiratory, metabolic,
congenital abnormalities, NICU admission, and length
of stay)
postzygotic error.2 It has been found in approximately 15%
of intrauterine growth restriction cases, compared with ⬍2%
of appropriately grown fetuses. The recurrence risk of aneu-
ploidy is approximately 1%, but a recurrence risk for con-
fined placental mosaicism has not been established.
Nonaneuploid genetic syndromes have also been associ-
ated with fetal growth restriction but may be more difficult to
identify without a known family history and/or detailed ge-
netic evaluation. Lower birth weights are also often identified
in infants born with structural malformations, especially
when cardiac, even in the presence of a normal fetal karyo-
type.3 Uniparental disomy (UPD) is the inheritance of two
homologous chromosomes from only one parent. There are
clinical syndromes which are known to be the result of UPD
(Silver Russell Syndrome, for example) and have significant
growth restriction as part of their phenotype.4 Although an
association with poor fetal growth has been established, UPD
is an uncommon finding in most cases.5 The risk for FGR
recurrence from these causes is dependent on the specific
associated condition.
Congenital infections, namely rubella, cytomegalovirus,
toxoplasmosis, herpes simplex, and varicella, have been as-
sociated with FGR.6-9 Despite this clear association, the pro-
portion of growth restriction attributed to congenital infec-
tion is low (5%),10 and they are not expected to recur.
For a variety of reasons, fetuses within multiple gestations
have an increased incidence of growth restriction. The inci-
dence of growth restriction in twins is 15% to 25%,11-13 mak-
ing multiple gestations responsible for approximately 5% of
all cases of FGR. There is a significant increase in the rate of
fetal growth abnormalities in direct relationship to the num-
ber of fetuses present.14 This may be related to a reduction in
cell size or a relative reduction in nutrient supply as the
nutritional demands of the fetuses increase. This form of FGR
is usually mild. Nevertheless, other contributing factors may
include an increased incidence of placental and umbilical
cord abnormalities (velamentous insertions), a greater likeli-
hood of structural malformations and vascular anastomoses
in monozygotic multiples, and an increased incidence of ma-
127
ternal complications linked with poor fetal growth. There are
no data to assess recurrence risks for FGR when the index
case is a multiple gestation. However, the risks in a subse-
quent singleton pregnancy are likely to be increased mini-
mally, if at all.
Placental Factors
Umbilical cord and placental abnormalities are frequently
identified in pregnancies complicated by poor fetal growth. A
single umbilical artery is present in approximately 0.4% of
pregnancies15 and has been associated with fetal structural
malformations, particularly cardiac. In cases of an isolated
two-vessel cord, FGR is estimated to be up to twice as com-
mon as in pregnancies with three-vessel cords.16 Velamen-
tous cord insertions, which enter the fetal membranes instead
of the placental parenchyma, have a reported incidence of 1%
to 2%.15 They have been associated with higher rates of low
birth weight (OR 2.3), small-for-gestational age infants (OR
1.5), and preterm delivery (OR 2.1)17 compared with umbil-
ical cords normally inserted into the placenta. This suggests
that at least some of these low-birth-weight and SGA births
have FGR. Circumvallate placentation is defined as an ele-
vated edge of the placenta ⬎50% of the circumference, and
has been associated with poor fetal growth and prematuri-
ty.18 These factors are generally considered to have low re-
currence rates.
Placental bleeding at any trimester places a pregnancy at
increased risk for adverse outcomes. The incidence of first
trimester intrauterine hematoma is reported to be 3% in the
general population with increased risks of hypertensive dis-
orders of pregnancy (2- to 4-fold), abruption (5-fold), pre-
term delivery (2-fold), and FGR (2.4-fold).19 Abruption at
term is also significantly associated with FGR (2-fold in-
creased risk), stillbirth, preterm delivery, and pregnancy-in-
duced hypertension.20,21 Placental bleeding at any gestational
age in a pregnancy complicated by FGR may be a clinical
manifestation of a chronic placental disorder that can recur.
Although the majority of low-birth-weight neonates deliv-
ered from pregnancies complicated by placenta previa are
small due to preterm gestational age at birth, at least one
report estimated that as much as 3.7% of FGR is attributable
to placenta previa.22
Microscopically, many placental lesions have been identi-
fied in cases of abnormal fetal growth. Placental infarctions
have been associated with FGR and abnormal fetal blood
flow.23 Placental examination from term pregnancies compli-
cated by idiopathic FGR also found a high incidence of in-
farction (24%).24 The placenta can also be the target of im-
mune-mediated injury, such as occurs with massive fibrin
deposition and chronic villitis.
Massive perivillous fibrin deposition, previously referred
to as maternal floor infarct, is a significant placental lesion
characterized by a heavy deposition of fibrin in the decidua
basalis and extending into the intervillous space, preventing
appropriate maternal–fetal exchange of nutrients. It is be-
lieved to be the result of an immune-mediated maternal re-
sponse and has been associated with high rates of poor fetal
128
outcomes, including a 15% to 40% fetal death rate, a 30% to
60% preterm birth rate, and a 50% to 100% rate of FGR.25,26
Another potential immune-mediated lesion is chronic vil-
litis of unknown etiology (VUE). Chronic villitis has been
found in approximately 30% of pregnancies complicated by
FGR.24,27 Other, rare placental abnormalities include placen-
tal mesenchymal dysplasia, which is a placenta vascular mal-
formation that is often confused clinically with a partial hy-
datiform mole. This abnormality can predispose to placental
thrombosis. In one series, 50% of the cases were associated
with FGR and 43% of the pregnancies were complicated by a
fetal death.28
Maternal Factors
Multiple maternal factors have been implicated in poor fetal
growth. Careful review of the maternal history for potential
contributing factors can sometimes identify nutritional dis-
orders, anemia and maternal hypoxia-related conditions, en-
vironmental exposures (particularly tobacco or cocaine use),
and conditions with maternal vascular disease. Any review
should include a family history, as it has been shown that
familial factors influence the risk of SGA births.29
Malnutrition is an uncommon, but nonetheless important,
risk factor for poor fetal growth, especially in developing
countries. The effect of starvation was best studied in a Dutch
cohort during the famine of 1944 to 1945. Pregnant women
under such severe nutritional deprivation experienced
weight loss and a drop in birth weight by 250 to 300 g.30
Women with eating disorders have also been shown to have
higher rates of SGA births.31 Correction of such nutritional
deficiency is likely to reduce recurrence risk.
Maternal conditions leading to hypoxemia can lead to a
reduction in fetal growth potential. Studies have inconsis-
tently linked maternal anemia, including sickle cell anemia,
and low birth weight.32-34 Chronic respiratory disease, such
as asthma, can also lead to decreased fetal growth through
fetal hypoxia.35 Likewise, women with congenital cyanotic
heart disease and those living at high altitude are at higher
risk for lower birth weight babies.36,37
Maternal substance abuse, including tobacco, alcohol, and
cocaine, is an important preventable cause of poor fetal
growth. The mechanism may involve direct toxic damages of
these substances as well as associated comorbidities, such as
inadequate nutrition, maternal infections, etc. Smoking is
associated with an increased risk of delivering a low-birth-
weight or SGA infant in a dose-dependent fashion.38,39 It has
been estimated that approximately 20% of low-birth-weight
and SGA births are attributable to maternal smoking.40 Bada
and coworkers estimated that, if smoking could be com-
pletely prevented during pregnancy, 13.8% of FGR cases
would be eliminated.41 FGR is one of the major features of
fetal alcohol syndrome, which is also associated with facial
dysmorphia and central nervous system disorders.42 The ad-
verse effects of prenatal cocaine exposure on fetal growth43 as
well as on placental abruption, preterm birth, and intrauter-
ine fetal demise have been well established. Various thera-
peutic drugs, such as warfarin, folic acid antagonists, and
W.L. Kinzler and L. Kaminsky
anticonvulsants, can also be associated with FGR. The risk for
recurrence of FGR for these exposures is likely linked to their
continued presence or their discontinuation.
Clinical maternal vascular disease secondary to chronic
hypertension, renal disease, diabetes mellitus, and collagen
vascular disease, especially when complicated by preeclamp-
sia, is the most common cause of impaired fetal growth,
accounting for nearly a third of FGR cases.2 Both preeclamp-
sia and FGR may share a similar pathophysiology involving
abnormal placentation leading to placental insufficiency.44
Chronic hypertension is associated with a two- to threefold
increase in the rate of FGR, an association mostly due to the
presence of superimposed preeclampsia.45 In fact, when
growth restriction cases due to preeclampsia, smoking, and
malnutrition are excluded, diabetes and hypertension may
no longer be independent risk factors.46 The association of
chronic hypertension and poor fetal growth may also be par-
tially mediated by the effect of antihypertensive medications,
such as beta-blockers.47 The risk of FGR in pregnancies af-
fected by pregestational diabetes is dependent on the severity
and duration of the disease.45 The incidence of FGR in
chronic renal disease has been reported to be as high as
23%.48 Patients with systemic lupus have an eightfold in-
creased risk for developing FGR,45,49-51 with the highest risks
noted in women diagnosed before pregnancy and those with
active renal and central nervous system involvement.49-51
These risk factors will persist in subsequent pregnancies.
Inherited thrombophilias are a group of genetic conditions
that increase the risk of thromboembolic disease. They in-
clude Factor V Leiden (FVL), prothrombin G20210A muta-
tion, protein C deficiency, protein S deficiency, antithrombin
III deficiency, and MTHFR mutation, as well as other, less
studied, familial conditions. Theoretically, placental throm-
bosis in patients with inherited thrombophilias may lead to
an increased risk for FGR, although the published data are
conflicting. A number of studies have demonstrated an asso-
ciation between maternal inherited thrombophilias and
FGR.52-55 However, other studies were unable to show an
association.56-59 Based on the conflicting current data, inher-
ited thrombophilia in isolation does not seem to be a major
risk factor for most cases of FGR. However, the contributing
role of thrombophilias in combination with other risk factors,
including previous FGR, may be important. Antiphospho-
lipid antibody syndrome (with or without underlying sys-
temic lupus) is an acquired thrombophilia, which has been
linked to several recurrent adverse pregnancy outcomes, in-
cluding FGR, fetal death, and recurrent miscarriages.60,61
Evaluation Options to
Assess FGR Etiologies and Risks
Once the diagnosis of FGR has been confirmed and the above
etiologies have been evaluated by history and examination,
there may continue to be gaps in knowledge that may have a
significant impact on further management. Some of these
gaps, however, can be filled with the addition of a few simple
steps. If not already done, consider having the previous pla-
cental slides reviewed for histologic abnormalities by a peri-
Fetal growth restriction
natal pathologist. If there is evidence of a prior abruption, or
placental thromboses and/or infarctions are noted, it is im-
portant to assess for maternal risk factors that may contribute
to coagulation abnormalities. Testing for acquired and inher-
itable thrombophilias is recommended in these cases, partic-
ularly when the growth restriction is severe, associated with
preterm delivery, or noted in the presence of a family history
of thromboembolic disease. Specific evaluations would in-
clude maternal testing for lupus anticoagulant, anticardio-
lipin antibodies (IgG and IgM), and ␤2-glycoprotein-1 anti-
bodies. It is important to remember that 10% to 15% of
women with systemic lupus erythematosus will have second-
ary antiphospholipid antibody syndrome and should be
tested if their antiphospholipid status is not already known.62
Genetic thrombophilia testing should include an evaluation
for deficiencies in protein C, protein S, and antithrombin III
and the presence of the Factor V Leiden and prothrombin
gene mutations. If immune-mediated placental dysfunction
is suspected, testing for the antiphospholipid antibody syn-
drome and screening for other autoimmune disorders are
warranted. There is insufficient information to support test-
ing the affected offspring for the presence of thrombophilias
at this time.
If the prior child was found to have structural malforma-
tions (prenatally or postnatally diagnosed), and/or there have
been concerns about development delay, genetic counseling
and possible evaluation by a pediatric geneticist is recom-
mended. Review of prior records, including autopsy reports
or infant discharge summaries, can be very helpful, as parents
may not be fully aware of known or suspected diagnoses. If
there has been a documented or suspected case of aneu-
ploidy, parental karyotypes should be considered. This is
particularly important for cases of aneuploidy other than the
autosomal trisomies thought to be the result of meiotic non-
disjunction, such as unbalanced translocations and ring
chromosomes. A formal genetics evaluation is also essential
in detecting and counseling about nonaneuploid genetic syn-
dromes.
In women with an underlying medical condition, assessing
the severity of the disorder can also provide insight into the
ongoing obstetrical risks. This would include determining
the presence of renal dysfunction in women with systemic
lupus or other autoimmune processes and evaluating the
degree of vascular and/or end-organ disease in women with
long-standing diabetes or chronic hypertension.
Assess Risks for a Subsequent Pregnancy
The diagnosis and/or risk factors that have been identified in
the above steps will allow appropriate counseling regarding
the risk(s) to subsequent pregnancies (Table 2). It is clear that
the data on etiology-specific FGR recurrence risks are sparse.
Recently, it has been recognized that women with a history of
FGR are at risk for multiple adverse pregnancy outcomes in
subsequent pregnancies that include recurrent FGR, pre-
eclampsia, and abruption.63 These risks are particularly rele-
vant in the setting of an acquired or inherited thrombophil-
ia.64-68 The recurrence rate of adverse pregnancy outcomes in
129
women with untreated inherited or acquired thrombophilia
is approximately 66% to 83%.63,69 A cohort study of 491
patients with a history of adverse pregnancy outcomes has
demonstrated that the presence of a maternal thrombophilia
is associated with fetal loss after 14 weeks (OR 3.4, 95% CI
1.9-6.1), abruption (OR 3.6, 95% CI 1.4-9.1), and pre-
eclampsia (OR 3.2, 95% CI 1.2-8.6).70 Women who deliv-
ered infants ⬍3rd percentile may be three times more likely
to have initial or recurrent preeclampsia in the next preg-
nancy compared with those who deliver infants ⬎10th per-
centile.71 They may also be at increased risk of fetal demise,
especially when the previous fetal growth abnormalities were
identified at early gestational ages.72 Interestingly, of the 23%
of women experiencing recurrent SGA in one study, the poor
fetal growth was not more severe the second time.73
Previous abruption is a risk factor for FGR, as well as other
adverse obstetrical outcomes. Recurrent placental abruption
has been observed in 22% of subsequent pregnancies.74 After
an abruption, the risk of a SGA infant is 18.5%, the risk of a
spontaneous preterm birth is 36%, and the risk of pregnancy-
induced hypertension is 6%.75 A previous SGA birth in-
creases the risk of abruption by 1.6-fold and by 2.5- to 6.0-
fold if there is preexisting chronic hypertension or diabetes.76
If a first delivery has been complicated by a preterm birth,
SGA infant, or perinatal death, the risk of an abruption in the
second pregnancy is 7/1000 if no abruption was present in
the initial pregnancy and 33/1000 if there was a prior abrup-
tion.77
If there has been a history of FGR and placental infarction,
the risk of recurrent growth restriction is high. It has been
estimated to be 61% when two or more prior pregnancies
have been similarly affected.78 Recurrent villitis has been
noted in 17% of gestations, and has been associated with
FGR, pregnancy loss, preterm delivery, and postnatal death.
There is an even higher rate of recurrence of massive inter-
villous fibrin deposition and poor fetal growth (67%).79 Pla-
cental mesenchymal dysplasia is a rare finding with an un-
likely risk of recurrence.
Prevention of Recurrent FGR
The importance of a thorough evaluation for potential etiol-
ogies in evaluating a woman’s risk of adverse obstetrical out-
comes as the result of a prior FGR birth cannot be overem-
phasized. A comprehensive assessment will lead to
appropriate counseling and, in many cases, will allow the
implementation of targeted risk-specific strategies to reduce
recurrence (Fig. 1).
If there is an opportunity for preconceptional care, it
should focus on the elimination of known maternal expo-
sures (cocaine, smoking, alcohol), folic acid supplementation
to reduce the risk of congenital malformations, and the opti-
mization of maternal medical conditions. Low prepregnancy
body mass index (BMI) is a risk factor for FGR. If a woman
continues to have a suboptimal BMI in the next pregnancy,
this risk persists. However, an increase in maternal BMI be-
tween pregnancies has been associated with a decreased SGA
risk.80 Although prospective trials of weight gain are lacking,
130 W.L. Kinzler and L. Kaminsky

Table 2 Recurrence Risks of Etiologies and FGR Based on Etiology of the Poor Fetal Growth in the Previous
Pregnancy1,3,10-13,16-18,20,21,24,25,27,28,45,48,52-55
Risk of Recurrence of Etiologic Risk of SGA with
Previous Pregnancy Condition Factor in Subsequent Pregnancy Recurrent Risk Factor
Fetal
Autosomal trisomy 1% or maternal age-related risk Abnormality-specific risk
Sex chromosome abnormality <1% Abnormality-specific risk
Triploidy <1% 100%
Unbalanced translocation, de novo <1% Abnormality-specific risk
Unbalanced translocation, inherited Variable Abnormality-specific risk
Autosomal recessive conditions 25% Abnormality-specific risk
Structural malformations, isolated Variable, 3-5% for multifactorial inheritance Abnormality-specific risk
Congenital infection <1% Infection-specific risk
Multifetal gestation Variable, 3% of live births Up to 25%
Maternal
Malnutrition Situation dependent Minimal risk if treated
Maternal conditions leading to hypoxemia Variable depending on condition Largely unknown, but likely
higher than background risk
Substance abuse Situation dependent Substance-specific risk
Maternal vascular disease (chronic Generally persistent Largely unknown, but consider
hypertension, renal disease, diabetes very high risk (at least 50%)
mellitus, collagen vascular disease)
Inherited or acquired thrombophilia Generally persistent Up to 30-83% if untreated
Placental abruption 22% At least 18%, even without
recurrent abruption
Placental
Single umbilical artery 0.4% Up to 7%
Velamentous cord insertion 1-2% 15-20%
Circumvallate placentation 6% Largely unknown
Placental infarction 24% 61% untreated
Villitis 17% 53%
Massive perivillous fibrin deposition 67% 50-100%

patients should be counseled about this potentially modifi-
able risk factor. Other nutritional supplements, such as fish
oil, are unproven.81 In cases of underlying medical condi-
tions (diabetes, systemic lupus, hypertension, asthma), the
woman’s health should be optimized before subsequent
pregnancies and actively managed during the pregnancy in a
multidisciplinary fashion.
If assisted reproduction is required, there should be cau-
tious use of ovulation induction agents and attention paid to
the number of embryos transferred as it relates not only to the
chance of successful implantation, but also to the risks of
multifetal gestations.
Any pregnancy at risk for a fetal growth abnormality
should be screened in the first trimester to establish early and
accurate gestational dating. Subsequent assessments of fetal
growth trends will depend heavily on accurate dating. When
possible, a crown–rump length in the first trimester is best. If
a second trimester ultrasound alone is available due to a delay
in presenting for prenatal care, the transcerebellar diameter
should be measured, as it provides the most accurate dating
in the 2nd and even 3rd trimesters.82 For women at the
highest risk for FGR, serial fetal growth ultrasounds should
be considered at approximately 4- to 6-week intervals to
assess fetal growth trends.
In those couples at risk for having an aneuploid conceptus,
several options for screening and prenatal diagnosis are avail-
able. In couples at high risk of recurrent autosomal trisomies
or in those in which a balanced translocation has been iden-
tified, in vitro fertilization with preimplantation genetic di-
agnosis can be offered. Others may opt for assisted reproduc-
tion with the use of a gamete donor. Once a pregnancy is
achieved, early prenatal diagnosis with either chorionic vil-
lous sampling or amniocentesis is available. For women un-
decided about invasive testing, prenatal screening should be
offered. First trimester combined nuchal translucency and
biochemical screening is an excellent start, with a subsequent
detailed sonographic fetal anatomy survey. For some non-
aneuploid genetic syndromes, genetic testing is available. It is
important to involve a provider specialized in genetics to
assist in coordinating this testing and also to aid in targeting
the fetal ultrasound.
Detailed sonography should also assess umbilical cord ab-
normalities, such as single umbilical artery. Placental cord
insertion should be visualized to rule out a velamentous cord
insertion. The placental cord insertion can be identified in
99% of cases with gray scale and color Doppler ultrasound,83
with identification of a velamentous insertion having a sen-
sitivity of 100%, specificity of 99.8%, a positive predictive
value of 83%, and a negative predictive value of 100%.84
Other placental anomalies, such as placenta previa and cir-
Fetal growth restriction 131

Fetal Growth 1st trimester CRL

Restriction Serial growth ultrasounds

Identify probable
etiology

Maternal Fetal Placental

Malnutrition Increase BMI

Nutrition consult Chromosomal
Abnormalities Umbilical Cord Ultrasound
Maternal Hypoxia- Optimize Abnormalities evaluation
related conditions underlying disease Non-chromosomal
Abnormalities Immune-mediated IVIG
Substance Abuse Counseling/Detox Injury (fibrin
deposition, chronic
Smoking cessation villitis)

Maternal Vascular Optimize Genetic counseling Low-dose

Disease underlying disease Prenatal diagnosis (CVS, Placental infarction ASA ±
amniocentesis) heparin
Prenatal screening
Thrombophilias Heparin Targeted ultrasound

Placental Low-dose ASA

Abruption
Uterine artery Dopplers
Preeclampsia

Figure 1 Management of subsequent pregnancy based on presumed etiology of FGR.

cumvallate placentation, should be noted. The sonographic
diagnosis of placental abruption relies on the identification of
a thickened placenta, a hematoma (retroplacental, subchori-
onic, or preplacental),85 or the presence of intraamniotic
blood.
Uterine artery Doppler velocimetry has been utilized as a
screening tool for pregnancies at high risk of complications
from ischemic placental disease. At 20 weeks’ gestation, bi-
lateral diastolic notching and mean resistance index of
⬎90th%ile had a positive predictive value of 57% for severe
preeclampsia ⫾ FGR and a 93% positive predictive value for
mild or severe disease.86 Even in women with previous ad-
verse pregnancy outcomes on low-dose aspirin therapy, the
presence of a diastolic notch at 23 weeks gestation was asso-
ciated with a higher rate of vascular complications such as
preeclampsia and FGR (31% versus 5%).87
There may be a modest benefit of low-dose aspirin use in
pregnancies at high risk for poor fetal growth from specific
maternal or placental conditions. Although a benefit has not
been demonstrated by all studies,88 many have demonstrated
a significant reduction in the risk of FGR among high-risk
women treated with low-dose aspirin.89,90 A meta-analysis of
low-dose aspirin use suggested an 18% reduction in FGR, but
a much greater effect (OR 0.35) when therapy was instituted
before 17 weeks gestation. Given the excellent safety profile
of low-dose aspirin use in pregnancy, it seems reasonable to
offer this to women at significant risk of recurrent FGR, start-
ing as early in the pregnancy as possible. It has been found to
be especially beneficial in those with a history of recurrent
FGR and placental infarction, reducing the incidence of FGR
from 61% in the untreated to 13% in the treated pregnan-
cies.78
In the setting of antiphospholipid antibody syndrome (ei-
ther primary or secondary), women should receive low-dose
aspirin and prophylactic heparin during pregnancy. Several
randomized control trials have investigated this issue and
have demonstrated improved outcomes compared with pla-
cebo or with aspirin alone.91-94 The optimal management of
pregnancies complicated by recurrent chronic villitis or mas-
sive fibrin deposition has not been definitively determined.
Although low-dose aspirin and/or heparin have been utilized
with some benefit,79 these lesions are not the result of a co-
agulation abnormality and may be best treated with intrave-
nous immunoglobulin95 due to the suspected immune etiol-
ogy.
In high-risk women with inherited thrombophilias and
adverse pregnancy events, heparin has been used to improve
obstetrical outcomes. Heparin prophylaxis (compared with
aspirin) has been shown to improve live birth rates (86%
versus 29%) and reduce the incidence of FGR (10% versus
132
30%) in women heterozygous for either FVL or prothrombin
G20210A mutation or with protein S deficiency.96 Other tri-
als examining the use of heparin and/or low-dose aspirin for
prevention of recurrent adverse pregnancy outcomes in
women with genetic thrombophilias had relatively small
numbers of subjects, were observational, included heteroge-
neous groups of patients, had various dosages of heparin, and
often used historical controls.63,69,97-99 Nevertheless, these
studies suggest that there may be some benefit to using hep-
arin in selected circumstances.
Targeted Areas for Future Research
Despite the vast amount of research that has been done on
FGR, there are many knowledge gaps that persist, particu-
larly in the areas of defining etiology-specific risks and inter-
ventions for preventing recurrence. The heterogeneity of the
condition has hindered our ability to determine optimal
treatments for individual cases. In addition, our understand-
ing of the complex biologic– environmental interactions and
genetic susceptibilities that exist is limited. Future research
should attempt to use risk-specific inclusion criteria and
should take into consideration the array of adverse outcomes
that can result from similar underlying conditions (ie, isch-
emic placental disease).
Conclusions
In summary, poor fetal growth can result from a myriad of
fetal, placental, and maternal conditions. Since many of these
factors can persist throughout subsequent pregnancies,
women should be counseled and managed appropriately to
minimize future adverse outcomes. It is also important to
recognize that risk factors for FGR overlap the risk factors for
many other obstetrical concerns, such as recurrent miscar-
riage, preeclampsia, abruption, and fetal death. Therefore,
future pregnancies should be given close attention to the
development of these possible events.
References
1. Snijders RJ, Sherrod C, Gosden CM, et al: Fetal growth retardation:
associated malformations and chromosomal abnormalities. Am J Ob-
stet Gynecol 168:547-555, 1993
2. Creasy RLR: Maternal–Fetal Medicine. Philadelphia, PA, Saunders,
2005
3. Khoury MJ, Erickson JD, Cordero JF, et al: Congenital malformations
and intrauterine growth retardation: a population study. Pediatrics 82:
83-90, 1988
4. Hannula K, Lipsanen-Nyman M, Kristo P, et al: Genetic screening for
maternal uniparental disomy of chromosome 7 in prenatal and postna-
tal growth retardation of unknown cause. Pediatrics 109:441-448,
2002
5. Kotzot D, Lurie IW, Mehes K, et al: No evidence of uniparental disomy
2, 6, 14, 16, 20, and 22 as a major cause of intrauterine growth retar-
dation. Clin Genet 58:177-180, 2000
6. Brown ZA, Vontver LA, Benedetti J, et al: Effects on infants of a first
episode of genital herpes during pregnancy. N Engl J Med 317:1246-
1251, 1987
7. Meyberg-Solomayer GC, Fehm T, Muller-Hansen I, et al: Prenatal ul-
trasound diagnosis, follow-up, and outcome of congenital varicella syn-
drome. Fetal Diagn Ther 21:296-301, 2006
8. Donner C, Liesnard C, Content J, et al: Prenatal diagnosis of 52 preg-
W.L. Kinzler and L. Kaminsky
nancies at risk for congenital cytomegalovirus infection. Obstet
Gynecol 82:481-486, 1993
9. Daffos F, Forestier F, Capella-Pavlovsky M, et al: Prenatal management
of 746 pregnancies at risk for congenital toxoplasmosis. N Engl J Med
318:271-275, 1988
10. Khan NA, Kazzi SN: Yield and costs of screening growth-retarded in-
fants for torch infections. Am J Perinatol 17:131-135, 2000
11. Arbuckle TE, Wilkins R, Sherman GJ: Birth weight percentiles by ges-
tational age in Canada. Obstet Gynecol 81:39-48, 1993
12. Houlton MC, Marivate M, Philpott RH: The prediction of fetal growth
retardation in twin pregnancy. Br J Obstet Gynaecol 88:264-273, 1981
13. Secher NJ, Kaern J, Hansen PK: Intrauterine growth in twin pregnan-
cies: prediction of fetal growth retardation. Obstet Gynecol 66:63-68,
1985
14. Sherer DM, Divon MY: Fetal growth in multifetal gestation. Clin Obstet
Gynecol 40:764-770, 1997
15. Bjoro K Jr: Vascular anomalies of the umbilical cord. I. Obstetric im-
plications. Early Hum Dev 8:119-127, 1983
16. Predanic M, Perni SC, Friedman A, et al: Fetal growth assessment and
neonatal birth weight in fetuses with an isolated single umbilical artery.
Obstet Gynecol 105:1093-1097, 2005
17. Heinonen S, Ryynanen M, Kirkinen P, et al: Perinatal diagnostic eval-
uation of velamentous umbilical cord insertion: clinical, Doppler, and
ultrasonic findings. Obstet Gynecol 87:112-117, 1996
18. Rolschau J: Circumvallate placenta and intrauterine growth retarda-
tion. Acta Obstet Gynecol Scand Suppl 72:11-14, 1978
19. Nagy S, Bush M, Stone J, et al: Clinical significance of subchorionic and
retroplacental hematomas detected in the first trimester of pregnancy.
Obstet Gynecol 102:94-100, 2003
20. Ananth CV, Berkowitz GS, Savitz DA, et al: Placental abruption and
adverse perinatal outcomes. J Am Med Assoc 282:1646-1651, 1999
21. Sheiner E, Shoham-Vardi I, Hallak M, et al: Placental abruption in term
pregnancies: clinical significance and obstetric risk factors. J Matern
Fetal Neonatal Med 13:45-49, 2003
22. Ananth CV, Demissie K, Smulian JC, et al: Relationship among placenta
previa, fetal growth restriction, and preterm delivery: a population-
based study. Obstet Gynecol 98:299-306, 2001
23. Laurini R, Laurin J, Marsal K: Placental histology and fetal blood flow in
intrauterine growth retardation. Acta Obstet Gynecol Scand 73:529-
534, 1994
24. Salafia CM, Vintzileos AM, Silberman L, et al: Placental pathology of
idiopathic intrauterine growth retardation at term. Am J Perinatol
9:179-184, 1992
25. Bane AL, Gillan JE: Massive perivillous fibrinoid causing recurrent
placental failure. Br J Obstet Gynaecol 110:292-295, 2003
26. Mandsager NT, Bendon R, Mostello D, et al: Maternal floor infarction of
the placenta: prenatal diagnosis and clinical significance. Obstet Gy-
necol 83:750-754, 1994
27. Bjoro K Jr, Myhre E: The role of chronic non-specific inflammatory
lesions of the placenta in intra-uterine growth retardation. Acta Pathol
Microbiol Immunol Scand [A] 92:133-137, 1984
28. Pham T, Steele J, Stayboldt C, et al: Placental mesenchymal dysplasia is
associated with high rates of intrauterine growth restriction and fetal
demise: a report of 11 new cases and a review of the literature. Am J Clin
Pathol 126:67-78, 2006
29. Svensson AC, Pawitan Y, Cnattingius S, et al: Familial aggregation of
small-for-gestational-age births: the importance of fetal genetic effects.
Am J Obstet Gynecol 194:475-479, 2006
30. Stein AD, Ravelli AC, Lumey LH: Famine, third-trimester pregnancy
weight gain, and intrauterine growth: the Dutch Famine Birth Cohort
Study. Hum Biol 67:135-150, 1995
31. Kouba S, Hallstrom T, Lindholm C, et al: Pregnancy and neonatal
outcomes in women with eating disorders. Obstet Gynecol 105:255-
260, 2005
32. Murphy JF, O’Riordan J, Newcombe RG, et al: Relation of haemoglobin
levels in first and second trimesters to outcome of pregnancy. Lancet
1:992-995, 1986
33. Steer P, Alam MA, Wadsworth J, et al: Relation between maternal
Fetal growth restriction
haemoglobin concentration and birth weight in different ethnic groups.
Br Med J 310:489-491, 1995
34. Lu ZM, Goldenberg RL, Cliver SP, et al: The relationship between
maternal hematocrit and pregnancy outcome. Obstet Gynecol 77:190-
194, 1991
35. Sheiner E, Mazor M, Levy A, et al: Pregnancy outcome of asthmatic
patients: a population-based study. J Matern Fetal Neonatal Med 18:
237-240, 2005
36. Jensen GM, Moore LG: The effect of high altitude and other risk factors
on birthweight: independent or interactive effects? Am J Public Health
87:1003-1007, 1997
37. Galan HL, Rigano S, Radaelli T, et al: Reduction of subcutaneous mass,
but not lean mass, in normal fetuses in Denver, Colorado. Am J Obstet
Gynecol 185:839-844, 2001
38. Hammoud AO, Bujold E, Sorokin Y, et al: Smoking in pregnancy re-
visited: findings from a large population-based study. Am J Obstet
Gynecol 192:1856-1862, discussion 1862-1863, 2005
39. Spinillo A, Capuzzo E, Nicola SE, et al: Factors potentiating the smok-
ing-related risk of fetal growth retardation. Br J Obstet Gynaecol 101:
954-958, 1994
40. U.S. Department of Health and Human Services. Women and Smoking:
A Report of the Surgeon General. Public Health Service, Office of the
Surgeon General, 2001
41. Bada HS, Das A, Bauer CR, et al: Low birth weight and preterm births:
etiologic fraction attributable to prenatal drug exposure. J Perinatol
25:631-637, 2005
42. Floyd RL, O’Connor MJ, Sokol RJ, et al: Recognition and prevention of
fetal alcohol syndrome. Obstet Gynecol 106:1059-1064, 2005
43. Bada HS, Das A, Bauer CR, et al: Gestational cocaine exposure and
intrauterine growth: maternal lifestyle study. Obstet Gynecol 100:916-
924, 2002
44. Ness RB, Sibai BM: Shared and disparate components of the pathophys-
iologies of fetal growth restriction and preeclampsia. Am J Obstet Gy-
necol 195:40-49, 2006
45. Bernstein PS, Divon MY: Etiologies of fetal growth restriction. Clin
Obstet Gynecol 40:723-729, 1997
46. Villar J, Carroli G, Wojdyla D, et al: Preeclampsia, gestational hyper-
tension and intrauterine growth restriction, related or independent
conditions? Am J Obstet Gynecol 194:921-931, 2006
47. Abalos E, Duley L, Steyn DW, et al: Antihypertensive drug therapy for
mild to moderate hypertension during pregnancy. Cochrane Database
of Systematic Reviews 2001:CD002252
48. Stettler RW, Cunningham FG: Natural history of chronic proteinuria
complicating pregnancy. Am J Obstet Gynecol 167:1219-1224, 1992
49. Yasmeen S, Wilkins EE, Field NT, et al: Pregnancy outcomes in women
with systemic lupus erythematosus. J Matern Fetal Med 10:91-96,
2001
50. Rahman P, Gladman DD, Urowitz MB: Clinical predictors of fetal out-
come in systemic lupus erythematosus. J Rheumatol 25:1526-1530,
1998
51. Julkunen H, Jouhikainen T, Kaaja R, et al: Fetal outcome in lupus
pregnancy: a retrospective case-control study of 242 pregnancies in
112 patients. Lupus 2:125-131, 1993
52. Kupferminc MJ, Rimon E, Ascher-Landsberg J, et al: Perinatal outcome
in women with severe pregnancy complications and multiple throm-
bophilias. J Perinat Med 32:225-227, 2004
53. Kupferminc MJ, Many A, Bar-Am A, et al: Mid-trimester severe intra-
uterine growth restriction is associated with a high prevalence of
thrombophilia. Br J Obstet Gynaecol 109:1373-1376, 2002
54. Martinelli P, Grandone E, Colaizzo D, et al: Familial thrombophilia and
the occurrence of fetal growth restriction. Haematologica 86:428-431,
2001
55. Howley HE, Walker M, Rodger MA: A systematic review of the associ-
ation between factor V Leiden or prothrombin gene variant and intra-
uterine growth restriction. Am J Obstet Gynecol 192:694-708, 2005
56. Infante-Rivard C, Rivard GE, Yotov WV, et al: Absence of association of
thrombophilia polymorphisms with intrauterine growth restriction.
N Engl J Med 347:19-25, 2002
57. Salomon O, Seligsohn U, Steinberg DM, et al: The common prothrom-
133
botic factors in nulliparous women do not compromise blood flow in
the feto-maternal circulation and are not associated with preeclampsia
or intrauterine growth restriction. Am J Obstet Gynecol 191:
2002-2009, 2004
58. Franchi F, Cetin I, Todros T, et al: Intrauterine growth restriction and
genetic predisposition to thrombophilia. Haematologica 89:444-449,
2004
59. Infante-Rivard C, Rivard GE, Guiguet M, et al: Thrombophilic poly-
morphisms and intrauterine growth restriction. Epidemiology 16:281-
287, 2005
60. Yasuda M, Takakuwa K, Tokunaga A, et al: Prospective studies of the
association between anticardiolipin antibody and outcome of preg-
nancy. Obstet Gynecol 86:555-559, 1995
61. Levine JS, Branch DW, Rauch J: The antiphospholipid syndrome.
N Engl J Med 346:752-763, 2002
62. Alarcon-Segovia D: Clinical manifestations of the antiphospholipid
syndrome. J Rheumatol 19:1778-1781, 1992
63. Paidas MJ, Ku DH, Arkel YS: Screening and management of inherited
thrombophilias in the setting of adverse pregnancy outcome. Clin Peri-
natol 31:783-805, 2004
64. Alfirevic Z, Roberts D, Martlew V: How strong is the association be-
tween maternal thrombophilia and adverse pregnancy outcome? A sys-
tematic review. Eur J Obstet Gynecol Reprod Biol 101:6-14, 2002
65. Robertson L, Wu O, Langhorne P, et al: Thrombophilia in pregnancy: a
systematic review. Br J Haematol 132:171-196, 2006
66. Kupferminc MJ, Eldor A, Steinman N, et al: Increased frequency of
genetic thrombophilia in women with complications of pregnancy.
N Engl J Med 340:9-13, 1999
67. Lim W, Crowther MA, Eikelboom JW: Management of antiphospho-
lipid antibody syndrome: a systematic review. J Am Med Assoc 295:
1050-1057, 2006
68. ACOG Practice Bulletin #68: Antiphospholipid syndrome. Obstet Gy-
necol 106:1113-1121, 2005
69. Stella CL, Sibai BM: Thrombophilia and adverse maternal-perinatal
outcome. Clin Obstet Gynecol 49:850-860, 2006
70. Roque H, Paidas MJ, Funai EF, et al: Maternal thrombophilias are not
associated with early pregnancy loss. Thromb Haemost 91:290-295,
2004
71. Rasmussen S, Irgens LM, Albrechtsen S, et al: Predicting preeclampsia
in the second pregnancy from low birth weight in the first pregnancy.
Obstet Gynecol 96:696-700, 2000
72. Salihu HM, Sharma PP, Aliyu MH, et al: Is small for gestational age a
marker of future fetal survival in utero? Obstet Gynecol 107:851-856,
2006
73. Kuno N, Itakura A, Kurauchi O, et al: Decrease in severity of intrauter-
ine growth retardation in subsequent pregnancies. Int J Gynaecol Ob-
stet 51:219-224, 1995
74. Furuhashi M, Kurauchi O, Suganuma N: Pregnancy following placental
abruption. Arch Gynecol Obstet 267:11-13, 2002
75. Rasmussen S, Albrechtsen S, Dalaker K: Obstetric history and the risk
of placenta previa. Acta Obstet Gynecol Scand 79:502-507, 2000
76. Rasmussen S, Irgens LM, Dalaker K: A history of placental dysfunction
and risk of placental abruption. Paediatr Perinat Epidemiol 13:9-21,
1999
77. Rasmussen S, Irgens LM, Albrechtsen S, et al: Women with a history of
placental abruption: when in a subsequent pregnancy should special
surveillance for a recurrent placental abruption be initiated? Acta Ob-
stet Gynecol Scand 80:708-712, 2001
78. Wallenburg HC, Rotmans N: Prevention of recurrent idiopathic fetal
growth retardation by low-dose aspirin and dipyridamole. Am J Obstet
Gynecol 157:1230-1235, 1987
79. Fuke Y, Aono T, Imai S, et al: Clinical significance and treatment of
massive intervillous fibrin deposition associated with recurrent fetal
growth retardation. Gynecol Obstet Invest 38:5-9, 1994
80. Cheng CJ, Bommarito K, Noguchi A, et al: Body mass index change
between pregnancies and small for gestational age births. Obstet Gy-
necol 104:286-292, 2004
81. Olsen SF, Secher NJ, Tabor A, et al: Randomised clinical trials of fish oil
134
supplementation in high risk pregnancies. Fish Oil Trials In Pregnancy
(FOTIP) Team. Br J Obstet Gynaecol 107:382-395, 2000
82. Chavez MR, Ananth CV, Smulian JC, et al: Fetal transcerebellar diam-
eter measurement with particular emphasis in the third trimester: a
reliable predictor of gestational age. Am J Obstet Gynecol 191:979-984,
2004
83. Sepulveda W, Rojas I, Robert JA, et al: Prenatal detection of velamen-
tous insertion of the umbilical cord: a prospective color Doppler ultra-
sound study. Ultrasound Obstet Gynecol 21:564-569, 2003
84. Nomiyama M, Toyota Y, Kawano H: Antenatal diagnosis of velamen-
tous umbilical cord insertion and vasa previa with color Doppler im-
aging. Ultrasound Obstet Gynecol 12:426-429, 1998
85. Nyberg DA, Cyr DR, Mack LA, et al: Sonographic spectrum of placental
abruption. AJR Am J Roentgenol 148:161-164, 1987
86. Chan FY, Pun TC, Lam C, et al: Pregnancy screening by uterine artery
Doppler velocimetry: which criterion performs best? Obstet Gynecol
85:596-602, 1995
87. Haddad B, Uzan M, Breart G, et al: Uterine Doppler wave form and the
prediction of the recurrence of pre-eclampsia and intra-uterine growth
retardation in patients treated with low-dose aspirin. Eur J Obstet Gy-
necol Reprod Biol 62:179-183, 1995
88. Low-dose aspirin in prevention and treatment of intrauterine growth
retardation and pregnancy-induced hypertension. Italian study of as-
pirin in pregnancy. Lancet 341:396-400, 1993
89. Ebrashy A, Ibrahim M, Marzook A, et al: Usefulness of aspirin therapy
in high-risk pregnant women with abnormal uterine artery Doppler
ultrasound at 14-16 weeks pregnancy: randomized controlled clinical
trial. Croat Med J 46:826-831, 2005
90. Uzan S, Beaufils M, Breart G, et al: Prevention of fetal growth retarda-
W.L. Kinzler and L. Kaminsky
tion with low-dose aspirin: findings of the EPREDA trial. Lancet
337:1427-1431, 1991
91. Kutteh WH: Antiphospholipid antibody-associated recurrent preg-
nancy loss: treatment with heparin and low-dose aspirin is superior to
low-dose aspirin alone. Am J Obstet Gynecol 174:1584-1589, 1996
92. Rai R, Cohen H, Dave M, et al: Randomised controlled trial of aspirin
and aspirin plus heparin in pregnant women with recurrent miscarriage
associated with phospholipid antibodies (or antiphospholipid antibod-
ies). Br Med J 314:253-257, 1997
93. Farquharson RG, Quenby S, Greaves M: Antiphospholipid syndrome
in pregnancy: a randomized, controlled trial of treatment. Obstet Gy-
necol 100:408-413, 2002
94. Empson M, Lassere M, Craig JC, et al: Recurrent pregnancy loss with
antiphospholipid antibody: a systematic review of therapeutic trials.
Obstet Gynecol 99:135-144, 2002
95. Chang P, Millar D, Tsang P, et al: Intravenous immunoglobulin in
antiphospholipid syndrome and maternal floor infarction when stan-
dard treatment fails: a case report. Am J Perinatol 23:125-129, 2006
96. Gris JC, Mercier E, Quere I, et al: Low-molecular-weight heparin versus
low-dose aspirin in women with one fetal loss and a constitutional
thrombophilic disorder. Blood 103:3695-3699, 2004
97. Kupferminc MJ, Fait G, Many A, et al: Low-molecular-weight heparin
for the prevention of obstetric complications in women with thrombo-
philias. Hypertens Pregnancy 20:35-44, 2001
98. Brenner B, Hoffman R, Blumenfeld Z, et al: Gestational outcome in
thrombophilic women with recurrent pregnancy loss treated by enox-
aparin. Thromb Haemost 83:693-697, 2000
99. Grandone E, Brancaccio V, Colaizzo D, et al: Preventing adverse ob-
stetric outcomes in women with genetic thrombophilia. Fertil Steril
78:371-375, 2002
Preeclampsia Recurrence and Prevention
Gary A. Dildy III, MD,* Michael A. Belfort, MD, PhD,† and John C. Smulian, MD, MPH‡

Women with a previous pregnancy complicated by preeclampsia have an increased risk for
recurrence in subsequent pregnancies. For severe preeclamptic women in an initial preg-
nancy, recurrence rates for any type of preeclampsia are very high, approaching 50% in
some studies. Significant maternal and fetal complications are more common in recurrent
preeclampsia compared with an initial episode. For women who have experienced a
pregnancy complicated by preeclampsia, a systematic evaluation for underlying risk factors
may identify a specific pathway suitable for a specific intervention. Although some progress
has been made in developing potential therapeutic options to prevent preeclampsia recur-
rence, there is a great need for better data to determine who will benefit most from any
specific therapy.
Semin Perinatol 31:135-141 © 2007 Elsevier Inc. All rights reserved.

KEYWORDS preeclampsia, eclampsia, risk factors, recurrence, prevention, HELLP syndrome

P reeclampsia complicates approximately 5% to 10% of

nulliparous pregnancies1 and is consistently among the
top three causes of maternal death in both developed and
developing countries.2-4 Two-thirds of cases will be mild and
the other third severe in degree.1 Preeclampsia is considered
a disease of nulliparous women, as it is twice as common in
primigravidas as it is in women who have previously given
birth.5 It is well known that women with a previous preg-
nancy complicated by preeclampsia have an increased risk
for recurrence in subsequent pregnancies. For severe pre-
eclamptic women in an initial pregnancy, recurrence rates for
any type of preeclampsia are very high, approaching 50% in
some studies. Significant maternal and fetal complications
are more common in recurrent preeclampsia compared with
an initial episode. Thus, accurate and thorough counseling
regarding recurrence risks and potential preventive measures
will assist women and their caregivers to make important
decisions pertaining to future childbearing.
*Department of Obstetrics and Gynecology, LSU Health Sciences Center,
New Orleans, LA.
†Department of Obstetrics and Gynecology, University of Utah Health Sci-
ences Center, Salt Lake City, UT.
‡Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology
and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical
School, New Brunswick, NJ.
Address reprint requests to Gary A. Dildy III, MD, Maternal Fetal Medicine
Center, St. Mark’s Hospital, 1140 East 3900 South, Suite 390, Salt Lake
City, Utah 84124. E-mail: Gary.Dildy@HCAhealthcare.com
Preeclampsia Risk Factors
Many factors for preeclampsia have been described in the
obstetrical literature, and the majority will persist in subse-
quent pregnancies (Table 1).6 Preeclampsia tends to be a
disease of first pregnancy in women with no other obvious
risk factors; however, underlying medical conditions with
vascular or renal implications (diabetes mellitus, chronic hy-
pertension) and conditions with increased trophoblast mass
(multifetal gestation or hydrops fetalis) substantially increase
the risk. As preeclampsia is likely a syndrome of multiple
etiologies and many underlying factors persist across preg-
nancies, a significant risk factor for future preeclampsia is a
prior history of preeclampsia.
The Epidemiology of
Preeclampsia Recurrence
A number of studies have examined the risk for preeclampsia
recurrence in subsequent pregnancies, and all have indicated
a significantly increased risk (Table 2). The highest risks for
recurrence are found most consistently when the initial case
was preterm, severe, or complicated by eclampsia, HELLP
(hemolysis, elevated liver enzymes, and low platelet count)
syndrome, or fetal growth restriction. However, good data
are still relatively sparse because definitions for preeclampsia
often vary from study to study.
Campbell and coworkers studied a population of pregnant
women (n ⫽ 29,851) whose first recorded pregnancy oc-
curred between the years 1967 and 1978 in Aberdeen, Scot-
land and had ⬎2 subsequent pregnancies during that same

0146-0005/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. 135
doi:10.1053/j.semperi.2007.03.005
136 G.A. Dildy III, M.A. Belfort, and J.C. Smulian

Table 1 The Strength of the Association of Selected Risk Factors for Preeclampsia*
Risk Factor Associated with Preeclampisa Reference OR (95% CI)
Preeclampsia in a previous pregnancy Hnat18 3.88 (2.98-5.05)
Duckitt48 7.19 (5.85-8.83)
First pregnancy Conde-Agudelo49 2.38 (2.28-2.49)
Duckitt48 2.91 (1.28-6.61)
Multifetal gestation Sibai50 2.62 (2.03-3.38)
Conde-Agudelo49 2.10 (1.90-2.32)
Duckitt48 2.93 (2.04-4.21)
Chronic hypertension Conde-Agudelo49 1.99 (1.78-2.22)
Gestational diabetes Conde-Agudelo49 1.93 (1.66-2.25)
Pregestational diabetes Duckitt48 3.56 (2.54-4.99)
Vascular and connective tissue disease Stamilio51 6.9 (1.1-42.3)
Nephropathy
Urinary tract infection Abi-Said52 4.23 (1.27-14.06)
Antiphospholipid antibody syndrome Robertson53 2.73 (1.65-4.51)
Duckitt48 9.72 (4.34-21.75)
Genetic factors (eg, thrombophilias) Robertson53
Factor V Leiden heterozygosity 2.19 (1.46-3.27)
Prothrombin heterozygosity 2.54 (1.52-4.23)
MTHFR homozygosity 1.37 (1.07-1.76)
Hyperhomocysteinemia 3.49 (1.21-10.11)
Obesity (BMI >35 kg/m2) Sibai1 3.38 (1.91-6.00)
Maternal age >35 years Conde-Agudelo49 1.67 (1.58-1.77)
Family history of preeclampsia Duckitt48 2.90 (1.70-4.93)
Fetal malformation Conde-Agudelo49 1.26 (1.16-1.37)
Abnormal maternal serum markers Dugoff54
(AFP, hCG, uE3, Inhibin A)
Inhibin A >2.0 MOM 2.39 (1.75-3.26)
2 abnormal markers 3.65 (2.79-4.78)
African-American race Tucker55 1.2 (0.8-1.7)
Abbreviations: AFP, alpha fetoprotein; HCG, human chorionic gonadotropin; uE3, unconjugated estriol.
*Presented as odds ratio (OR) and 95% confidence intervals (CI).

time period (n ⫽ 6637).7 Women were categorized as nor-
motensive (68.0%), mildly preeclamptic (26.3%), protein-
uric preeclamptic (5.6%), and eclamptic (0.2%). They found
that the overall incidence of preeclampsia in a second preg-
nancy was less than that in a first pregnancy, but was depen-
dent on the outcome of the first pregnancy. If the first preg-
nancy was complicated simply by proteinuric preeclampsia,
the incidence in the second pregnancy was 7.5%, whereas
those who were normotensive in the first pregnancy had a
low rate of proteinuric preeclampsia in the second pregnancy

Table 2 Summary of Studies that Present the Risk for Recurrence of Preeclampsia
Author Study Population Rate of Recurrence
Campbell7 Preeclampsia (n ⴝ 279) Preeclampsia 7.5%
Sibai9 Second trimester severe preeclampsia (n ⴝ 169) Any preeclampsia 65%
<28 weeks 21%
28-36 weeks 21%
37-40 weeks 24%
van Rijn8 Preeclampsia with delivery <34 weeks Preeclampsia 25%
Sullivan 12 HELLP (n ⴝ 161) Preeclampsia 43%
HELLP 27%
Sibai11 HELLP (n ⴝ 192) Preeclampsia 19%
HELLP 3%
Chames13 HELLP with delivery <28 weeks (n ⴝ 62) Preeclampsia 55%
HELLP 6%
Adelusi14 Eclampsia (n ⴝ 64) Eclampsia 16%
Sibai16 Eclampsia (n ⴝ 366) Preeclampsia 22%
Eclampsia 2%
Trogstad17 Preeclampsia singleton (n ⴝ 19,960) Preeclampsia 14.1%
Preeclampsia twins (n ⴝ 325) Preeclampsia 6.8%
Preeclampsia recurrence and prevention
of 0.7%. However, women who had proteinuric preeclamp-
sia in conjunction with a low-birth-weight (⬍2500 g) infant
in their first pregnancy had double the incidence of protein-
uric preeclampsia in their second pregnancy (11.9% versus
6.6%), compared with similar women with a normal infant
birth weight during first pregnancy.
Van Rijn and coworkers studied primiparous women who
delivered between 1993 and 2002 at the University Medical
Center Utrecht in The Netherlands who had a history of early
onset preeclampsia resulting in delivery before 34 weeks of
gestation.8 Preeclampsia recurred in 25% (30/120) of women
in their second pregnancy. Five percent delivered before 34
weeks of gestation and 17% between 34 and 37 weeks of
gestation.
Sibai and colleagues9 reported subsequent pregnancy out-
comes in women with severe second trimester preeclampsia.
Of these 125 women, 108 had 169 subsequent pregnancies.
For the subsequent pregnancies, approximately one-third
were normotensive and two-thirds were complicated by pre-
eclampsia. Of the women with preeclampsia, approximately
one-third developed a recurrence at ⬍28 weeks, one-third at
28 to 36 weeks, and one-third at 37 to 40 weeks.
Preeclampsia
Recurrence After HELLP Syndrome
Sibai and coworkers10 described a retrospective analysis of
112 women with HELLP syndrome from 1977 to 1985. In
this series, 38 women had 49 subsequent pregnancies.10 One
patient (2.6%) had recurrent HELLP syndrome in 2 subse-
quent pregnancies, both complicated by abruption and fetal
death. These investigators extended their series to the years
1977 to 1992, with follow up on 341 patients, of which 152
had subsequent pregnancies.11 Maternal complications in-
cluded preeclampsia (19%), recurrent HELLP syndrome
(3%), and placental abruption (2%). Perinatal complications
included preterm birth (21%), intrauterine growth restric-
tion (12%), and perinatal death (4%). Those with preexisting
chronic hypertension had higher rates of preeclampsia (75%)
but no significant increase in recurrent HELLP syndrome
(5%). Perinatal complications such as preterm birth (80%),
intrauterine growth restriction (45%), placental abruption
(20%), and perinatal death (40%) were significantly higher
among chronic hypertensives with previous HELLP syn-
drome. Interestingly, all of the above conditions, including
preeclampsia, preterm birth, fetal growth restriction, placen-
tal abruption, and perinatal death, are considered to have
overlapping etiologic mechanisms that relate to abnormal
placentation. Thus, a pregnancy with preeclampsia in an ini-
tial pregnancy appears to be at risk for these other pregnancy
complications and should be managed accordingly.
A retrospective study of 481 women with HELLP syn-
drome between the years 1980 and 1991 analyzed 161 of 195
subsequent pregnancies in 122 patients.12 Of these 161 preg-
nancies, 43% had preeclampsia and 27% had HELLP syn-
drome. A previous delivery ⬍32 weeks of gestation was a risk
factor for recurrence of prematurity at a similar gestational
age secondary to preeclampsia in 61% of cases.
137
Chames and coworkers reported the outcomes of subse-
quent pregnancies in women with a history of HELLP syn-
drome for which delivery occurred at ⬍28 weeks of gesta-
tion.13 Women were delivered in Memphis, TN (1984-1998)
and Lexington, KY (1994-1998). Data were available in 69
patients; there were 76 subsequent pregnancies among 48
women, of which 62 progressed beyond 20 weeks of gesta-
tion. Preeclampsia developed in 55% (34), of which 7 were
mild and 27 were severe. Recurrent HELLP occurred in 6%.
There were no cases of eclampsia; however, significant peri-
natal complications were frequent. Preterm birth (⬍37
weeks of gestation) occurred in 53%. Newborns were growth
restricted in 27%, and the overall perinatal mortality rate was
11%. Women with chronic hypertension had greater overall
morbidity.
Preeclampsia Recurrence After Eclampsia
Eclampsia recurrence is to some extent dependent on ade-
quacy of prenatal care and peripartum practices, including
methods to control hypertensive crisis and prevention of
eclamptic seizures vis-a-vis magnesium sulfate. Adelusi and
Ojengbede14 reported a prospective study of 64 eclamptics
from Ibadan, Nigeria of whom 16% experienced recurrent
eclampsia despite the benefit of antenatal care. Chesley’s
seminal account of eclampsia recurrence during the early
20th century reported a recurrence risk range of 0% to 21%
from published series, with an approximately 5% risk for
viable gestations.15
Sibai and coworkers studied 223 women whose pregnan-
cies were complicated by eclampsia between the years 1977
and 1989, with an average follow up of 7.2 years.16 Of the
366 subsequent pregnancies, 22% were complicated by pre-
eclampsia and 1.9% by eclampsia. Within the nulliparous
group, women who had eclampsia before 37 weeks of gesta-
tion in the index pregnancy had significantly higher inci-
dences of preeclampsia and poor perinatal outcome in sub-
sequent pregnancies, compared with those who had
eclampsia at or beyond 37 weeks of gestation. Of the normo-
tensive women, 10% had chronic hypertension on follow up.
The highest incidence of chronic hypertension was in those
with eclampsia at ⬍30 weeks of gestation (18%) and the
lowest incidence (5%) in those with eclampsia at ⬎37 weeks
of gestation.
Preeclampisa Recurrence
After Multiple Gestations
Although multiple gestations are considered at risk for pre-
eclampsia, it is not clear whether women developing this
complication are clearly at risk for recurrence in the same
degree as for singleton pregnancies. Only 1 study has ad-
dressed this issue. Trogstad and coworkers examined the
Norway birth registry from 1967 to 1998, including 550,218
women.17 For women with a previous singleton pregnancy
complicated by preeclampsia, the recurrence rate was 14.1%
compared with the recurrence rate for twins of 6.8%, which
was much closer to the population risk. This suggests that
different potential etiologies for preeclampsia present differ-
138
ent risks for recurrence. This is particularly important when
designing a recurrence prevention strategy, since no single
therapy would be expected to target all potential etiologies.
Clinical Features of
Recurrent Preeclampsia
Hnat and coworkers18 reported on 2934 nulliparous women
with an initial episode of preeclampsia and 598 women with
recurrent preeclampsia. Two of the more severe presenta-
tions of this disorder, eclampsia and HELLP syndrome, oc-
curred in the nulliparous cases with an incidence of 0.34%
and 0.21%, respectively. The same severe preeclampsia com-
plications examined in the women with recurrent preeclamp-
sia were approximately 5-fold higher: 1.67% for eclampsia
and 1.00% for HELLP syndrome. In addition, recurrent pre-
eclampsia was more commonly associated with other perina-
tal complications, such as preterm birth (67% versus 33%),
abruptio placentae (8% versus 2%), and fetal death (7% ver-
sus 1%). Therefore, recurrent preeclampsia is clearly associ-
ated with more severe disease and with more severe associ-
ated morbidities.
Preeclampsia Pathogenesis
Relevant to Recurrence
To understand the rationale and interpret some of the large
randomized controlled trials aimed at preventing preeclamp-
sia, it is important to understand proposed theories of the
pathophysiology of this disorder. Most of the etiologies in-
volve some form of physiologic change that promotes vascu-
lar endothelial damage, relative placental hypoxia, and oxi-
dative stress injury.
1. Abnormal angiogenesis and resultant placental ischemia
hypothesis: In this hypothesis poor second wave trophoblast
invasion of the spiral arteries leads to placental ischemia
which causes increased deportation of trophoblast into the
maternal circulation which results in endothelial cell dys-
function.19 Failed second wave invasion has been associated
with many factors, including abnormal circulating levels of
soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth
factor (PlGF), and vascular endothelial growth factor
(VEGF),20 maternal infection with CMV,21 prolactin abnor-
malities,22 and deficiencies of trace metals.23 Gene abnormal-
ities linked with trophoblast invasiveness have also been pro-
posed to influence preeclampsia risk.
2. Very low-density lipoprotein (VLDL) versus toxicity-
preventing activity (TxPA) hypothesis: Arbogast and cowork-
ers,24 proposed that preeclampsia may result from an un-
usual accumulation of VLDL which leads to endothelial
damage. This hypothesis was based on the observation that,
in many women who subsequently develop preeclampsia,
circulating free fatty acids (FFA) are increased 15 to 20 weeks
before the onset of disease. These FFA adversely affect endo-
thelial physiology leading to vasoconstriction. In some preg-
nant women (who are known to have low albumin concen-
trations), the burden of transporting extra FFA from adipose
G.A. Dildy III, M.A. Belfort, and J.C. Smulian
tissue to the liver as a response to the increased energy de-
mands of pregnancy may reduce the concentration of TxPA
to a point where the VLDLs cause endothelial injury.24,25
3. Hyperdynamic disease hypothesis: According to the hy-
perdynamic disease model,26 early in pregnancy, preeclamp-
tic patients have an elevated cardiac output with compensa-
tory vasodilatation. As the disease progresses, there is a
subsequent hemodynamic crossover to low cardiac output
and high resistance circulation coinciding with the onset of
the clinical syndrome. During the hyperdynamic phase, the
dilated systemic terminal arterioles and renal afferent arte-
rioles may expose capillary beds to systemic pressures and
increased flow, eventually leading to endothelial cell injury
characteristic of preeclampsia injury.27
4. Immune/immunogenetic maladaptation hypothesis: The
interaction between decidual leukocytes and invading cy-
totrophoblast cells is essential for normal trophoblast inva-
sion and development. Immune maladaptation may cause
the shallow invasion of the spiral arteries by the endovascular
cytotrophoblast cells, resulting in endothelial cell dysfunc-
tion mediated by an increased decidual release of cytokines,
proteolytic enzymes, and free radical species.28
5. The genetic hypothesis: It has been hypothesized that
the development of preeclampsia– eclampsia may be based
on a single recessive gene or a dominant gene with incom-
plete penetrance, dependent on the fetal genotype. However,
no specific genes have been identified and no defined inher-
itance pathway has been determined sufficient to clearly
identify a specific gene pathway. There are data to support
increased risk of preeclampsia in women who themselves
were born of a preeclamptic pregnancy.29 Women born of a
normal pregnancy, but whose mother had preeclampsia with
one her other pregnancies, also have an increased risk.30 Esp-
lin and coworkers29 showed that not only do maternal genet-
ics play a role, but men born of a preeclamptic pregnancy are
more likely to father children from a preeclamptic pregnancy
than those born of normal pregnancy. Skjaerven and col-
leagues suggest that the genes that determine maternal sus-
ceptibility to preeclampsia are different from the paternal
genes that trigger preeclampsia through the fetus.30
6. Genetic-conflict hypothesis: In both flowering plants
and mammalian pregnancies, there is genetic conflict due to
competing interests of maternal and paternal genes regarding
the volume of nutrients transferred from mother to fetus.31
The more resources a fetus is able to take from its mother, the
larger it will be at birth and the better its chances for survival
and reproduction. However, the greater the nutritional de-
mands of the pregnancy, the greater the cost to the mother’s
future reproductive potential. Paternal genes in the fetus and
placenta may seek to maximize the transfer of nutrients from
mother to baby (because the mother’s future offspring may
have a different father); maternal genes on the other hand
tend to moderate the flow of resources in an effort to preserve
her reproductive potential for future pregnancies. This inher-
ent competition may contribute to genetic imprinting; that is,
genes that behave differently in an organism depending on
whether they were inherited from the mother or from the
father. In mice, the paternal genes control the growth of the
Preeclampsia recurrence and prevention 139

Table 3 Proposed Evaluation Options for Women with a His- Recommended

tory Suggesting a High Rate of Preeclampsia Recurrence in
Order to Target Interventions
History & physical examination
Chronic diseases
Family history
Other historical risk factors for recurrence
Review of placental pathology from previous affected
pregnancy (eg, thrombi or infarcts, especially with fetal
growth restriction, may benefit from low dose heparin)
Thrombophilia evaluation (inherited and acquired)
Antinuclear antibody if clinically suspicious for
autoimmune disease
Early glucola if clinically appropriate
Baseline labs for later comparison
Complete blood count, platelets, serum creatinine, BUN,
uric acid, liver enzymes, urinalysis, 24-hour urine for
total protein content
Uterine artery Doppler screening to determine the intensity
of ultrasound surveillance needed later in the
pregnancy
Serial ultrasounds for evaluation of fetal growth
Antepartum fetal surveillance if indications present
placenta, whereas maternal genes are predominantly respon-
sible for embryo formation. The placenta—as an agent of
paternal genes—invades the maternal tissues to parasitize
maternal blood supply and support fetal growth. The genetic
conflict theory posits when for whatever reason placentation
is abnormal and fetal growth is adversely impacted, the pla-
centa somehow activates genes that enhance blood flow to
the fetus at a cost to the mother. Preeclampsia may well
represent such a situation, and recent data show that in this
condition the placenta produces excess amounts of sFlt1
(soluble FMS like tyrosine kinase 1), leading to endothelial
injury and vasoconstriction. Given the low resistance of the
placental bed when maternal vasoconstriction occurs, a
greater proportion of the maternal blood is shunted to the
placental circulation. Data show that elevation in sFLT1 oc-
curs well before the development of the clinical condition of
preeclampsia.20
Evaluation and Management
of Women at Risk for Recurrence
Because there are a significant number of risk factors and
potential etiologic mechanisms leading to preeclampsia, an
attempt should be made to identify those risk factors and
pathways that offer opportunities for intervention. In this
way, a rational pathway-specific strategy for prevention of
preeclampsia recurrence can be developed. (Table 3).
Prevention of
Recurrent Preeclampsia
Women with any of the following characteristics should be
considered at particularly high risk for recurrent preeclamp-
sia and stand to benefit the most from prevention strategies,
even if there is only a modest effect on recurrence rates. These
include preeclampsia that was complicated by high degree of
severity, preterm birth, HELLP syndrome, eclampsia, fetal
growth restriction, abruptio placenta, oligohydramnios, peri-
natal death, a strong family history, or a history of vascular
lesions on placental histology. Women with any of these
should be targeted for the most intensive etiologic evalua-
tions and condition-specific therapy when warranted.
Only a few interventions have been sufficiently well-stud-
ied to demonstrate any consistent efficacy for preeclampsia
recurrence prevention (Table 4). Antiplatelet therapy (pri-
marily low-dose aspirin) has been studied most vigorously,
and appears to provide a modest effect in preventing pre-
eclampsia. Two published literature reviews have indicated
that there is a 14-19% reduction in preeclampsia in high-risk
women (especially those with previous preeclampsia) using
low-dose aspirin, generally 81 mg/d.32,33 It has been sug-
gested that aspirin works through a variety of mechanisms,
chiefly by increasing the prostacyclin to thromboxane ratio in
the vascular endothelium and by reducing sensitivity to an-
giotensin II. However, other actions are also likely. Aspirin
does not appear to be effective in preventing preeclampsia

Table 4 Reviews and Randomized Clinical Trials for Preeclampsia Recurrence Prevention
Agent Study Population N Odds Ratio (95% CI)
Aspirin Coomarasamy33 High risk 12,416 0.86 (0.79-0.94)
Duley32 High risk 33,439 0.81 (0.75-0.88)
Calcium Hofmeyr34 Meta-analysis low risk 15,206 0.48 (0.33-0.69)
Meta-analysis high risk 587 0.22 (0.12-0.42)
Magnesium Spatling35 General low-risk 568 NS
Sibai36 Normotensive primigravidas 374 NS
Fish oil Makrides37 All risk 1,683 0.86 (0.59-1.27)
Vitamins CⴙE Poston41 High risk 2,410 0.97 (0.80-1.17)
Rumbold42 Nulliparous women 1,877 1.20 (0.82-1.75)
Heparin Mello46 Angiotensin converting enzyme 80 0.26 (0.08-0.86)
polymorphism in
nonthrombophilic women
with history of preeclampsia
Abbreviations: CI, confidence intervals; NS, not significant.
140
in low-risk women. Importantly, low-dose aspirin does
not appear to have an appreciably increased risk of mater-
nal, fetal, or neonatal complications. For at-risk pregnan-
cies, it probably can be stopped at 36 weeks.
Calcium supplementation up to 2 g per day appears to
decrease the incidence of preeclampsia significantly (12 trials
with 15,206 women, RR ⫽ 0.48, 95% CI 0.33-0.69), with a
greater effect in high-risk women that include those with
previous preeclampsia (5 trials with 587 women, RR ⫽ 0.22,
95% CI 0.12-0.42) and those with low baseline calcium in-
take (7 trials with 10,154 women, RR ⫽ 0.36, 95% CI 0.18-
0.70).34 It may work via parathyroid hormone, by reducing
intravascular calcium and lowering vascular contractility.
The use of calcium to prevent preeclampsia in low-risk
women is not supported by current literature.
Other potential therapies have been less well-studied, but
available data are disappointing. Two small trials of magne-
sium sulfate showed no significant reduction in preeclampsia
incidence.35,36 Likewise, fish oil supplements, progesterone,
and garlic have not been proven beneficial.37-39 Because pre-
eclampisa has been linked with an increase in oxidative
stress, several therapies with antioxidants have been pro-
posed. Most recently, vitamin C and vitamin E have been
evaluated in large prospective randomized trials for prevent-
ing preeclampsia. An early review that examined initial trials
suggested a potential benefit.40 However, two recent, larger
randomized trials by Poston and coworkers39 and Rumbold
and coworkers41,42 have shown no such benefit and, in fact,
indicated that there may actually be some potential harm.
Unfortunately, to date there have been no published ran-
domized trials of therapy to prevent recurrence for women
with previous preeclampsia who have a thrombophilia. Case
series and anecdotal reports suggest a potential benefit of
low-dose heparin (either unfractionated or low molecular
weight).43,44 This approach seems reasonable since placental
vascular lesions are more common when there is a significant
thrombophilia,45 but prospective randomized trials are
needed to support this as a standard of care.
Interestingly, heparin has been used to prevent preeclamp-
sia recurrence in women with the angiotensin-converting en-
zyme insertion/deletion polymorphism and a history of pre-
eclampsia. Mello and coworkers randomized 80 subjects
with a history of preeclampsia who were without chronic
disease or a demonstrable thrombophilia to either low mo-
lecular weight heparin prophylaxis or no treatment.46 There
were significant reductions in recurrence of preeclampsia
(28% versus 7%), onset of preeclampsia ⱕ34 weeks (21%
versus 2%), and fetal growth restriction (44% versus 10%).
The authors also monitored uterine artery blood flow by
Doppler and noted a significant improvement in uterine ar-
tery blood flow in the heparin treatment subjects. This sug-
gests that heparin may have a therapeutic role for prevention
of preeclampsia recurrence, but that role needs clarification.
At present there is no accepted consensus in the United
States regarding the best approach in preventing preeclamp-
sia in the general population or in high-risk women. The
most recent American College of Obstetricians and Gynecol-
ogists (ACOG) Practice Bulletin addressing preeclampsia,
G.A. Dildy III, M.A. Belfort, and J.C. Smulian
published in 2002, recommends no specific prophylactic
regimen to prevent preeclampsia.6 However, based on avail-
able data, it would seem reasonable, at the minimum, to offer
calcium (2 g per day) and/or low-dose aspirin (81 mg per
day) to high-risk women, given the perceived risk– benefit
ratio. Heparin, especially low-molecular-weight prepara-
tions, may also be considered in the presence of previous
preeclampsia with a significant thrombophilia, with placen-
tal vascular lesions, or after failure of calcium and low-dose
aspirin therapy.
Future Direction
Clearly, more research is needed to identify and refine inter-
ventions to prevent the recurrence of preeclampsia. By focus-
ing on this particularly high-risk population who have al-
ready had preeclampsia, it may be easier to successfully
develop prevention strategies that can be applied to the lower
risk women who lack obvious risk factors. Clinical areas
needing significant clarification currently include thrombo-
philias in recurrent preeclampsia and identification of the
women most likely to benefit from heparin preparations.
Further insight into the pathophysiology of preeclampsia at
the cellular and genomic level will likely create new oppor-
tunities for prevention. Recent reports looking at angiogenic
proteins, such as circulating soluble fms-like tyrosine kinase
1 (sFlt-1), placental growth factor (PlGF), vascular endothe-
lial growth factor (VEGF), and endoglin, have seemingly
identified a pathogenic role for these factors in the develop-
ment of preeclampsia.20,41 It is not clear yet whether these can
be useful for refining risk more precisely or if they might
allow potential intervention points for therapy, but this area
of research appears to have significant promise.47
References
1. Sibai BM, Ewell M, Levine RJ, et al: Risk factors associated with pre-
eclampsia in healthy nulliparous women. The Calcium for Preeclamp-
sia Prevention (CPEP) Study Group. Am J Obstet Gynecol 177:1003-
1010, 1997
2. Why Mothers Die: Report on Confidential Enquiries into Maternal
Deaths in the United Kingdom 1994-1996. London, HMSO, 1998
3. Chang J, Elam-Evans LD, Berg CJ, et al: Pregnancy-related mortality
surveillance–United States, 1991-1999. MMWR Surveill Summ 52:
1-8, 2003
4. Ujah IA, Aisien OA, Mutihir JT, et al: Factors contributing to maternal
mortality in north-central Nigeria: a seventeen-year review. Afr J Re-
prod Health 9:27-40, 2005
5. Trupin LS, Simon LP, Eskenazi B: Change in paternity: a risk factor for
preeclampsia in multiparas. Epidemiology 7:240-244, 1996
6. ACOG practice bulletin. Diagnosis and management of preeclampsia
and eclampsia. Number 33, January 2002, American College of Obste-
tricians and Gynecologists
7. Campbell DM, MacGillivray I, Carr-Hill R: Pre-eclampsia in second
pregnancy. Br J Obstet Gynaecol 92:131-140, 1985
8. van Rijn BB, Hoeks LB, Bots ML, et al: Outcomes of subsequent preg-
nancy after first pregnancy with early-onset preeclampsia. Am J Obstet
Gynecol 195:723-728, 2006
9. Sibai BM, Mercer B, Sarinoglu C: Severe preeclampsia in the second
trimester: recurrence risk and long-term prognosis. Am J Obstet Gy-
necol 165:1408-1412, 1991
10. Sibai BM, Taslimi MM, el-Nazer A, et al: Maternal-perinatal outcome
associated with the syndrome of hemolysis, elevated liver enzymes, and
Preeclampsia recurrence and prevention
low platelets in severe preeclampsia-eclampsia. Am J Obstet Gynecol
155:501-509, 1986
11. Sibai BM, Ramadan MK, Chari RS, et al: Pregnancies complicated by
HELLP syndrome (hemolysis, elevated liver enzymes, and low plate-
lets): subsequent pregnancy outcome and long-term prognosis. Am J
Obstet Gynecol 172:125-129, 1995
12. Sullivan CA, Magann EF, Perry KG Jr, et al: The recurrence risk of the
syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP)
in subsequent gestations. Am J Obstet Gynecol 171:940-943, 1994
13. Chames MC, Haddad B, Barton JR, et al: Subsequent pregnancy out-
come in women with a history of HELLP syndrome at ⱕ28 weeks of
gestation. Am J Obstet Gynecol 188:1504-1507, discussion 1507-
1508, 2003
14. Adelusi B, Ojengbede OA: Reproductive performance after eclampsia.
Int J Gynaecol Obstet 24:183-189, 1986
15. Chesley LC: Eclampsia: the remote prognosis. Semin Perinatol 2:99-
111, 1978
16. Sibai BM, Sarinoglu C, Mercer BM: Eclampsia. VII. Pregnancy outcome
after eclampsia and long-term prognosis. Am J Obstet Gynecol 166:
1757-1761, discussion 1761-1763, 1992
17. Trogstad L, Skrondal A, Stoltenberg C, et al: Recurrence risk of pre-
eclampsia in twin and singleton pregnancies. Am J Med Genet A 126:
41-45, 2004
18. Hnat MD, Sibai BM, Caritis S, et al: Perinatal outcome in women with
recurrent preeclampsia compared with women who develop pre-
eclampsia as nulliparas. Am J Obstet Gynecol 186:422-426, 2002
19. Brosens I: A study of the spiral arteries of the decidua basalis in nor-
motensive and hypertensive pregnancies. J Obstet Gynaecol Br Com-
monw 71:222-230, 1964
20. Levine RJ, Maynard SE, Qian C, et al: Circulating angiogenic factors and
the risk of preeclampsia. N Engl J Med 350:672-683, 2004
21. Grahame-Clarke C: Human cytomegalovirus, endothelial function and
atherosclerosis. Herpes 12:42-45, 2005
22. Parra A, Ramirez-Peredo J: The possible role of prolactin in preeclamp-
sia: 2001, a hypothesis revisited a quarter of century later. Med Hy-
potheses 59:378-384, 2002
23. Acikgoz S, Harma M, Harma M, et al: Comparison of angiotensin-
converting enzyme, malonaldehyde, zinc, and copper levels in pre-
eclampsia. Biol Trace Elem Res 113:1-8, 2006
24. Arbogast BW, Leeper SC, Merrick RD, et al: Which plasma factors bring
about disturbance of endothelial function in pre-eclampsia? Lancet
343:340-341, 1994
25. Lorentzen BEM, Clausen T, Henriksen T: Fasting serum free fatty acids
and triglycerides are increased before 20 weeks of gestation in women
who later develop preeclampsia. Hypertens Pregnancy 13:103-109,
1994
26. Easterling TR, Benedetti TJ: Preeclampsia: a hyperdynamic disease
model. Am J Obstet Gynecol 160:1447-1453, 1989
27. Bosio PM, McKenna PJ, Conroy R, et al: Maternal central hemodynam-
ics in hypertensive disorders of pregnancy. Obstet Gynecol 94:978-
984, 1999
28. Dekker GA, Sibai BM: Etiology and pathogenesis of preeclampsia: cur-
rent concepts. Am J Obstet Gynecol 179:1359-1375, 1998
29. Esplin MS, Fausett MB, Fraser A, et al: Paternal and maternal compo-
nents of the predisposition to preeclampsia. N Engl J Med 344:867-
872, 2001
30. Skjaerven R, Vatten LJ, Wilcox AJ, et al: Recurrence of pre-eclampsia
across generations: exploring fetal and maternal genetic components in
a population based cohort. Br Med J 331:877, 2005
31. Haig D: Altercation of generations: genetic conflicts of pregnancy. Am J
Reprod Immunol 35:226-232, 1996
32. Duley L, Henderson-Smart DJ, Knight M, et al: Antiplatelet agents for
preventing pre-eclampsia and its complications. Cochrane Database
Syst Rev CD004659, 2004
33. Coomarasamy A, Honest H, Papaioannou S, et al: Aspirin for preven-
141
tion of preeclampsia in women with historical risk factors: a systematic
review. Obstet Gynecol 101:1319-1332, 2003
34. Hofmeyr GJ, Atallah AN, Duley L: Calcium supplementation during
pregnancy for preventing hypertensive disorders and related problems.
Cochrane Database Syst Rev 3:CD001059, 2006
35. Spatling L, Spatling G: Magnesium supplementation in pregnancy. A
double-blind study. Br J Obstet Gynaecol 95:120-125, 1988
36. Sibai BM, Villar MA, Bray E: Magnesium supplementation during preg-
nancy: a double-blind randomized controlled clinical trial. Am J Obstet
Gynecol 161:115-119, 1989
37. Makrides M, Duley L, Olsen SF: Marine oil, and other prostaglandin
precursor, supplementation for pregnancy uncomplicated by pre-
eclampsia or intrauterine growth restriction. Cochrane Database Syst
Rev 3:CD003402, 2006
38. Meher S, Duley L: Garlic for preventing pre-eclampsia and its compli-
cations. Cochrane Database Syst Rev 3:CD006065, 2006
39. Meher S, Duley L: Progesterone for preventing pre-eclampsia and its
complications. Cochrane Database Syst Rev CD006175, 2006
40. Rumbold A, Duley L, Crowther C, et al: Antioxidants for preventing
pre-eclampsia. Cochrane Database Syst Rev CD004227, 2005
41. Poston L, Briley AL, Seed PT, et al: Vitamin C and vitamin E in pregnant
women at risk for pre-eclampsia (VIP trial): randomised placebo-con-
trolled trial. Lancet 367:1145-1154, 2006
42. Rumbold AR, Crowther CA, Haslam RR, et al: Vitamins C and E and the
risks of preeclampsia and perinatal complications. N Engl J Med 354:
1796-1806, 2006
43. Riyazi N, Leeda M, de Vries JI, et al: Low-molecular-weight heparin
combined with aspirin in pregnant women with thrombophilia and a
history of preeclampsia or fetal growth restriction: a preliminary study.
Eur J Obstet Gynecol Reprod Biol 80:49-54, 1998
44. Kupferminc MJ, Fait G, Many A, et al: Low-molecular-weight heparin
for the prevention of obstetric complications in women with thrombo-
philias. Hypertens Pregnancy 20:35-44, 2001
45. Arias F, Romero R, Joist H, et al: Thrombophilia: a mechanism of
disease in women with adverse pregnancy outcome and thrombotic
lesions in the placenta. J Matern Fetal Med 7:277-286, 1998
46. Mello G, Parretti E, Fatini C, et al: Low-molecular-weight heparin low-
ers the recurrence rate of preeclampsia and restores the physiological
vascular changes in angiotensin-converting enzyme DD women. Hy-
pertension 45:86-91, 2005
47. Widmer M, Villar J, Benigni A, et al: Mapping the theories of pre-
eclampsia and the role of angiogenic factors: a systematic review. Ob-
stet Gynecol 109:168-180, 2007
48. Duckitt K, Harrington D: Risk factors for pre-eclampsia at antenatal
booking: systematic review of controlled studies. Br Med J 330:565,
2005
49. Conde-Agudelo A, Belizan JM: Risk factors for pre-eclampsia in a large
cohort of Latin American and Caribbean women. Br J Obstet Gynaecol
107:75-83, 2000
50. Sibai BM, Hauth J, Caritis S, et al: Hypertensive disorders in twin versus
singleton gestations. National Institute of Child Health and Human
Development Network of Maternal-Fetal Medicine Units. Am J Obstet
Gynecol 182:938-942, 2000
51. Stamilio DM, Sehdev HM, Morgan MA, et al: Can antenatal clinical and
biochemical markers predict the development of severe preeclampsia?
Am J Obstet Gynecol 182:589-594, 2000
52. Abi-Said D, Annegers JF, Combs-Cantrell D, et al: Case-control study of
the risk factors for eclampsia. Am J Epidemiol 142:437-441, 1995
53. Robertson L, Wu O, Langhorne P, et al: Thrombophilia in pregnancy: a
systematic review. Br J Haematol 132:171-196, 2006
54. Dugoff L, Hobbins JC, Malone FD, et al: Quad screen as a predictor of
adverse pregnancy outcome. Obstet Gynecol 106:260-267, 2005
55. Tucker MJ, Berg CJ, Callaghan WM, et al: The Black-White disparity in
pregnancy-related mortality from 5 conditions: differences in preva-
lence and case-fatality rates. Am J Public Health 97:247-251, 2007
Recurrent Preterm Birth
Shali Mazaki-Tovi, MD,*,† Roberto Romero, MD,*,‡ Juan Pedro Kusanovic, MD,*
Offer Erez, MD,* Beth L. Pineles, BS,* Francesca Gotsch, MD,* Pooja Mittal, MD,*,†
Nandor Gabor Than, MD,* Jimmy Espinoza, MD,† and Sonia S. Hassan, MD†

Recurrent preterm birth is frequently defined as two or more deliveries before 37 completed
weeks of gestation. The recurrence rate varies as a function of the antecedent for preterm
birth: spontaneous versus indicated. Spontaneous preterm birth is the result of either
preterm labor with intact membranes or preterm prelabor rupture of the membranes. This
article reviews the body of literature describing the risk of recurrence of spontaneous and
indicated preterm birth. Also discussed are the factors which modify the risk for recurrent
spontaneous preterm birth (a short sonographic cervical length and a positive cervicovagi-
nal fetal fibronectin test). Patients with a history of an indicated preterm birth are at risk not
only for recurrence of this subtype, but also for spontaneous preterm birth. Individuals of
black origin have a higher rate of recurrent preterm birth.
Semin Perinatol 31:142-158. © 2007 Published by Elsevier Inc.

KEYWORDS recurrent preterm birth, indicated preterm birth, spontaneous preterm birth,
rupture of membranes, parturition

P reterm birth is the leading cause of perinatal morbidity

and mortality worldwide.1 A preterm delivery is a risk
factor for subsequent preterm birth.2-22 Preterm birth can be
the result of three obstetrical circumstances: 1) preterm labor
with intact membranes; 2) preterm prelabor rupture of mem-
branes (PROM); and 3) “indicated” preterm birth, which oc-
curs when maternal or fetal indications require delivery be-
fore 37 weeks of gestation. The most common indications are
preeclampsia and small for gestational age (SGA). Spontane-
ous preterm parturition is a syndrome caused by multiple
etiologies (Fig. 1), which are expressed by synchronous or
dyssynchronous activation of the common terminal pathway
of parturition. The reader is referred to recent reviews for full
consideration of this concept.23,24
Although many studies have focused on the rate of preterm
birth,25-57 an important consideration is whether these deliv-
eries are the result of spontaneous labor (with intact or rup-
tured membranes) or “indicated” preterm deliveries. The
*Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS,
Hutzel Women’s Hospital, Bethesda, MD, and Detroit, MI.
†Department of Obstetrics and Gynecology, Wayne State University/Hutzel
Women’s Hospital, Detroit, MI.
‡Center for Molecular Medicine and Genetics, Wayne State University, De-
troit, MI.
Address correspondence to Roberto Romero, MD, Perinatology Research
Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Women’s
Hospital, 3990 John R St., Box #4, Detroit, MI 48201. E-mail
warfiela@mail.nih.gov
need for this distinction is based on the premise that the risk
factors for recurrent preterm PROM, preterm labor with in-
tact membranes, preeclampsia, and/or SGA are different.
However, recent observations suggest that there may be over-
lap among these conditions,18,19 so that a patient with an
“indicated” preterm birth may also be at risk for spontaneous
preterm birth.18,19 The converse may also be true (ie, that a
patient with a spontaneous preterm birth is at risk for an
“indicated” preterm birth in a subsequent pregnancy).
This review will present a summary of the literature and
aims to clarify the risk of recurrent disease and the biological
basis for recurrent preterm birth.
Definition of Preterm Birth
Preterm deliveries are those occurring between fetal viability
and 37 completed weeks of gestation (menstrual age). How-
ever, the lower limit of gestational age used to define a pre-
term birth has ranged from 13 to 24 weeks of gestation
among various reports.21,58,59 Our view is that the delivery of
a previable fetus should be considered a spontaneous abor-
tion rather than a spontaneous preterm birth. Otherwise,
perinatal and infant mortality estimates in a population or
country will be biased by the frequency of late spontaneous
abortions.
The precise definition of viability, however, is subject to
debate given the increased frequency of survival at very low

142 0146-0005/07/$-see front matter © 2007 Published by Elsevier Inc.

doi:10.1053/j.semperi.2007.04.001
Recurrent preterm birth
Figure 1 Pathological processes implicated in the
preterm parturition syndrome. (Reproduced with
permission from Romero and coworkers.24)
gestational ages. Clearly, some infants can survive around 24
weeks of gestation, but none at 20 weeks. Therefore, we
propose the range of 24 to 36 6/7 weeks of gestation for the
definition of preterm birth. If and when technological ad-
vances allow substantial survival below 24 weeks of gesta-
tion, this definition should be revised.
A birth weight of 500 g has also been used to define the
lower limit of viability.11,60 The popularity of this definition
derives from its simplicity. Birthweights can easily be ob-
tained anywhere in the world at a very low cost. The limita-
tions of this approach are that viable neonates born at viable
gestational ages and affected by intrauterine growth restric-
tion (IUGR) may have birthweights below 500 g, and that
some previable infants may weigh more than 500 g. Ideally,
gestational age at birth should be used to define viability.
There are, however, practical obstacles derived from the un-
certainty of gestational age estimation in many countries.
This problem can be overcome in areas where ultrasound is
performed routinely in early pregnancy, but not elsewhere,
including underdeveloped countries. The criteria for the def-
inition of viability have implications for the calculation of
vital statistics and comparisons of these among different pop-
ulations.
Recurrent Preterm Birth
Recurrent preterm birth is defined as two or more deliveries
before 37 completed gestational weeks.2,9,12,59,61,62 However,
the definition among studies is not uniform. Criteria that
have varied and may affect estimation of the rate of recurrent
preterm birth include: 1) gestational age thresholds used for
defining the upper (ie, 35 or 36 weeks)9,12,63,64 and lower (ie,
13 to 28 weeks)10,59 limits of preterm birth; 2) inclusion of
multiple gestations65-67; 3) inclusion of spontaneous, as well
as indicated preterm births11,64; 4) the number of preterm
births required to fulfill the definition of recurrent preterm
143
birth8; and 5) the requirement that the preterm births be
consecutive.8
Recurrent
Spontaneous Preterm Birth
The Frequency of Recurrent
Spontaneous Preterm Birth
Recurrent spontaneous preterm birth is defined as more than
one preterm birth related to spontaneous onset of labor with
intact membranes or preterm PROM.
Several studies have consistently indicated that patients with
a previous spontaneous preterm birth are at risk for a subse-
quent spontaneous preterm delivery.2-22 Iams et al9 reported the
results of a secondary analysis of the data from the Preterm
Prediction Study, conducted under the leadership of Golden-
berg et al.68 Among 378 patients with a prior spontaneous pre-
term birth or spontaneous abortion in the second trimester (ges-
tational age range: 18-36 weeks), the rate of recurrent
spontaneous preterm birth (⬍35 weeks) varied between 14%
and 15%, in contrast to the 3% rate of spontaneous preterm
birth among 904 parous women with a previous uncomplicated
term delivery (Table 1).
The rate of recurrent preterm birth was modified accord-
ing to the sonographic cervical length in the index pregnancy
and the presence of a positive test for fetal fibronectin in
cervicovaginal fluid at 22 to 24 weeks of gestation.9 Among
women with a previous spontaneous preterm birth, the rate
of recurrence (⬍35 weeks) was the highest (64%) among
women with a sonographically short cervix (⬍25 mm) and a
positive fetal fibronectin test. The lowest rate of recurrence
(7%) occurred in patients with a sonographic cervical length
⬎35 mm and a negative fetal fibronectin test.9
Patients with a positive fibronectin test were at higher risk
for spontaneous recurrent preterm birth regardless of cervi-
144
Table 1 Probability and 95% Confidence Intervals of Sponta-
neous Recurrent Preterm Birth at Less Than 35 Weeks Ac-
cording to the Gestational Age of the Previous Spontaneous
Preterm Birth*
Gestational Age at Probability (95% CI)
Delivery in Previous of Spontaneous
Spontaneous Recurrent Preterm
Preterm Birth Birth at <35 Weeks
18-26 weeks 0.15 (0.05-0.37)
27-31 weeks 0.15 (0.05-0.38)
32-36 weeks 0.14 (0.05-0.32)
>37 weeks 0.03 (0.03-0.03)
*Modified from Iams, et al.9 with permission.
cal length: 28% for patients with a positive test compared to
only 7% for patients with a negative test. Similarly, a sono-
graphic short cervix contributed to the risk of recurrent spon-
taneous preterm birth. Among patients with a history of
spontaneous preterm birth and a short cervix, the rate of
recurrence was 25% if the fetal fibronectin test was negative
and 64% if the test was positive. This information can be used
to counsel patients about their risk of spontaneous preterm
birth. However, further investigation is required in which a
mathematical model is generated to predict the individual
risk for preterm birth based on clinical, sonographic, and
biochemical parameters in which results are expressed as
continuous variables rather than categorical results.
Mercer and coworkers10 performed a secondary analysis of
the same dataset using different data stratification in order to
evaluate the association between prior spontaneous preterm
birth and subsequent pregnancy outcome. Women with a
history of spontaneous preterm delivery (before 37 weeks of
gestation) had a 2.5-fold increased risk (95% confidence in-
terval (CI), 1.9-3.2) of spontaneous preterm delivery in a
subsequent pregnancy compared to women with no history
of spontaneous preterm delivery (21.7% versus 8.8%, re-
spectively, P ⬍ 0.001). This risk was particularly high when
the analysis focused on recurrent spontaneous preterm de-
livery before 28 weeks of gestation [relative risk (RR) 10.6,
95% CI 2.9-38.3].10 Moreover, the earlier the gestational age
of the first preterm delivery, the greater the risk for recurrent
spontaneous preterm birth (RR 2.4, 2.7, and 3.1 for prior
delivery at 35-36, 28-34, and 23-27 weeks of gestation, re-
spectively).10
Preterm Prelabor Rupture
of Membranes and Recurrent Preterm Birth
PROM is defined as spontaneous rupture of the chorioamni-
otic membranes before the onset of labor.69 Since the conse-
quences of PROM depend on the gestational age at which the
episode occurs, this condition has been classified as preterm
PROM or term PROM, depending on whether the rupture of
the membranes occurs before or after 37 weeks of gestation,
respectively.70-76 Term PROM occurs in approximately 10%
of pregnancies,70-72,74,77,78 whereas the frequency of preterm
PROM is 2% to 3.5%.70-72,74,77,78 Preterm PROM accounts for
30% to 40% of preterm deliveries,70-72,74,77,78 and it is a lead-
S. Mazaki-Tovi et al.
ing clinically identifiable cause of preterm birth and a major
contributor to perinatal morbidity and mortality.21,58,70-78
Analysis of data from the Collaborative Perinatal Project
demonstrated that, among women with a previous term de-
livery not complicated by PROM, the frequency of preterm
PROM in a subsequent pregnancy is 4%.79 In contrast,
among patients with two successive singleton pregnancies in
the dataset (n ⫽ 5230), the frequency of preterm PROM is
21% if the first pregnancy resulted in a preterm delivery due
to preterm PROM.79
Several investigators have confirmed the high recurrence
rate of preterm PROM: 1) Asrat and coworkers80 reported a
32% (95% CI 23.9-40.5) risk of recurrence in 121 patients
with a previous episode of preterm PROM; 2) Ekwo and
coworkers81 reported that women with preterm PROM in a
previous pregnancy had a 5.5-fold higher risk of preterm
PROM in a subsequent pregnancy than those in the control
group; and 3) Mercer and coworkers58 reported that, com-
pared to women with no history of preterm PROM, women
with previous preterm PROM had a higher risk of spontane-
ous preterm delivery due to preterm PROM in the index
pregnancy (13.5% versus 4.1%, P ⬍ 0.001; RR: 3.3, 95% CI
2.1-5.2) as well as a higher risk of preterm PROM at less than
28 weeks (1.8% versus 0.1%, P ⬍ 0.01; RR 13.5, 95% CI
23-80.3).
Mercer and coworkers82 used the Preterm Prediction
Study population to determine the risk factors for subsequent
preterm birth due to preterm PROM alone. Preterm PROM at
less than 35 weeks of gestation occurred in 2% of patients
and at less than 37 weeks in 4.5% of patients. Preterm PROM
accounted for 32.6% of all preterm deliveries. Clinical char-
acteristics associated with preterm birth due to preterm
PROM, derived from a multivariable analysis, and stratified
as preterm PROM ⬍37 and ⬍35 weeks are displayed in
Table 2. In nulliparous women, the risk factors for preterm
PROM were a cervical length ⱕ25 mm, working during preg-
nancy, and the presence of medical complications [the odds
ratios (OR) ranged between 3 and 3.7].82 Among multiparous
women, a previous preterm birth due to preterm PROM was
the primary risk factor for preterm PROM in a subsequent
pregnancy (OR for preterm PROM at ⬍35 weeks: 4.1; ⬍37
weeks: 3.1). Noteworthy is that a previous preterm birth
caused by preterm labor with intact membranes was also a
risk factor for preterm PROM, although the odds ratios were
lower than if the previous preterm birth was the result of
preterm PROM (OR for preterm PROM at ⬍35 weeks: 2.6;
⬍37 weeks: 1.8).82
Interestingly, the only risk factor consistently associated
with preterm PROM at ⬍37 and ⬍35 weeks in both nullip-
arous and multiparous women was a short cervical length.
Bacterial vaginosis was not found to be a risk factor for recur-
rent preterm birth.82
Among multiparous women, a short cervix, a positive fetal
fibronectin test, and a history of preterm birth following pre-
term PROM increased the frequency of recurrent preterm
PROM at ⬍35 weeks to 25%. If recurrent preterm PROM was
defined as ⬍37 weeks, the combination of these three risk
Recurrent preterm birth
Table 2 Risk Factors Associated with Preterm PROM (at Less Than 35 weeks) Stratified by Parity*
Risk Factor OR
Cervical length <25 mm 9.9
Previous preterm birth with preterm PROM – –
Previous preterm labor with intact membranes – –
Working during pregnancy 5.3
Medical complications 4.2
FFN (ⴙ) n.s.
BV n.s.
FFN (ⴙ) and absent BV n.s.
FFN (ⴚ) and present BV n.s.
*Modified from Mercer, et al.82 with permission. Abbreviations: FFN, fetal fibronectin; BV, bacterial vaginosis; n.s., non-significant.
factors increased the risk 7.8-fold over the reference group of
multiparous women who had none of these risk factors.82
The mechanisms responsible for the association between
previous preterm PROM, short cervix, and positive fetal fi-
bronectin and recurrent preterm birth caused by preterm
PROM have not been elucidated. It is likely that an insult
during gestation (eg, intrauterine infection) would be re-
solved by preterm labor with intact membranes or preterm
PROM. We have proposed83 that selection of the specific
phenotype may be determined by genetic and/or environ-
mental factors. For example, if patients carry DNA variants
which predispose to an excess production of matrix-degrad-
ing enzymes, such patients will go into premature labor after
rupture of membranes. On the other hand, if the genotype is
such that the generation of uterotonic agents rather than
matrix-degrading enzymes is favored, then preterm labor
with intact membranes will be the clinical expression of the
preterm parturition syndrome. The genotype may explain
the tendency for the same phenotype to occur in subsequent
pregnancies (ie, preterm PROM).
The relationship between a short cervix and preterm
PROM could be due to intrauterine infection.84,85 A long
cervix with a well-established mucus plug may serve as an
anatomical and biochemical host defense mechanism against
ascending intrauterine infection.86-92 A short cervix may pre-
dispose to ascending intrauterine infection by shortening the
distance between microorganisms in the lower genital tract
and the chorioamniotic membranes.89,93 In addition, the pro-
cess of cervical shortening may lead to the loss of the mucus
plug. Cervical mucus contains antimicrobial properties, at-
tributed at least in part to antimicrobial peptides such as
defensins, lactoferrin, calprotectin, and bacterial permeabil-
ity factor.86-90
The relationship between a positive cervicovaginal fetal
fibronectin test and subsequent preterm PROM has been at-
tributed to the presence of upper genital tract infection.68
This interpretation has been based on the association be-
tween a positive fetal fibronectin test in the midtrimester and
the subsequent demonstration of histologic chorioamnionitis
at the time of preterm delivery.68 However, studies in which
amniocentesis was performed in women with positive cervi-
covaginal fetal fibronectin have found that intraamniotic in-
fection or inflammation is present in less than 2% of patients
145
Nulliparous Multiparous
95% CI OR 95% CI
3.8-25.9 4.2 2.0-8.9
4.1 2.0-8.7
2.6 1.2-5.3
1.5-18.7 n.s. n.s.
1.1-16.0 n.s. n.s.
n.s. n.s. n.s.
n.s. n.s. n.s.
n.s. 9.0 3.6-22.5
n.s. 2.8 1.2-6.3
with a positive fibronectin test.94 Because fetal fibronectin is a
component of the extracellular matrix located in the chorion
leave95 and its abundance in cervicovaginal fluid increases
before both preterm68,96-109 and term labor,110-119 we propose
that detection of this protein is a marker of decidual/mem-
brane activation and, therefore, of the common terminal
pathway of parturition. Thus, a history of preterm PROM and
a positive test for fetal fibronectin in the midtrimester are
likely to reflect activation of the decidua/membrane compo-
nent of the pathway. We propose a sequence of events that
may explain the empirical observations reported by Mercer
and coworkers.82 A patient with a previous preterm PROM is
at risk for subsequent PROM.82 If such a patient has a short
cervix, the risk of recurrent preterm PROM would increase
because of ascending intrauterine infection. If the infection is
such that it activates chorion and decidua, then fetal fi-
bronectin will be positive. Of course, it is also possible that a
patient with preterm PROM would have activation of the
common terminal pathway (and therefore a positive test for
fetal fibronectin) with a long cervix.
Twin Gestation and Recurrent Preterm Birth
There are conflicting data as to whether preterm birth in the
context of a multiple gestation is a risk factor for preterm
birth in a future singleton pregnancy. Menard and cowork-
ers62 were the first to examine the recurrence rate after pre-
term birth of a twin gestation. The authors reported the out-
comes of 144 women who first delivered twins, followed by a
subsequent singleton gestation. Preterm delivery (before 37
weeks of gestation), occurred in 59.7% of twin gestations and
in 14.6% of the subsequent singleton pregnancies. Among
women who delivered preterm twins, 19.6% delivered pre-
term in the subsequent singleton pregnancy. Preterm birth in
twin gestations was associated with a significantly increased
risk of preterm delivery in a subsequent singleton pregnancy
(RR 2.87, 95% CI 1.02-8.09). Among the subset of patients
that delivered twins before 30 weeks, 42% of the subsequent
singleton pregnancies delivered preterm (RR 6.11, 95% CI
2.07-18.02). The RR of preterm birth of a singleton after
delivery of twins between 30 and 34 weeks of gestation was
3.63 (95% CI 1.02-12.92). However, women who delivered
146
twins between 34 and 37 weeks of gestation did not have an
increased risk for recurrent preterm birth.
In contrast, Rydhstrom59 reported that a preterm twin de-
livery, regardless of etiology, did not increase the risk of
recurrent preterm birth in a subsequent singleton gestation.
However, a prior preterm singleton delivery increased the
risk of preterm birth in subsequent singleton and twin preg-
nancies. Bloom and coworkers12 reported that women with a
singleton gestation that resulted in preterm birth at less than
35 weeks have an increased risk for recurrence (OR 5.6, 95%
CI 4.5-7.0). However, those whose first pregnancy resulted
in twins delivered at less than 35 weeks did not have a higher
risk of recurrent preterm birth (OR 1.9, 95% CI 0.46-8.14).
Cervical Insufficiency
as a Cause of Recurrent
Midtrimester Abortion/Preterm Birth
The clinical diagnosis of cervical insufficiency is traditionally
made in patients with a history of recurrent mid-trimester
spontaneous abortions and/or early preterm deliveries in
which “the basic process is thought to be the failure of the
cervix to remain closed during pregnancy.”120 Thus, both by
definition and clinical practice, the condition now termed
“cervical insufficiency” is recognized as one that recurs in
subsequent pregnancies.
Digital examination of the cervix was the method used to
determine cervical status (effacement, dilation, position, and
consistency) before the introduction of ultrasound. Cervical
sonography has become an objective and reliable method to
assess cervical length, which approximates cervical efface-
ment. The shorter the sonographic cervical length in the mid-
trimester, the higher the risk of spontaneous preterm labor/
delivery.121-125 However, there is no agreement concerning
what constitutes a sonographic short cervix. For example,
Iams et al122 proposed that a cervix of 26 mm or shorter at 24
weeks of gestation increases the risk for spontaneous preterm
delivery (RR: 6.19, 95% CI 3.84-9.97). The prevalence of
spontaneous preterm delivery (defined as less than 35 weeks)
in this study was 4.3%, and the positive predictive value was
17.8% for a cervical length ⱕ25 mm at 24 weeks of gesta-
tion.122 Other investigators have proposed a cut-off of 15
mm, because a cervical length of 15 mm or less is associated
with nearly a 50% rate of spontaneous preterm delivery at 32
weeks of gestation or less, when neonatal morbidity is sub-
stantial.123,125
Sonographic cervical length is not a screening test for
spontaneous preterm delivery, because only a small fraction
of all patients who will have a spontaneous preterm birth
have a short cervix in the mid-trimester. Previous studies
conducted at our institution have indicated that only 8% of
all patients who will have a preterm delivery at less than 32
weeks of gestation have a cervical length of 15 mm or less in
the mid-trimester.125 The converse is also true. Among
women with a short cervix, some have adverse pregnancy
outcomes and others have uncomplicated term deliver-
ies.66,121-123,126-140 Only half of women with a cervical length
of 15 mm or less deliver before 32 weeks of gestation.125 This
S. Mazaki-Tovi et al.
indicates that a short cervix should not be equated with “cer-
vical insufficiency.”
Sonographic cervical length can modify the a priori risk for
preterm delivery. For example, in patients with a history of
preterm delivery, a twin gestation, or a triplet gestation, a
short cervix confers an increased risk for preterm deliv-
ery.109,141-149 Indeed, among women with a history of spon-
taneous preterm birth, the risk of recurrence increases as
cervical length shortens.9
The hypothesis that cervical competence or sufficiency rep-
resents a spectrum was studied by Parikh and Mehta, who used
digital examination of the cervix and concluded that degrees of
cervical competence do not exist.150 Iams et al, using sono-
graphic examination of the cervix, suggested that cervical suffi-
ciency/insufficiency is a continuum,66 with a strong relationship
between cervical length in the index pregnancy and gestational
age at delivery in the first pregnancy. This relationship was
nearly linear; patients with a typical history of a cervical insuffi-
ciency (painless dilation) do not constitute a separate group
from those with a history of spontaneous preterm delivery (pre-
term labor or preterm PROM).66 Similar results have been re-
ported by Guzman et al.151 Collectively, these studies suggest a
relationship between a history of preterm delivery and the cer-
vical length in a subsequent pregnancy. Inasmuch as patients
with a short cervix are at increased risk for a mid-trimester
pregnancy loss (clinically referred to as “cervical insufficiency”)
or spontaneous preterm delivery with intact or ruptured mem-
branes,66,121-123,126-131,133-140,151,152 a short cervix could be con-
sidered the expression of a spectrum of cervical diseases or func-
tions.
We have proposed that cervical insufficiency is one of the
great “obstetrical syndromes.”153 Cervical ripening in the
mid-trimester may be the result of: 1) the loss of connective
tissue after a cervical operation such as conization154-156 or
LEEP procedure156; 2) a congenital disorder such as cervical
hypoplasia after diethylstilbestrol exposure157-160; 3) intra-
uterine infection161,162; and 4) a suspension of progesterone
action.163 There is experimental evidence that progesterone
can reverse cervical compliance induced by the administra-
tion of dexamethasone to pregnant sheep.164 Sherman165 has
also generated evidence that the administration of 17 alpha
hydroxyprogesterone caproate (17 OH P) may be beneficial
in patients with clinically diagnosed “cervical insufficiency”
and a cervical disorder that manifests itself with the clinical
presentation of “cervical insufficiency.” Each of these causes
of the syndrome could be affected by genetic or environmen-
tal factors. The possibility of novel and yet-to-be-discovered
mechanisms of disease playing a role must also be consid-
ered.
A proportion of patients presenting with asymptomatic
cervical dilation in the mid-trimester have microbial invasion
of the amniotic cavity (MIAC)161,162 that can be as high as
51.5%.162 Microbial invasion of the amniotic cavity may be
due to premature cervical dilation with the exposure of the
chorioamniotic membranes to the microbial flora of the
lower genital tract. Microorganisms may gain access to the
amniotic cavity by crossing intact membranes.162 Under
these circumstances, infection would be a secondary phe-
Recurrent preterm birth 147

Table 3 Odds Ratios for Recurrence of Preterm Delivery or Low-Birthweight Newborn by Race in Georgia, 1980-1995*

Maternal Characteristic in Second Delivery at 20-31 wk† Delivery at 32-36 wk†

Pregnancy White (n ⴝ 84) Black (n ⴝ 145) White (n ⴝ 712) Black (n ⴝ 1059)
Maternal age (years)
10-17 2.3 (0.9-5.6) 2.0 (1.2-3.5) 1.3 (0.8-2.0) 1.3 (1.1-1.7)
18-19 1.0 (0.5-2.0) 1.2 (0.8-2.0) 1.3 (1.0-1.7) 1.2 (1.0-1.4)
20-49 1.0 1.0 1.0 1.0
Initiation of prenatal care (trimester)
First 1.0 1.0 1.0 1.0
Second, third, or none 1.2 (0.6-2.2) 1.2 (0.8-1.7) 1.1 (0.9-1.4) 1.1 (1.0-1.3)
Interpregnancy interval, months
<6 1.1 (0.5-2.1) 1.4 (0.9-2.3) 1.0 (0.7-1.3) 1.2 (1.2-1.5)
6-11 1.6 (0.9-2.9) 0.9 (0.5-1.5) 1.2 (0.9-1.5) 1.1 (0.9-1.3)
12-47 1.0 1.0 1.0 1.0
>47 1.0 (0.4-2.1) 0.8 (0.4-1.5) 0.9 (0.7-1.2) 0.7 (0.6-0.9)
Goodness-of-fit P value‡ 0.72 0.33 0.29 0.93
Smoking during the pregnancy§
Yes 0.4 (0.2-1.1) 1.7 (0.2-14.5) 0.8 (0.6-1.2) 0.6 (0.3-1.1)
No 1.0 1.0 1.0 1.0
Modified from Adams, et al.11 with permission.
*Odds ratio for type of second pregnancy are controlled for all of the other variables in the table except smoking; figures in parentheses are
95% confidence intervals.
†Referent group is delivery in second pregnancy at gestation > 37 weeks.
‡Goodness-of-fit for model including all variables except smoking.
§Analysis restricted to second deliveries occurring from 1989 through 1995. Association adjusted for all other variables in the model.

nomenon to primary cervical disease. An alternative
explanation is that primary intrauterine infection (ascending,
hematogeneous166), or one caused by activation of microor-
ganisms present within the uterine cavity167 in the second
trimester of pregnancy produces myometrial contractility
and cervical ripening. Because uterine contractions are usu-
ally clinically silent in the mid-trimester of pregnancy, the
clinical picture of an infection-induced spontaneous abortion
may be indistinguishable from that of an incompetent cer-
vix.65,162 Recently, we have established that 9% (5/57) of
women with a short endocervix (less than 25 mm) have mi-
crobiologically proven intraamniotic infection,168 suggesting
that these infections are subclinical and may precede the
development of the clinical picture of acute “cervical insuffi-
ciency” (dilated and effaced cervix with bulging membranes).
The issue of whether subclinical intrauterine infection is a
cause of recurrent cervical insufficiency and preterm birth
has not been answered.
Women of African-American
Origin Have a Greater Risk of
Recurrent Preterm Birth than Caucasians
There is a well-established disparity in the rate of preterm
birth among ethnic groups in the U.S.8,11,169-176 Individuals of
African-American origin are at higher risk for recurrent pre-
term birth.
A large population-based cohort study11 in the state of
Georgia found that, among women who delivered between
20 and 31 weeks of gestation in their first pregnancy, black
women had a higher rate of recurrent preterm birth at 20 to
31 weeks than did white women [black ⫽ 13.4% (95% CI
11.4-15.6) versus white ⫽ 8.2% (95% CI 6.6-10.1)]. The
same was the case for deliveries between 32 and 36 weeks of
gestation.
Of interest was that teenagers whose first preterm delivery
occurred between 20 and 31 weeks of gestation had twice the
risk of recurrent preterm birth (20-31 weeks) than that of
women 20 to 49 years of age (Table 3). This observation was
significant only among African-American women.
Kitska and coworkers64 used a maternally linked database
from the Missouri Department of Health to study racial dis-
parities and recurrent preterm birth. The study focused on
368,633 mothers who had two or more deliveries between
1978 and 1997. The frequency of recurrent preterm birth
was 3.1% among African-Americans and 0.6% among Cau-
casians (RR, 5.40; 95% CI 5.06, 5.75). Logistic regression
analysis indicated that being of African-American descent
increased the risk for recurrent preterm birth independently
of other factors, such as medical complications and low so-
cioeconomic status (adjusted OR, 4.11; 95% CI 3.78, 4.47).
Two additional findings of this study were that: 1) the recur-
rent preterm birth in women of African-American origin oc-
curred at an earlier median gestational age than in Caucasian
women (31 weeks versus 33 weeks); and 2) the gestational
age of the recurrent preterm birth was similar to that of the
previous preterm birth and most likely to occur at the same
gestational age (Fig. 2). This finding was consistent among
individuals in both ethnic groups.
Additional Risk Factors
for Recurrent Preterm Birth
Several environmental factors have been implicated in recurrent
preterm birth. Cnattingius and coworkers61 studied the associ-
ation among smoking, previous very early preterm or moderate
148 S. Mazaki-Tovi et al.

Figure 2 Concordance in timing of preterm (20-34 6/7 weeks of gestation) birth in Missouri to a mother with previous
preterm birth, 1989 to 1997. The line represents the expected Gaussian curve if concordance in timing is a normally
distributed event. The bars represent the timing for each preterm birth after the initial preterm birth for all mothers (A),
Caucasians (B), or African Americans (C) in correlation with the expected normal curve. (Reproduced with permission
from Kistka and coworkers.64)

preterm delivery (before 32 weeks and at 32 to 36 weeks, re-
spectively), and the risk of a subsequent very preterm or mod-
erately preterm delivery in a population-based cohort of
243,858 women in Sweden. The OR for a very early preterm
second delivery among the women who smoked 1 to 9 cigarettes
per day was 1.4 (95% CI, 1.1, 1.7) and for those who smoked 10
or more cigarettes per day 1.6 (95% CI, 1.3, 2.0), as compared to
nonsmokers. Furthermore, women who stopped smoking be-
tween pregnancies were not at increased risk for very early or
moderate preterm delivery, whereas the women who started to
smoke in the second pregnancy had the same risk as those who
had continued to smoke.
Merlino et al177 investigated the association between ma-
ternal weight loss and recurrent preterm birth in a cohort of
1241 patients. Women whose body mass index (BMI) de-
creased more than 5 kg/m2 had more frequent recurrent pre-
term birth than those whose BMI did not (21.1% versus
9.3%, P ⱕ 0.01). For those with a term birth in the first
pregnancy, the rate of preterm birth in the subsequent preg-
nancy was not affected by a decline in BMI. In contrast,
women with a preterm birth in the first pregnancy had a
higher rate of recurrent preterm birth if BMI decreased more
than 5 kg/m2 (80.0% versus 28.2%, P ⫽ 0.01). Hence,
women whose BMI declines between pregnancies are at in-
creased risk for recurrent preterm birth.
The effect of sexual behavior on the risk of recurrent pre-
term birth was the subject of a secondary analysis of a mul-
ticentric observational study of the association between cer-
vical ultrasound at 16 to 18 weeks and the risk for recurrent
preterm birth. Women (n ⫽ 187) with singleton gestations
who were at high risk for preterm birth because of a prior
spontaneous preterm birth at less than 32 weeks of gestation
were included.178 A sexual history was obtained by interview
at the time of enrollment. Information gathered included the
number of sexual partners during the patient’s lifetime, the
number of sexual partners during the patient’s pregnancy,
and the frequency of sexual intercourse in the preceding
month. The greater the number of sexual partners in a wom-
an’s lifetime, the higher the frequency of recurrent preterm
birth (1 partner 19%, 2 to 3 partners 29%, more than 4
partners 44%, P ⱕ 0.007). Of interest, neither the frequency
of sexual intercourse during early pregnancy nor the number
of partners were risk factors for recurrent preterm birth,
which is consistent with previous reports.179-184
Recurrent preterm birth
Recurrent Indicated
Preterm Birth
Indicated preterm births are those resulting from delivery of
patients before term, due to complications that place the
mother and/or fetus at risk. Various authors include among
those complications hypertension-related disorders, obstet-
rical hemorrhage (placenta previa, placental abruption, and
other causes of antepartum hemorrhage), and all medically
induced preterm deliveries.12,40,185 Other investigators18 cat-
egorize indicated preterm births into: 1) ischemic placental
disease (ie, preeclampsia, SGA, placental abruption, and fetal
distress); and 2) miscellaneous (fetal malformations, placenta
previa, unexplained vaginal bleeding, chronic hypertension,
and others).
The incidence of indicated preterm birth has been re-
ported to range from 1% to 5.5% of all deliveries.12,176,186,187
However, indicated preterm birth accounts for approxi-
mately one-third of all preterm births.40,185,187
Meis et al185 reported a study examining the risk factors for
indicated preterm birth using the Preterm Prediction Study
data set. A history of a previous indicated preterm delivery
was associated with an OR of 2.8 (95% CI 1.5-5.4; P ⫽ 0.002;
multivariable analysis by logistic regression including other
risk factors for indicated preterm birth for recurrent preterm
birth).
Bloom et al12 reported the largest study conducted today in
a single unit and concluded that an indicated preterm deliv-
ery in singleton gestations is associated with an OR of 5.4
(95% CI 3.1-9.2) for recurrent preterm birth at less than 35
weeks of gestation in comparison to patients who delivered at
term in their first pregnancy. Patients who had an indicated
preterm birth between 24 and 28 weeks had an OR of 12.5
(95% CI 3.8-40.7) for recurrent preterm delivery and 10
(95% CI 4.8-20.8) if they were delivered between 29 and 32
weeks of gestation. In contrast, patients who were delivered
between 33 and 34 weeks did not have a higher risk for
recurrent preterm birth.
Patients with one prior preterm birth had an OR of 2.4
(95% CI 1.5-4.1) for indicated preterm delivery compared to
women with no history of preterm birth. Moreover, the OR
increases to 5.2 (95% CI 2.2-11.9) when the patients had two
or more previous preterm deliveries.176 Collectively, these
studies suggest that indicated preterm birth is not an isolated
event and puts the patient at risk for a subsequent indicated,
as well as spontaneous, preterm birth.
The subjects of recurrent preeclampsia and SGA are dis-
cussed elsewhere in this issue of the Seminars.
Is the Recurrence Risk
for Preterm Birth Different
for Spontaneous Versus
Indicated Preterm Birth?
Preterm births have been classified as “spontaneous” or “in-
dicated” because of the implicit assumption that preterm la-
149
bor with intact membranes and preterm PROM share patho-
physiologic features and clinical presentation (spontaneous
onset of labor). Preterm preeclampsia, fetal distress, and se-
vere IUGR—the most common causes of indicated preterm
birth186— usually occur in the absence of spontaneous par-
turition. Thus, the presence or absence of spontaneous par-
turition has been a sharp dividing line between the pheno-
types of indicated and nonindicated preterm birth.
One can also argue that the mechanisms of disease responsi-
ble for the phenotypes are shared within the conditions respon-
sible for spontaneous preterm birth and within the conditions
responsible for indicated preterm birth. For example, MIAC
with bacteria is common in preterm labor188-204 and preterm
PROM,93,205-211 but rare in preeclampsia and IUGR. In contrast,
“failure of physiologic transformation of the spiral arteries” can
be observed in all of these four conditions,212,213 but is more
prevalent and severe in preeclampsia and IUGR214-220 than in
preterm labor and preterm PROM.212,213
Ananth and coworkers18 provided evidence in support of this
view, but also noted that spontaneous preterm birth in the first
pregnancy may be followed by an indicated preterm birth in the
subsequent pregnancy and vice versa. The observations are de-
rived from a population-based retrospective cohort study of
births in Missouri in which analyses were restricted to women
who delivered their first two consecutive singleton live births
during the study period of 1989 to 1997.18 The key observation
was that, if the first pregnancy resulted in a spontaneous or
indicated preterm birth, then women were more likely to have
the same type of preterm birth (spontaneous or indicated) in the
second pregnancy. Indeed, women with spontaneous preterm
birth before 35 weeks of gestation in the first pregnancy had an
OR of 3.6 (95% CI 3.2-4.0) for preterm birth before 35 weeks in
the second pregnancy. However, the risk for a medically indi-
cated preterm birth was also increased (OR 2.5, 95% CI 2.1-
3.0).18
Similarly, women who delivered at less than 35 weeks be-
cause of a medical indication in the first pregnancy were much
more likely to have an indicated preterm birth at less than 35
weeks of gestation in their subsequent pregnancy (OR 10.6,
95% CI 9.1-12.4). However, these patients were also at in-
creased risk of having a spontaneous preterm birth (OR 1.6,
95% CI 1.3-2.1), although that risk was lower than the risk of
having an indicated preterm birth.18 Similar findings were evi-
dent in pregnancies that ended at less than 32 weeks (Table 4).
The greatest risk for recurrence of preterm birth was observed
when women delivered their first preterm birth at less than 28
weeks of gestation. The magnitude of the risk for recurrence of
preterm birth decreased progressively as gestational age at de-
livery of the first preterm birth increased.18
Issues on the Management
and Prevention of a Patient
with a History of Preterm Birth
Prevention of Recurrent Preterm Birth
Progesterone Administration
Progesterone plays a central role in pregnancy. The proposed
functions of progesterone include maintenance of myome-
150
Table 4 Recurrence of Preterm Birth at <37, <35, and <32 Weeks and Subtypes in Second Pregnancy Based on Preterm Birth
at <37, <35, and <32 Weeks in the First Pregnancy, Respectively: Missouri, 1989 to 1997*
Preterm Birth in Second Pregnancy, Adjusted OR (95% CI)
Preterm Birth in the First All Preterm
Pregnancy Births
Preterm birth at <37 wks
Preterm birth at <37 wks 2.9 (2.8, 3.0)
Spontaneous preterm birth 2.8 (2.7, 3.0)
Medically indicated preterm birth 3.0 (2.8, 3.3)
Preterm birth at <35 wks
Preterm birth at <35 wks 3.6 (3.4, 3.9)
Spontaneous preterm birth 3.3 (3.0, 3.6)
Medically indicated preterm birth 4.6 (4.0, 5.2)
Preterm birth at <32 wks
Preterm birth at <32 wks 4.9 (4.2, 5.7)
Spontaneous preterm birth 4.5 (3.8, 5.4)
Medically indicated preterm birth 5.8 (4.5, 7.4)
Reproduced, with permission, from Ananth et al.18
*ORs are adjusted for maternal age (second birth), education (second birth), marital status, race/ethnicity, smoking and alcohol use,
prepregnancy body mass index, and lack of or late initiation of prenatal care and interpregnancy interval.
trial quiescence, downregulation of gap-junction formation,
and inhibition of cervical ripening.221-223
Prevention of recurrent preterm birth by progesterone ad-
ministration has been a matter of debate in the literature for
decades.224-242 This section will review the results of random-
ized clinical trials and meta-analyses published recently.
da Fonseca et al243 recently published a randomized, dou-
ble-blind, placebo-controlled trial of vaginal progesterone
versus placebo in decreasing the rate of spontaneous preterm
birth. The trial included patients with at least one previous
spontaneous preterm birth, a prophylactic cervical cerclage,
or a uterine malformation (n ⫽ 142). Patients were allocated
to receive either daily progesterone (100 mg) or placebo by
vaginal suppository from 24 to 34 weeks of gestation. The
rates of preterm delivery at both less than 37 weeks and less
than 34 weeks were lower in the progesterone group than in
the placebo group [for 37 weeks; progesterone: 13.8% (10/
72) versus placebo: 28.5% (20/70); P ⫽ 0.03 and for 34
weeks; progesterone: 2.8% (2/72) versus placebo: 18.6%
(13/70); P ⫽ 0.002].
Meis et al244 reported the results of a double-blind placebo-
controlled clinical trial comparing the effects of intramuscu-
lar 17-␣ hydroxyprogesterone caproate (17-OH P) versus
placebo. Patients with a history of spontaneous preterm de-
livery (n ⫽ 463) were enrolled at 16 to 20 weeks of gestation
and randomly assigned in a 2:1 ratio to receive weekly injec-
tions of 250 mg of 17-OH P or an inert oil placebo until either
delivery or 36 weeks of gestation. Treatment with 17-OH P
significantly reduced the rate of preterm delivery at less than
37 weeks [17-OH P 36.3% versus placebo 54.9%, RR 0.66
(95% CI 0.54-0.81)] and less than 35 weeks of gestation
[17-OH P 20.6% versus placebo 30.7%, RR 0.67 (95% CI
0.48-0.93)]. Moreover, neonates born to women treated with
17 OH P had significantly lower rates of necrotizing entero-
colitis [17 OH P 0% versus placebo 2.6%, RR could not be
calculated], intraventricular hemorrhage [17-OH P 1.3% ver-
S. Mazaki-Tovi et al.
Spontaneous Preterm Medically Preterm
Births Indicated Births
2.7 (2.5, 2.9) 3.3 (3.1, 3.6)
3.2 (3.1, 3.4) 1.7 (1.5, 1.9)
1.0 (0.9, 1.2) 7.7 (7.0, 8.5)
3.1 (2.8, 3.4) 4.8 (4.3, 5.4)
3.6 (3.2, 4.0) 2.5 (2.1, 3.0)
1.6 (1.3, 2.1) 10.6 (9.1, 12.4)
4.1 (3.4, 4.9) 6.5 (5.2, 8.0)
4.6 (3.7, 5.6) 4.3 (3.1, 5.8)
2.7 (1.8, 4.1) 11.3 (8.4, 15.1)
sus placebo 5.2%, RR 0.25 (95% CI 0.8-0.82)], and need for
supplemental oxygen [17-OH P 14.9% versus placebo
23.8%, RR 0.62 (95% CI 0.42-0.92)].
Of interest, the effect of 17-OH P in preventing recurrent
preterm delivery was demonstrated only in patients whose
previous preterm delivery had occurred between 20 and 33.9
weeks of gestation.245 Moreover, it has been estimated that
4.7 women would need to be treated to prevent one recurrent
preterm delivery among patients who had delivered between
20 to 27.9 weeks of gestation in a previous pregnancy. The
number needed to treat is similar for women who had deliv-
ered at 28 to 33.9 weeks. Of note, 17-OH P was not associ-
ated with a reduction in the rate of recurrent preterm deliv-
eries in patients whose previous preterm delivery had
occurred between 34 to 36.9 weeks of gestation.
The efficacy of 17-OH P in singleton gestations was not
demonstrated in twin gestations.246 In this trial, no significant
differences were found between the groups in the rates of
spontaneous or indicated preterm birth.
In a 2006 Cochrane review, Dodd and coworkers247 re-
ported the results of 6 randomized trials including 988 pa-
tients randomized to receive either 17-OH P or placebo. The
administration of 17-OH P was associated with reduced risks
for preterm delivery before 37 weeks of gestation (6 studies,
RR 0.65, 95% CI 0.54-0.79) and before 34 weeks gestation (1
study, RR 0.15, 95% CI 0.04-0.64). Moreover, treatment
with progesterone was associated with lower risks for birth
weight below 2500 g (4 studies, RR 0.63, 95% CI 0.49-0.81)
and intraventricular hemorrhage (1 study, RR 0.63, 95% CI
0.08-0.82). No difference in perinatal death was found be-
tween treatment groups (5 studies, RR 0.66, 95% CI 0.37-
1.19). There were no interactions between the dose of pro-
gesterone (⬎500 mg versus ⬍500 mg 17-OH P weekly) or
gestational age at commencing progesterone administration
and the reported outcomes (ie, preterm delivery, neonatal
morbidity, and mortality). These results were in accord with
Recurrent preterm birth
a previous meta-analysis by this group.248 Additionally, the
authors stated that there is currently insufficient information
concerning the safety of progesterone supplementation.
Sanchez-Ramos et al249 reported another meta-analysis in-
cluding 10 randomized clinical trails and a total of 1339
patients; 8 trials used 17-OH P and 2 used other progesta-
tional agents for the prevention of recurrent preterm birth or
recurrent abortion. Patients who were treated with progesta-
tional agents had a reduced risk of preterm delivery com-
pared to patients in the placebo group (OR 0.45, 95% CI
0.25-0.80). The number needed to treat to prevent a single
preterm delivery was 10 (95% CI 6-24). A similar effect was
observed when only trials using 17-OH P were included (OR
0.45, 95% CI 0.25-0.80), and the number needed to treat
was 8 (95% CI 5-19).
Odibo et al250 performed a cost-effectiveness analysis of
the treatment with 17-OH P for the prevention of preterm
birth. The cost savings per quality-adjusted life year gained
by using 17-OH P was $3090 in women with a prior preterm
delivery at ⬍32 weeks and $2963 in women who had deliv-
ered at 32 to 37 weeks of gestation. Moreover, the cost per
additional preterm delivery avoided with the use of 17-OH P
was $35,319 in women with a previous preterm delivery at
⬍32 weeks and $36,093 in women who had delivered at 32
to 37 weeks of gestation.
In a recent meeting of the Prematurity Interest Group of
the Society for Maternal–Fetal Medicine, da Fonseca and co-
workers reported the results of a randomized clinical trial of
vaginal progesterone administration to women with a short
cervix (⬍15 mm). A 40% reduction in the rate of preterm
birth by was found in women treated with vaginal progester-
one (da Fonseca E, Nicolaides K, personal communication).
In contrast, the largest randomized clinical trial of vaginal
progesterone in women with a history of previous preterm
delivery did not demonstrate a beneficial effect of vaginal
progesterone (Lewis D and coworkers, personal communica-
tion). The FDA has raised questions about a safety signal.251
However, this concern was not identified in the trial in
twins.246 A review of embryo toxicity in animals has been
recently published.252
In summary, it seems that the administration of progester-
one may be an effective intervention to reduce the rate of
preterm delivery in a subset of women with a previous pre-
term delivery. Women with a short cervix may also benefit
from this intervention.
Treatment of Bacterial Vaginosis
Treatment of patients with bacterial vaginosis and a history of
preterm birth is controversial. Whereas some investigators
have argued strongly in favor of treatment,253 others believe
that this intervention is not justifiable.254-258 Controversy
over the choice of antibiotic also exists, with evidence that
early treatment with clindamycin is preferable to treatment
with metronidazole.259-262 There is no evidence that treat-
ment of patients with a previous preterm delivery with inter-
conceptional antibiotics will prevent a subsequent preterm
birth.263,264
151
The Use of Cerclage
The clinical value of cervical cerclage has been subject
of many observational and randomized clinical tri-
als,14,131,133,134,138,265-286 and the studies have been the topic of
several systematic reviews.287-289 The evidence suggests the
following conclusions:
1) Cervical cerclage in women with a sonographic short
cervix (15 mm or less) and a low risk for preterm de-
livery (by history) does not reduce the rate of sponta-
neous preterm birth.286
2) The effectiveness of cervical cerclage in women with a
sonographic short cervix and a high risk (by history)
for the prevention of preterm delivery is controver-
sial.14,136,277,278,290
3) The role of prophylactic cerclage in high-risk patients
without a sonographic short cervix for the prevention
of preterm delivery/midtrimester abortion (by history)
is unclear.269-271,278,285 Whereas the largest trial con-
ducted before the introduction of ultrasound evalua-
tion of the cervix suggested a modest beneficial ef-
fect,271 other trials269,270 and systematic reviews120
before the use of ultrasound have indicated that the
evidence of effectiveness is either weak or nonexistent.
4) In patients at risk for preterm delivery, serial sono-
graphic examination of the cervix followed by cerclage
in those who shortened the cervix is a reasonable alter-
native to prophylactic placement of a cerclage based on
uncontrolled studies.131,282,291
This evidence indicates that only patients with the clinical
presentation of “acute cervical insufficiency” and those with a
pregnancy history consistent with “cervical insufficiency”
and progressive shortening of the cervix demonstrated with
ultrasound may benefit from cerclage placement. However,
important to consider is that each conclusion is based on the
results of only one randomized clinical trial.278,283 Sakai and
coworkers demonstrated that the inflammatory status of the
endocervix may be an additional criterion to distinguish
those patients who would benefit from cerclage placement
from those in whom this intervention may be ineffective or
harmful.292
Summary
The evaluation of a patient with a previous preterm birth
begins with an examination of the obstetrical circumstances
responsible for this complication. If the preterm birth was
“indicated,” then the risk of recurrence is related to the spe-
cific condition, such as preterm preeclampsia, preterm severe
IUGR, placenta previa, etc. The reader is referred to the rel-
evant articles in this volume of the Seminars for details about
recurrence rate, monitoring of the index pregnancy, and in-
terventions.
If the previous preterm birth was the result of spontaneous
labor (with intact or ruptured membranes), the information
provided in this article can be used to counsel the patient
about the likelihood of recurrence. In general, most patients
152
with a previous spontaneous preterm birth will deliver at
term in a subsequent pregnancy.2-22 However, the earlier the
gestational age of the preterm birth, the higher the likelihood
of recurrence. It is important to be aware that recurrent pre-
term births tend to occur at the same gestational age.10,12,18
Counseling should ideally be conducted before conception,
and efforts should be made to identify potentially treatable
causes such as a Mullerian duct abnormalities. However, the
attributable risk of these conditions for preterm birth is ex-
tremely low.
The estimates of risk of recurrence for spontaneous pre-
term birth can be improved by performing a sonographic
examination of the uterine cervix and a fetal fibronectin test.
A long cervix and a negative fetal fibronectin test reduce the
risk just as a short cervix and a positive fetal fibronectin test
increase the risk.9,122
No intervention has been proven effective in reducing the
rate of preterm birth in patients with a positive fetal fibronec-
tin test.293,294 Similarly, the management of patients with a
short cervix remains controversial. Evidence suggests that
cervical cerclage does not prevent preterm birth in women
with a short cervix who do not have a history of previous
preterm birth.286 Similarly, a prophylactic cerclage has not
been effective in reducing the rate of preterm birth in patients
at risk for midtrimester abortion or spontaneous preterm
birth.138,277,282 In contrast, one randomized clinical trial of
patients with risk factors or symptoms of cervical insuffi-
ciency and a shortened cervix (⬍25 mm before 27 weeks of
gestation) in the index pregnancy found a benefit of “thera-
peutic cerclage.”278 Although further studies are required to
identify effective interventions and the patients who will ben-
efit from them, monitoring cervical length with ultrasound
and offering cerclage based on individual risk assessment is a
reasonable management strategy.
Acknowledgments
This research was supported by the Intramural Research Pro-
gram of the National Institute of Child Health and Human
Development, NIH, DHHS.
References
1. Lawn JE, Cousens S, Zupan J: 4 million neonatal deaths: When?
Where? Why? Lancet 365:891-900, 2005
2. Carr-Hill RA, Hall MH: The repetition of spontaneous preterm labour.
Br J Obstet Gynaecol 92:921-928, 1985
3. Ekwo EE, Gosselink CA, Moawad A: Previous pregnancy outcomes
and subsequent risk of preterm rupture of amniotic sac membranes.
Br J Obstet Gynaecol 100:536-541, 1993
4. Kristensen J, Langhoff-Roos J, Kristensen FB: Implications of idio-
pathic preterm delivery for previous and subsequent pregnancies.
Obstet Gynecol 86:800-804, 1995
5. Gibb DM, Salaria DA: Transabdominal cervicoisthmic cerclage in the
management of recurrent second trimester miscarriage and preterm
delivery. Br J Obstet Gynaecol 102:802-806, 1995
6. Guinn DA, Goldenberg RL, Hauth JC, et al: Risk factors for the devel-
opment of preterm premature rupture of the membranes after arrest of
preterm labor. Am J Obstet Gynecol 173:1310-1315, 1995
7. Kramer MS, Coates AL, Michoud MC, et al: Maternal asthma and
idiopathic preterm labor. Am J Epidemiol 142:1078-1088, 1995
8. Ekwo E, Moawad A: The risk for recurrence of premature births to
S. Mazaki-Tovi et al.
African-American and white women. J Assoc Acad Minor Phys
9:16-21, 1998
9. Iams JD, Goldenberg RL, Mercer BM, et al: The Preterm Prediction
Study: recurrence risk of spontaneous preterm birth. National Insti-
tute of Child Health and Human Development Maternal-Fetal Medi-
cine Units Network. Am J Obstet Gynecol 178:1035-1040, 1998
10. Mercer BM, Goldenberg RL, Moawad AH, et al: The preterm predic-
tion study: effect of gestational age and cause of preterm birth on
subsequent obstetric outcome. National Institute of Child Health and
Human Development Maternal-Fetal Medicine Units Network. Am J
Obstet Gynecol 181:1216-1221, 1999
11. Adams MM, Elam-Evans LD, Wilson HG, et al: Rates of and factors
associated with recurrence of preterm delivery. JAMA 283:1591-
1596, 2000
12. Bloom SL, Yost NP, McIntire DD, et al: Recurrence of preterm birth in
singleton and twin pregnancies. Obstet Gynecol 98:379-385, 2001
13. Koike T, Minakami H, Izumi A, et al: Recurrence risk of preterm birth
due to preeclampsia. Gynecol Obstet Invest 53:22-27, 2002
14. Berghella V, Odibo AO, Tolosa JE: Cerclage for prevention of preterm
birth in women with a short cervix found on transvaginal ultrasound
examination: a randomized trial. Am J Obstet Gynecol 191:1311-1317,
2004
15. Yost NP, Owen J, Berghella V, et al: Number and gestational age of
prior preterm births does not modify the predictive value of a short
cervix. Am J Obstet Gynecol 191:241-246, 2004
16. Tekesin I, Eberhart LH, Schaefer V, et al: Evaluation and validation of
a new risk score (CLEOPATRA score) to predict the probability of
premature delivery for patients with threatened preterm labor. Ultra-
sound Obstet Gynecol 26:699-706, 2005
17. Durnwald CP, Walker H, Lundy JC, et al: Rates of recurrent preterm
birth by obstetrical history and cervical length. Am J Obstet Gynecol
193:1170-1174, 2005
18. Ananth CV, Getahun D, Peltier MR, et al: Recurrence of spontaneous
versus medically indicated preterm birth. Am J Obstet Gynecol 195:
643-650, 2006
19. Ananth CV, Vintzileos AM: Epidemiology of preterm birth and its
clinical subtypes. J Matern Fetal Neonatal Med 19:773-782, 2006
20. Meis PJ, Klebanoff M, Dombrowski MP, et al: Does progesterone
treatment influence risk factors for recurrent preterm delivery? Obstet
Gynecol 106:557-561, 2005
21. Mercer B, Milluzzi C, Collin M: Periviable birth at 20 to 26 weeks of
gestation: proximate causes, previous obstetric history and recurrence
risk. Am J Obstet Gynecol 193:1175-1180, 2005
22. Mercer BM, Macpherson CA, Goldenberg RL, et al: Are women with
recurrent spontaneous preterm births different from those without
such history? Am J Obstet Gynecol 194:1176-1184, 2006
23. Romero R, Espinoza J, Kusanovic JP, et al: The preterm parturition
syndrome. Br J Obstet Gynaecol 113:17-42, 2006 (suppl 3)
24. Romero R, Espinoza J, Mazor M, et al: The preterm parturition syn-
drome, in Critchely H, Bennett P, Thornton S (eds): Preterm Birth.
London, RCOG Press, 2004, pp 28-60
25. Joseph KS, Kramer MS, Marcoux S, et al: Determinants of preterm
birth rates in Canada from 1981 through 1983 and from 1992
through 1994. N Engl J Med 339:1434-1439, 1998
26. Preterm singleton births: United States, 1989-1996. MMWR Morb
Mortal Wkly Rep 48:185-189, 1999
27. Vintzileos AM, Ananth CV, Smulian JC, et al: The impact of prenatal
care in the United States on preterm births in the presence and ab-
sence of antenatal high-risk conditions. Am J Obstet Gynecol 187:
1254-1257, 2002
28. Little RE, Gladen BC, Birmingham K, et al: Preterm birth rates in Avon
County, England, and urban Ukraine. Eur J Obstet Gynecol Reprod
Biol 113:154-159, 2004
29. Morken NH, Kallen K, Hagberg H, et al: Preterm birth in Sweden
1973-2001: rate, subgroups, and effect of changing patterns in mul-
tiple births, maternal age, and smoking. Acta Obstet Gynecol Scand
84:558-565, 2005
30. Davidoff MJ, Dias T, Damus K, et al: Changes in the gestational age
Recurrent preterm birth
distribution among U.S. singleton births: impact on rates of late
preterm birth, 1992 to 2002. Semin Perinatol 30:8-15, 2006
31. Papiernik E: Is the high rate of preterm birth in the United States
linked to previous induced abortions? Pediatrics 118:795-796, 2006
32. Fuchs K, Wapner R: Elective cesarean section and induction and their
impact on late preterm births. Clin Perinatol 33:793-801, 2006
33. Hamilton BE, Minino AM, Martin JA, et al: Annual summary of vital
statistics: 2005. Pediatrics 119:345-360, 2007
34. Collins JW Jr, David RJ, Simon DM, et al: Preterm birth among African
American and white women with a lifelong residence in high-income
Chicago neighborhoods: an exploratory study. Ethn Dis 17:113-117,
2007
35. Gazaway P, Mullins CL: Prevention of preterm labor and premature
rupture of the membranes. Clin Obstet Gynecol 29:835-849, 1986
36. Nwaesei CG, Young DC, Byrne JM, et al: Preterm birth at 23 to 26
weeks’ gestation: is active obstetric management justified? Am J Obstet
Gynecol 157:890-897, 1987
37. Mueller-Heubach E, Guzick DS: Evaluation of risk scoring in a pre-
term birth prevention study of indigent patients. Am J Obstet Gynecol
160:829-835, 1989
38. Roberts WE, Morrison JC, Hamer C, et al: The incidence of preterm
labor and specific risk factors. Obstet Gynecol 76:85S-89S, 1990
39. Yan JS, Yin CS: No decline in preterm birth rate over three decades. Int
J Gynaecol Obstet 34:1-5, 1991
40. Tucker JM, Goldenberg RL, Davis RO, et al: Etiologies of preterm birth
in an indigent population: is prevention a logical expectation? Obstet
Gynecol 77:343-347, 1991
41. Kramer MS, McLean FH, Eason EL, et al: Maternal nutrition and
spontaneous preterm birth. Am J Epidemiol 136:574-583, 1992
42. Multicenter randomized, controlled trial of a preterm birth prevention
program. Collaborative Group on Preterm Birth Prevention. Am J
Obstet Gynecol 169:352-366, 1993
43. Hobel CJ, Ross MG, Bemis RL, et al: The West Los Angeles Preterm
Birth Prevention Project. I. Program impact on high-risk women. Am J
Obstet Gynecol 170:54-62, 1994
44. Harbert GM Jr: Efforts to reduce low birth weight and preterm births:
a statewide analysis (Virginia). Am J Obstet Gynecol 171:329-338,
1994
45. Lubarsky SL, Schiff E, Friedman SA, et al: Obstetric characteristics
among nulliparas under age 15. Obstet Gynecol 84:365-68, 1994
46. Kristensen J, Langhoff-Roos J, Kristensen FB: Idiopathic preterm de-
liveries in Denmark. Obstet Gynecol 85:549-552, 1995
47. Gardner MO, Goldenberg RL, Cliver SP, et al: The origin and outcome
of preterm twin pregnancies. Obstet Gynecol 85:553-557, 1995
48. Graf RA, Perez-Woods R: Trends in preterm labor. J Perinatol 12:51-
58, 1992
49. Berkowitz GS, Papiernik E: Epidemiology of preterm birth. Epidemiol
Rev 15:414-443, 1993
50. Heaman MI, Sprague AE, Stewart PJ: Reducing the preterm birth rate:
a population health strategy. J Obstet Gynecol Neonatal Nurs 30:20-
29, 2001
51. Mauldin JG, Newman RB: Preterm birth risk assessment. Semin Peri-
natol 25:215-222, 2001
52. Kramer MS: The epidemiology of adverse pregnancy outcomes: an
overview. J Nutr 133:1592S-1596S, 2003
53. Wen SW, Smith G, Yang Q, et al: Epidemiology of preterm birth and
neonatal outcome. Semin Fetal Neonatal Med 9:429-435, 2004
54. Bibby E, Stewart A: The epidemiology of preterm birth. Neuro Endo-
crinol Lett 25:43-47, 2004 (suppl 1)
55. Higgins RD, Delivoria-Papadopoulos M, Raju TN: Executive summary
of the workshop on the border of viability. Pediatrics 115:1392-1396,
2005
56. Raju TN: Epidemiology of late preterm (near-term) births. Clin Peri-
natol 33:751-763, 2006
57. Steer P: The epidemiology of preterm labor: a global perspective. J
Perinat Med 33:273-276, 2005
58. Mercer BM: Preterm premature rupture of the membranes. Obstet
Gynecol 101:178-193, 2003
153
59. Rydhstroem H: Gestational duration in the pregnancy after a preterm
twin delivery. Am J Obstet Gynecol 178:136-139, 1998
60. Fanaroff AA, Stoll BJ, Wright LL, et al: Trends in neonatal morbidity
and mortality for very low birthweight infants. Am J Obstet Gynecol
196:147-148, 2007
61. Cnattingius S, Granath F, Petersson G, et al: The influence of gesta-
tional age and smoking habits on the risk of subsequent preterm
deliveries. N Engl J Med 341:943-948, 1999
62. Menard MK, Newman RB, Keenan A, et al: Prognostic significance of
prior preterm twin delivery on subsequent singleton pregnancy. Am J
Obstet Gynecol 174:1429-1432, 1996
63. Krymko H, Bashiri A, Smolin A, et al: Risk factors for recurrent pre-
term delivery. Eur J Obstet Gynecol Reprod Biol 113:160-163, 2004
64. Kitska ZA, Palomar L, Lee KA, et al: Racial disparity in the frequency
of recurrence of preterm birth. Am J Obstet Gynecol 196:131, 2007
65. Romero R, Mazor M, Gomez R, et al: Cervix, incompetence and pre-
mature labor. The Fetus 3:1-10, 1993
66. Iams JD, Johnson FF, Sonek J, et al: Cervical competence as a contin-
uum: a study of ultrasonographic cervical length and obstetric perfor-
mance. Am J Obstet Gynecol 172:1097-1103, 1995
67. Rydhstrom H: Twin pregnancy and the effects of prophylactic leave of
absence on pregnancy duration and birth weight. Acta Obstet Gynecol
Scand 67:81-84, 1988
68. Goldenberg RL, Mercer BM, Meis PJ, et al: The preterm prediction
study: fetal fibronectin testing and spontaneous preterm birth.
NICHD Maternal Fetal Medicine Units Network. Obstet Gynecol 87:
643-648, 1996
69. Keirse MJ, Ohlsson A, Treffers PE, et al: Prelabour rupture of the
membranes preterm, in Chalmers I, Enkin M, Keirse MJ (eds): Effec-
tive Care in Pregnancy and Childbirth. Oxford, Oxford University
Press, 1989, p 666
70. Sachs M, Baker TH: Spontaneous premature rupture of the mem-
branes. Am J Obstet Gynecol 97:888, 1967
71. Gunn GC, Mishell DR Jr, Morton DG: Premature rupture of the fetal
membranes: a review. Am J Obstet Gynecol 106:469-483, 1970
72. Christensen KK, Christensen P, Ingemarsson I, et al: A study of com-
plications in preterm deliveries after prolonged premature rupture of
the membranes. Obstet Gynecol 48:670-677, 1976
73. Johnson JW, Daikoku NH, Niebyl JR, et al: Premature rupture of the
membranes and prolonged latency. Obstet Gynecol 57:547-556, 1981
74. Daikoku NH, Kaltreider DF, Khouzami VA, et al: Premature rupture
of membranes and spontaneous preterm labor: maternal endometritis
risks. Obstet Gynecol 59:13-20, 1982
75. Gibbs RS, Blanco JD: Premature rupture of the membranes. Obstet
Gynecol 60:671-679, 1982
76. Shubert PJ, Diss E, Iams JD: Etiology of preterm premature rupture of
membranes. Obstet Gynecol Clin North Am 19:251-263, 1992
77. Lebherz TB, Hellman LP, Madding R, et al: Double-blind study of
premature rupture of the membranes: A report of 1,896 cases. Am J
Obstet Gynecol 87:218-225, 1963
78. Fayez JA, Hasan AA, Jonas HS, et al: Management of premature rup-
ture of the membranes. Obstet Gynecol 52:17-21, 1978
79. Naeye RL: Factors that predispose to premature rupture of the fetal
membranes. Obstet Gynecol 60:93-98, 1982
80. Asrat T, Lewis DF, Garite TJ, et al: Rate of recurrence of preterm
premature rupture of membranes in consecutive pregnancies. Am J
Obstet Gynecol 165:1111-1115, 1991
81. Ekwo EE, Gosselink CA, Moawad A: Unfavorable outcome in penul-
timate pregnancy and premature rupture of membranes in successive
pregnancy. Obstet Gynecol 80:166-172, 1992
82. Mercer BM, Goldenberg RL, Meis PJ, et al: The Preterm Prediction
Study: prediction of preterm premature rupture of membranes
through clinical findings and ancillary testing. The National Institute
of Child Health and Human Development Maternal-Fetal Medicine
Units Network. Am J Obstet Gynecol 183:738-745, 2000
83. Romero R, Tromp G: High-dimensional biology in obstetrics and
gynecology: functional genomics in microarray studies. Am J Obstet
Gynecol 195:360-363, 2006
84. Rizzo G, Capponi A, Vlachopoulou A, et al: Ultrasonographic assess-
154
ment of the uterine cervix and interleukin-8 concentrations in cervical
secretions predict intrauterine infection in patients with preterm labor
and intact membranes. Ultrasound Obstet Gynecol 12:86-92, 1998
85. Gomez R, Romero R, Nien JK, et al: A short cervix in women with
preterm labor and intact membranes: a risk factor for microbial inva-
sion of the amniotic cavity. Am J Obstet Gynecol 192:678-689, 2005
86. Eggert-Kruse W, Botz I, Pohl S, et al: Antimicrobial activity of human
cervical mucus. Hum Reprod 15:778-784, 2000
87. Hein M, Helmig RB, Schonheyder HC, et al: An in vitro study of
antibacterial properties of the cervical mucus plug in pregnancy. Am J
Obstet Gynecol 185:586-592, 2001
88. Hein M, Valore EV, Helmig RB, et al: Antimicrobial factors in the
cervical mucus plug. Am J Obstet Gynecol 187:137-144, 2002
89. Evaldson G, Malmborg AS, Nord CE, et al: Bacteroides fragilis, Strep-
tococcus intermedius and group B streptococci in ascending infection
of pregnancy. An animal experimental study. Gynecol Obstet Invest
15:230-241, 1983
90. Cole AM: Innate host defense of human vaginal and cervical mucosae.
Curr Top Microbiol Immunol 306:199-230, 2006
91. Svinarich DM, Wolf NA, Gomez R, et al: Detection of human defensin
5 in reproductive tissues. Am J Obstet Gynecol 176:470-475, 1997
92. Romero R, Gomez R, Araneda H, et al: Cervical mucus inhibits microbial
growth: a host defense mechanism to prevent ascending infection in preg-
nant and non-pregnant women. Am J Obstet Gynecol A57, 1993
93. Espinoza J, Chaiworapongsa T, Romero R, et al: Antimicrobial peptides in
amniotic fluid: defensins, calprotectin and bacterial/permeability-increas-
ing protein in patients with microbial invasion of the amniotic cavity,
intra-amniotic inflammation, preterm labor and premature rupture of
membranes. J Matern Fetal Neonatal Med 13:2-21, 2003
94. Yoon BH, Romero R, Moon JB, et al: The frequency and clinical sig-
nificance of intra-amniotic inflammation in patients with a positive
cervical fetal fibronectin. Am J Obstet Gynecol 185:1137-1142, 2001
95. Leitich H, Kaider A: Fetal fibronectin– how useful is it in the prediction of
preterm birth? Br J Obstet Gynaecol 110:66-70, 2003 (suppl 20)
96. Chang TC, Chew TS, Pang M, et al: Cervicovaginal foetal fibronectin
in the prediction of preterm labour in a low-risk population. Ann
Acad Med Singapore 26:776-780, 1997
97. Goldenberg RL, Mercer BM, Iams JD, et al: The preterm prediction
study: patterns of cervicovaginal fetal fibronectin as predictors of
spontaneous preterm delivery. National Institute of Child Health and
Human Development Maternal-Fetal Medicine Units Network. Am J
Obstet Gynecol 177:8-12, 1997
98. Malak TM, Sizmur F, Bell SC, et al: Fetal fibronectin in cervicovaginal
secretions as a predictor of preterm birth. Br J Obstet Gynaecol 103:
648-653, 1996
99. Parker J, Bell R, Brennecke S: Fetal fibronectin in the cervicovaginal
fluid of women with threatened preterm labour as a predictor of
delivery before 34 weeks’ gestation. Aust N Z J Obstet Gynaecol 35:
257-261, 1995
100. Burrus DR, Ernest JM, Veille JC: Fetal fibronectin, interleukin-6, and
C-reactive protein are useful in establishing prognostic subcategories of
idiopathic preterm labor. Am J Obstet Gynecol 173:1258-1262, 1995
101. Chuileannain FN, Bell R, Brennecke S: Cervicovaginal fetal fibronec-
tin testing in threatened preterm labour: translating research findings
into clinical practice. Aust N Z J Obstet Gynaecol 38:399-402, 1998
102. Goffeng AR, Holst E, Milsom I, et al: Fetal fibronectin and microor-
ganisms in vaginal fluid of women with complicated pregnancies.
Acta Obstet Gynecol Scand 76:521-527, 1997
103. Lopez RL, Francis JA, Garite TJ, et al: Fetal fibronectin detection as a
predictor of preterm birth in actual clinical practice. Am J Obstet
Gynecol 182:1103-1106, 2000
104. Nageotte MP, Casal D, Senyei AE: Fetal fibronectin in patients at
increased risk for premature birth. Am J Obstet Gynecol 170:20-25,
1994
105. Oliveira T, de Souza E, Mariani-Neto C, et al: Fetal fibronectin as a
predictor of preterm delivery in twin gestations. Int J Gynaecol Obstet
62:135-139, 1998
106. Morrison JC, ?? RW III, Botti JJ, et al: Prediction of spontaneous
S. Mazaki-Tovi et al.
preterm birth by fetal fibronectin and uterine activity. Obstet Gynecol
87:649-655, 1996
107. Wennerholm UB, Holm B, Mattsby-Baltzer I, et al: Fetal fibronectin,
endotoxin, bacterial vaginosis and cervical length as predictors of
preterm birth and neonatal morbidity in twin pregnancies. Br J Obstet
Gynaecol 104:1398-1404, 1997
108. Tolino A, Ronsini S, Zullo F, et al: Fetal fibronectin as a screening test
for premature delivery in multiple pregnancies. Int J Gynaecol Obstet
52:3-7, 1996
109. Goldenberg RL, Iams JD, Miodovnik M, et al: The preterm prediction
study: risk factors in twin gestations. National Institute of Child
Health and Human Development Maternal-Fetal Medicine Units Net-
work. Am J Obstet Gynecol 175:1047-1053, 1996
110. Sciscione A, Hoffman MK, DeLuca S, et al: Fetal fibronectin as a
predictor of vaginal birth in nulliparas undergoing preinduction cer-
vical ripening. Obstet Gynecol 106:980-985, 2005
111. Imai M, Tani A, Saito M, et al: Significance of fetal fibronectin and
cytokine measurement in the cervicovaginal secretions of women at
term in predicting term labor and post-term pregnancy. Eur J Obstet
Gynecol Reprod Biol 97:53-58, 2001
112. Mijovic JE, Demianczuk N, Olson DM, et al: Prostaglandin endoper-
oxide H synthase mRNA expression in the fetal membranes correlates
with fetal fibronectin concentration in the cervico-vaginal fluids at
term: evidence of enzyme induction before the onset of labour. Br J
Obstet Gynaecol 107:267-273, 2000
113. Rozenberg P, Goffinet F, Hessabi M: Comparison of the Bishop score,
ultrasonographically measured cervical length, and fetal fibronectin
assay in predicting time until delivery and type of delivery at term.
Am J Obstet Gynecol 182:108-113, 2000
114. Kiss H, Ahner R, Hohlagschwandtner M, et al: Fetal fibronectin as a
predictor of term labor: a literature review. Acta Obstet Gynecol Scand
79:3-7, 2000
115. Garite TJ, Casal D, Garcia-Alonso A, et al: Fetal fibronectin: a new tool
for the prediction of successful induction of labor. Am J Obstet Gy-
necol 175:1516-1521, 1996
116. Ahner R, Egarter C, Kiss H, et al: Fetal fibronectin as a selection
criterion for induction of term labor. Am J Obstet Gynecol 173:1513-
1517, 1995
117. Ahner R, Kiss H, Egarter C, et al: Fetal fibronectin as a marker to
predict the onset of term labor and delivery. Am J Obstet Gynecol
172:134-137, 1995
118. Lockwood CJ, Senyei AE, Dische MR, et al: Fetal fibronectin in cervi-
cal and vaginal secretions as a predictor of preterm delivery. N Engl
J Med 325:669-674, 1991
119. Brady K, Duff P, Yancey MK: Plasma fibronectin concentrations dur-
ing normal term labor. Obstet Gynecol 75:619-621, 1990
120. Grant A: Cervical cerclage to prolong pregnancy, in Chalmers I, Enkin
M, Keirse MJNC (eds): Effective Care in Pregnancy and Childbirth
(vol. 1). New York, NY, Oxford University Press, 1989, pp 633-646
121. Andersen HF, Nugent CE, Wanty SD, et al: Prediction of risk for
preterm delivery by ultrasonographic measurement of cervical length.
Am J Obstet Gynecol 163:859-867, 1990
122. Iams JD, Goldenberg RL, Meis PJ, et al: The length of the cervix and
the risk of spontaneous premature delivery. National Institute of
Child Health and Human Development Maternal Fetal Medicine Unit
Network. N Engl J Med 334:567-572, 1996
123. Heath VC, Southall TR, Souka AP, et al: Cervical length at 23 weeks of
gestation: prediction of spontaneous preterm delivery. Ultrasound
Obstet Gynecol 12:312-317, 1998
124. Taipale P, Hiilesmaa V: Sonographic measurement of uterine cervix at
18-22 weeks’ gestation and the risk of preterm delivery. Obstet Gy-
necol 92:902-907, 1998
125. Hassan SS, Romero R, Berry SM, et al: Patients with an ultrasono-
graphic cervical length ⱕ15 mm have nearly a 50% risk of early
spontaneous preterm delivery. Am J Obstet Gynecol 182:1458-1467,
2000
126. Kushnir O, Vigil DA, Izquierdo L, et al: Vaginal ultrasonographic
assessment of cervical length changes during normal pregnancy. Am J
Obstet Gynecol 162:991-993, 1990
Recurrent preterm birth
127. Okitsu O, Mimura T, Nakayama T, et al: Early prediction of preterm
delivery by transvaginal ultrasonography. Ultrasound Obstet Gynecol
2:402-409, 1992
128. Guzman ER, Rosenberg JC, Houlihan C, et al: A new method using
vaginal ultrasound and transfundal pressure to evaluate the asymp-
tomatic incompetent cervix. Obstet Gynecol 83:248-252, 1994
129. Guzman ER, Pisatowski DM, Vintzileos AM, et al: A comparison of
ultrasonographically detected cervical changes in response to trans-
fundal pressure, coughing, and standing in predicting cervical incom-
petence. Am J Obstet Gynecol 177:660-665, 1997
130. Guzman ER, Vintzileos AM, McLean DA, et al: The natural history of
a positive response to transfundal pressure in women at risk for cer-
vical incompetence. Am J Obstet Gynecol 176:634-638, 1997
131. Guzman ER, Forster JK, Vintzileos AM, et al: Pregnancy outcomes in
women treated with elective versus ultrasound-indicated cervical cer-
clage. Ultrasound Obstet Gynecol 12:323-327, 1998
132. Guzman ER, Mellon C, Vintzileos AM, et al: Longitudinal assessment
of endocervical canal length between 15 and 24 weeks’ gestation in
women at risk for pregnancy loss or preterm birth. Obstet Gynecol
92:31-37, 1998
133. Berghella V, Daly SF, Tolosa JE, et al: Prediction of preterm delivery
with transvaginal ultrasonography of the cervix in patients with high-
risk pregnancies: does cerclage prevent prematurity? Am J Obstet
Gynecol 181:809-815, 1999
134. Hassan SS, Romero R, Maymon E, et al: Does cervical cerclage prevent
preterm delivery in patients with a short cervix? Am J Obstet Gynecol
184:1325-1329, 2001
135. Macdonald R, Smith P, Vyas S: Cervical incompetence: the use of
transvaginal sonography to provide an objective diagnosis. Ultra-
sound Obstet Gynecol 18:211-216, 2001
136. Rust OA, Atlas RO, Reed J, et al: Revisiting the short cervix detected by
transvaginal ultrasound in the second trimester: why cerclage therapy
may not help. Am J Obstet Gynecol 185:1098-1105, 2001
137. To MS, Skentou C, Liao AW, et al: Cervical length and funneling at 23
weeks of gestation in the prediction of spontaneous early preterm
delivery. Ultrasound Obstet Gynecol 18:200-203, 2001
138. Berghella V, Haas S, Chervoneva I, et al: Patients with prior second-
trimester loss: prophylactic cerclage or serial transvaginal sonograms?
Am J Obstet Gynecol 187:747-751, 2002
139. Williams M, Iams JD: Cervical length measurement and cervical cerclage
to prevent preterm birth. Clin Obstet Gynecol 47:775-783, 2004
140. Althuisius SM, Dekker GA: A five century evolution of cervical incom-
petence as a clinical entity. Curr Pharm Des 11:687-697, 2005
141. Ramin KD, Ogburn PL Jr, Mulholland TA, et al: Ultrasonographic
assessment of cervical length in triplet pregnancies. Am J Obstet Gy-
necol 180:1442-1445, 1999
142. Souka AP, Heath V, Flint S, et al: Cervical length at 23 weeks in twins
in predicting spontaneous preterm delivery. Obstet Gynecol 94:450-
454, 1999
143. Guzman ER, Walters C, O’Reilly-Green C, et al: Use of cervical ultra-
sonography in prediction of spontaneous preterm birth in twin ges-
tations. Am J Obstet Gynecol 183:1103-1107, 2000
144. Guzman ER, Walters C, O’Reilly-Green C, et al: Use of cervical ultra-
sonography in prediction of spontaneous preterm birth in triplet ges-
tations. Am J Obstet Gynecol 183:1108-1113, 2000
145. To MS, Skentou C, Cicero S, et al: Cervical length at 23 weeks in
triplets: prediction of spontaneous preterm delivery. Ultrasound Ob-
stet Gynecol 16:515-518, 2000
146. Yang JH, Kuhlman K, Daly S, et al: Prediction of preterm birth by
second trimester cervical sonography in twin pregnancies. Ultrasound
Obstet Gynecol 15:288-291, 2000
147. Maymon R, Herman A, Jauniaux E, et al: Transvaginal sonographic
assessment of cervical length changes during triplet gestation. Hum
Reprod 16:956-960, 2001
148. Skentou C, Souka AP, To MS, et al: Prediction of preterm delivery in
twins by cervical assessment at 23 weeks. Ultrasound Obstet Gynecol
17:7-10, 2001
149. Vayssiere C, Favre R, Audibert F, et al: Cervical length and funneling
at 22 and 27 weeks to predict spontaneous birth before 32 weeks in
155
twin pregnancies: a French prospective multicenter study. Am J
Obstet Gynecol 187:1596-1604, 2002
150. Parikh MN, Mehta AC: Internal cervical os during the second half of
pregnancy. J Obstet Gynaecol Br Emp 68:818-821, 1961
151. Guzman ER, Mellon R, Vintzileos AM, et al: Relationship between
endocervical canal length between 15-24 weeks gestation and obstet-
ric history. J Matern Fetal Med 7:269-272, 1998
152. Andersen HF: Transvaginal and transabdominal ultrasonography of
the uterine cervix during pregnancy. J Clin Ultrasound 19:77-83,
1991
153. Romero R: Prenatal medicine: the child is the father of the man.
Prenatal Neonatal Med 1:8-11, 1996
154. Moinian M, Andersch B: Does cervix conization increase the risk of
complications in subsequent pregnancies? Acta Obstet Gynecol Scand
61:101-103, 1982
155. Kristensen J, Langhoff-Roos J, Wittrup M, et al: Cervical conization
and preterm delivery/low birth weight. A systematic review of the
literature. Acta Obstet Gynecol Scand 72:640-644, 1993
156. Raio L, Ghezzi F, Di Naro E, et al: Duration of pregnancy after carbon
dioxide laser conization of the cervix: influence of cone height. Obstet
Gynecol 90:978-982, 1997
157. Craig CJ: Congenital abnormalities of the uterus and foetal wastage. S
Afr Med J 47:2000-2005, 1973
158. Mangan CE, Borow L, Burtnett-Rubin MM, et al: Pregnancy outcome
in 98 women exposed to diethylstilbestrol in utero, their mothers, and
unexposed siblings. Obstet Gynecol 59:315-319, 1982
159. Ludmir J, Landon MB, Gabbe SG, et al: Management of the diethyl-
stilbestrol-exposed pregnant patient: a prospective study. Am J Obstet
Gynecol 157:665-669, 1987
160. Levine RU, Berkowitz KM: Conservative management and pregnancy
outcome in diethylstilbestrol-exposed women with and without gross
genital tract abnormalities. Am J Obstet Gynecol 169:1125-1129,
1993
161. Mays JK, Figueroa R, Shah J, et al: Amniocentesis for selection before
rescue cerclage. Obstet Gynecol 95:652-655, 2000
162. Romero R, Gonzalez R, Sepulveda W, et al: Infection and labor. VIII.
Microbial invasion of the amniotic cavity in patients with suspected
cervical incompetence: prevalence and clinical significance. Am J Ob-
stet Gynecol 167:1086-1091, 1992
163. Bengtsson LP: Cervical insufficiency. Acta Obstet Gynecol Scand 47:
7-35, 1968 (suppl 1)
164. Stys SJ, Clewell WH, Meschia G: Changes in cervical compliance at
parturition independent of uterine activity. Am J Obstet Gynecol 130:
414-418, 1978
165. Sherman AI: Hormonal therapy for control of the incompetent os of
pregnancy. Obstet Gynecol 28:198-205, 1966
166. Boggess KA, Madianos PN, Preisser JS, et al: Chronic maternal and
fetal Porphyromonas gingivalis exposure during pregnancy in rabbits.
Am J Obstet Gynecol 192:554-557, 2005
167. Romero R, Espinoza J, Mazor M: Can endometrial infection/inflam-
mation explain implantation failure, spontaneous abortion, and pre-
term birth after in vitro fertilization? Fertil Steril 82:799-804, 2004
168. Hassan S, Romero R, Hendler I, et al: A sonographic short cervix as the
only clinical manifestation of intra-amniotic infection. J Perinat Med
34:13-19, 2006
169. Blackmore-Prince C, Kieke B Jr, Kugaraj KA, et al: Racial differences in
the patterns of singleton preterm delivery in the 1988 National Ma-
ternal and Infant Health Survey. Matern Child Health J 3:189-197,
1999
170. Simhan HN, Bodnar LM: Prepregnancy body mass index, vaginal
inflammation, and the racial disparity in preterm birth. Am J Epide-
miol 163:459-466, 2006
171. Ananth CV, Misra DP, Demissie K, et al: Rates of preterm delivery
among Black women and White women in the United States over two
decades: an age-period-cohort analysis. Am J Epidemiol 154:657-
665, 2001
172. State-specific changes in singleton preterm births among black and
white women: United States, 1990 and 1997. MMWR Morb Mortal
Wkly Rep 49:837-840, 2000
156
173. Schieve LA, Handler A: Preterm delivery and perinatal death among
black and white infants in a Chicago-area perinatal registry. Obstet
Gynecol 88:356-363, 1996
174. Blackmore CA, Savitz DA, Edwards LJ, et al: Racial differences in the
patterns of preterm delivery in central North Carolina, USA. Paediatr
Perinat Epidemiol 9:281-295, 1995
175. Schulman ED: Preterm delivery among women in the South Carolina
Medicaid High Risk Channeling Project. J Health Care Poor Under-
served 6:352-367, 1995
176. Savitz DA, Dole N, Herring AH, et al: Should spontaneous and med-
ically indicated preterm births be separated for studying aetiology?
Paediatr Perinat Epidemiol 19:97-105, 2005
177. Merlino A, Laffineuse L, Collin M, et al: Impact of weight loss between
pregnancies on recurrent preterm birth. Am J Obstet Gynecol 195:
818-821, 2006
178. Yost NP, Owen J, Berghella V, et al: Effect of coitus on recurrent
preterm birth. Obstet Gynecol 107:793-797, 2006
179. Klebanoff MA, Nugent RP, Rhoads GG: Coitus during pregnancy: is it
safe? Lancet 2:914-917, 1984
180. Berghella V, Klebanoff M, McPherson C, et al: Sexual intercourse
association with asymptomatic bacterial vaginosis and Trichomonas
vaginalis treatment in relationship to preterm birth. Am J Obstet Gy-
necol 187:1277-1282, 2002
181. Kurki T, Ylikorkala O: Coitus during pregnancy is not related to
bacterial vaginosis or preterm birth. Am J Obstet Gynecol 169:1130-
1134, 1993
182. Read JS, Klebanoff MA: Sexual intercourse during pregnancy and
preterm delivery: effects of vaginal microorganisms. The Vaginal In-
fections and Prematurity Study Group. Am J Obstet Gynecol 168:514-
519, 1993
183. Brustman LE, Raptoulis M, Langer O, et al: Changes in the pattern of
uterine contractility in relationship to coitus during pregnancies at
low and high risk for preterm labor. Obstet Gynecol 73:166-168,
1989
184. Wagner NN, Butler JC, Sanders JP: Prematurity and orgasmic coitus
during pregnancy: data on a small sample. Fertil Steril 27:911-915,
1976
185. Meis PJ, Goldenberg RL, Mercer BM, et al: The preterm prediction
study: risk factors for indicated preterm births. Maternal-Fetal Medi-
cine Units Network of the National Institute of Child Health and
Human Development. Am J Obstet Gynecol 178:562-567, 1998
186. Ananth CV, Vintzileos AM: Maternal-fetal conditions necessitating a
medical intervention resulting in preterm birth. Am J Obstet Gynecol
195:1557-1563, 2006
187. Meis PJ, Goldenberg RL, Mercer B, et al: The preterm prediction
study: significance of vaginal infections. National Institute of Child
Health and Human Development Maternal-Fetal Medicine Units Net-
work. Am J Obstet Gynecol 173:1231-1235, 1995
188. Romero R, Mazor M, Wu YK, et al: Infection in the pathogenesis of
preterm labor. Semin Perinatol 12:262-279, 1988
189. Romero R, Sirtori M, Oyarzun E, et al: Infection and labor. V. Preva-
lence, microbiology, and clinical significance of intraamniotic infec-
tion in women with preterm labor and intact membranes. Am J Obstet
Gynecol 161:817-824, 1989
190. Romero R, Sepulveda W, Baumann P, et al: The preterm labor syn-
drome: Biochemical, cytologic, immunologic, pathologic, microbio-
logic, and clinical evidence that preterm labor is a heterogeneous
disease. Am J Obstet Gynecol 288, 1993
191. Romero R, Yoon BH, Mazor M, et al: The diagnostic and prognostic
value of amniotic fluid white blood cell count, glucose, interleukin-6,
and gram stain in patients with preterm labor and intact membranes.
Am J Obstet Gynecol 169:805-816, 1993
192. Romero R, Mazor M, Munoz H, et al: The preterm labor syndrome.
Ann N Y Acad Sci 734:414-429, 1994
193. Gomez R, Romero R, Nien JK, et al: Idiopathic vaginal bleeding during
pregnancy as the only clinical manifestation of intrauterine infection.
J Matern Fetal Neonatal Med 18:31-37, 2005
194. Espinoza J, Goncalves LF, Romero R, et al: The prevalence and clinical
S. Mazaki-Tovi et al.
significance of amniotic fluid ‘sludge’ in patients with preterm labor
and intact membranes. Ultrasound Obstet Gynecol 25:346-352, 2005
195. Jacobsson B, Mattsby-Baltzer I, Andersch B, et al: Microbial invasion
and cytokine response in amniotic fluid in a Swedish population of
women in preterm labor. Acta Obstet Gynecol Scand 82:120-128,
2003
196. Helmig BR, Romero R, Espinoza J, et al: Neutrophil elastase and
secretory leukocyte protease inhibitor in prelabor rupture of mem-
branes, parturition and intra-amniotic infection. J Matern Fetal Neo-
natal Med 12:237-246, 2002
197. Edwards RK, Clark P, Locksmith GJ, et al: Performance characteristics
of putative tests for subclinical chorioamnionitis. Infect Dis Obstet
Gynecol 9:209-214, 2001
198. Yoon BH, Chang JW, Romero R: Isolation of Ureaplasma urealyticum
from the amniotic cavity and adverse outcome in preterm labor. Ob-
stet Gynecol 92:77-82, 1998
199. Rizzo G, Capponi A, Vlachopoulou A, et al: The diagnostic value of
interleukin-8 and fetal fibronectin concentrations in cervical secre-
tions in patients with preterm labor and intact membranes. J Perinat
Med 25:461-468, 1997
200. Garry D, Figueroa R, Guero-Rosenfeld M, et al: A comparison of rapid
amniotic fluid markers in the prediction of microbial invasion of the
uterine cavity and preterm delivery. Am J Obstet Gynecol 175:1336-
1341, 1996
201. Rizzo G, Capponi A, Rinaldo D, et al: Interleukin-6 concentrations in
cervical secretions identify microbial invasion of the amniotic cavity in
patients with preterm labor and intact membranes. Am J Obstet Gy-
necol 175:812-817, 1996
202. Mazor M, Hershkovitz R, Ghezzi F, et al: Intraamniotic infection in
patients with preterm labor and twin pregnancies. Acta Obstet Gy-
necol Scand 75:624-627, 1996
203. Mazor M, Furman B, Wiznitzer A, et al: Maternal and perinatal out-
come of patients with preterm labor and meconium-stained amniotic
fluid. Obstet Gynecol 86:830-833, 1995
204. Baumann P, Romero R, Berry S, et al: Evidence of participation of the
soluble tumor necrosis factor receptor I in the host response to intra-
uterine infection in preterm labor. Am J Reprod Immunol 30:184-
193, 1993
205. Maymon E, Romero R, Pacora P, et al: A role for the 72 kDa gelatinase
(MMP-2) and its inhibitor (TIMP-2) in human parturition, premature
rupture of membranes and intraamniotic infection. J Perinat Med
29:308-316, 2001
206. Jacobsson B, Mattsby-Baltzer I, Andersch B, et al: Microbial invasion
and cytokine response in amniotic fluid in a Swedish population of
women with preterm prelabor rupture of membranes. Acta Obstet
Gynecol Scand 82:423-431, 2003
207. Park KH, Chaiworapongsa T, Kim YM, et al: Matrix metalloproteinase
3 in parturition, premature rupture of the membranes, and microbial
invasion of the amniotic cavity. J Perinat Med 31:12-22, 2003
208. Romero R, Yoon BH, Mazor M, et al: A comparative study of the
diagnostic performance of amniotic fluid glucose, white blood cell
count, interleukin-6, and gram stain in the detection of microbial
invasion in patients with preterm premature rupture of membranes.
Am J Obstet Gynecol 169:839-851, 1993
209. Romero R, Quintero R, Oyarzun E, et al: Intraamniotic infection and
the onset of labor in preterm premature rupture of the membranes.
Am J Obstet Gynecol 159:661-666, 1988
210. Romero R, Ghidini A, Mazor M, et al: Microbial invasion of the am-
niotic cavity in premature rupture of membranes. Clin Obstet Gy-
necol 34:769-778, 1991
211. Romero R, Baumann P, Gomez R, et al: The relationship between
spontaneous rupture of membranes, labor, and microbial invasion of
the amniotic cavity and amniotic fluid concentrations of prostaglan-
dins and thromboxane B2 in term pregnancy. Am J Obstet Gynecol
168:1654-1664, 1993
212. Kim YM, Chaiworapongsa T, Gomez R, et al: Failure of physiologic
transformation of the spiral arteries in the placental bed in preterm
premature rupture of membranes. Am J Obstet Gynecol 187:1137-
1142, 2002
Recurrent preterm birth
213. Kim YM, Bujold E, Chaiworapongsa T, et al: Failure of physiologic
transformation of the spiral arteries in patients with preterm labor and
intact membranes. Am J Obstet Gynecol 189:1063-1069, 2003
214. Lyall F: Mechanisms regulating cytotrophoblast invasion in normal
pregnancy and pre-eclampsia. Aust N Z J Obstet Gynaecol 46:266-
273, 2006
215. Robertson WB, Brosens I, Dixon HG: The pathological response of the
vessels of the placental bed to hypertensive pregnancy. J Pathol Bac-
teriol 93:581-592, 1967
216. Gerretsen G, Huisjes HJ, Elema JD: Morphological changes of the
spiral arteries in the placental bed in relation to pre-eclampsia and
fetal growth retardation. Br J Obstet Gynaecol 88:876-881, 1981
217. Sheppard BL, Bonnar J: Ultrastructural abnormalities of placental villi
in placentae from pregnancies complicated by intrauterine fetal
growth retardation: their relationship to decidual spiral arterial le-
sions. Placenta 1:145-156, 1980
218. Norwitz ER: Defective implantation and placentation: laying the blue-
print for pregnancy complications. Reprod Biomed Online 13:591-
599, 2006
219. Burton GJ, Jauniaux E: Placental oxidative stress: from miscarriage to
preeclampsia. J Soc Gynecol Investig 11:342-352, 2004
220. Redman CW: Immunological aspects of pre-eclampsia. Baillieres Clin
Obstet Gynaecol 6:601-615, 1992
221. Chwalisz K: The use of progesterone antagonists for cervical ripening
and as an adjunct to labour and delivery. Hum Reprod 9:131-161,
1994 (suppl 1)
222. Gorodeski IG, Geier A, Lunenfeld B, et al: Progesterone (P) receptor
dynamics in estrogen primed normal human cervix following P injec-
tion. Fertil Steril 47:108-113, 1987
223. Stjernholm Y, Sahlin L, Akerberg S, et al: Cervical ripening in humans:
potential roles of estrogen, progesterone, and insulin-like growth fac-
tor-I. Am J Obstet Gynecol 174:1065-1071, 1996
224. Johnson JW, Austin KL, Jones GS, et al: Efficacy of 17alpha-hy-
droxyprogesterone caproate in the prevention of premature labor.
N Engl J Med 293:675-680, 1975
225. Hill LM, Johnson CE, Lee RA: Prophylactic use of hydroxyprogester-
one caproate in abdominal surgery during pregnancy. A retrospective
evaluation. Obstet Gynecol 46:287-290, 1975
226. Breart G, Lanfranchi M, Chavigny C, et al: A comparative study of the
efficiency of hydroxyprogesterone caproate and of chlormadinone
acetate in the prevention of premature labor. Int J Gynaecol Obstet
16:381-384, 1979
227. Johnson JW, Lee PA, Zachary AS, et al: High-risk prematurity: pro-
gestin treatment and steroid studies. Obstet Gynecol 54:412-418,
1979
228. Hartikainen-Sorri AL, Kauppila A, Tuimala R: Inefficacy of 17 alpha-
hydroxyprogesterone caproate in the prevention of prematurity in
twin pregnancy. Obstet Gynecol 56:692-695, 1980
229. Hauth JC, LC III, Brekken AL, et al: The effect of 17 alpha-hy-
droxyprogesterone caproate on pregnancy outcome in an active-duty
military population. Am J Obstet Gynecol 146:187-190, 1983
230. Yemini M, Borenstein R, Dreazen E, et al: Prevention of premature
labor by 17 alpha-hydroxyprogesterone caproate. Am J Obstet Gy-
necol 151:574-577, 1985
231. Goldstein P, Berrier J, Rosen S, et al: A meta-analysis of randomized
control trials of progestational agents in pregnancy. Br J Obstet Gynae-
col 96:265-274, 1989
232. Daya S: Efficacy of progesterone support for pregnancy in women
with recurrent miscarriage. A meta-analysis of controlled trials. Br J
Obstet Gynaecol 96:275-280, 1989
233. Keirse MJ: Progestogen administration in pregnancy may prevent pre-
term delivery. Br J Obstet Gynaecol 97:149-154, 1990
234. Meis PJ, Aleman A: Progesterone treatment to prevent preterm birth.
Drugs 64:2463-2474, 2004
235. Noblot G, Audra P, Dargent D, et al: The use of micronized proges-
terone in the treatment of menace of preterm delivery. Eur J Obstet
Gynecol Reprod Biol 40:203-209, 1991
236. Iams JD: Supplemental progesterone to prevent preterm birth. Am J
Obstet Gynecol 188:303, 2003
157
237. Brancazio LR, Murtha AP, Heine RP: Prevention of recurrent preterm
delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med
349:1087-1088, 2003
238. Doggrell SA: Recurrent hope for the treatment of preterm delivery.
Expert Opin Pharmacother 4:2363-66, 2003
239. Einstein FH, Bracero LA: Progesterone and preterm birth. Am J Obstet
Gynecol 190:1798-1799, 2004
240. Keirse MJ: Progesterone and preterm: seventy years of “deja vu” or
“still to be seen”? Birth 31:230-235, 2004
241. Di Renzo GC, Mattei A, Gojnic M, et al: Progesterone and pregnancy.
Curr Opin Obstet Gynecol 17:598-600, 2005
242. Ness A, Dias T, Damus K, et al: Impact of the recent randomized trials
on the use of progesterone to prevent preterm birth: a 2005 follow-up
survey. Am J Obstet Gynecol 195:1174-1179, 2006
243. da Fonseca EB, Bittar RE, Carvalho MH, et al: Prophylactic adminis-
tration of progesterone by vaginal suppository to reduce the incidence
of spontaneous preterm birth in women at increased risk: a random-
ized placebo-controlled double-blind study. Am J Obstet Gynecol
188:419-424, 2003
244. Meis PJ, Klebanoff M, Thom E, et al: Prevention of recurrent preterm
delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med
348:2379-2385, 2003
245. Spong CY, Meis PJ, Thom EA, et al: Progesterone for prevention of
recurrent preterm birth: impact of gestational age at previous delivery.
Am J Obstet Gynecol 193:1127-1131, 2005
246. Caritis S, Rouse DJ: A randomized controlled trial of 17-hydroxipro-
gesterone caproate (17-OHPC) for the prevention of preterm birth in
twins. Am J Obstet Gynecol 6:S2, 2007
247. Dodd JM, Flenady V, Cincotta R, et al: Prenatal administration of
progesterone for preventing preterm birth. Cochrane Database Syst
Rev CD004947, 2006
248. Dodd JM, Crowther CA, Cincotta R, et al: Progesterone supplemen-
tation for preventing preterm birth: a systematic review and meta-
analysis. Acta Obstet Gynecol Scand 84:526-533, 2005
249. Sanchez-Ramos L, Kaunitz AM, Delke I: Progestational agents to pre-
vent preterm birth: a meta-analysis of randomized controlled trials.
Obstet Gynecol 105:273-279, 2005
250. Odibo AO, Stamilio DM, Macones GA, et al: 17alpha-hydroxyproges-
terone caproate for the prevention of preterm delivery: a cost-effec-
tiveness analysis. Obstet Gynecol 108:492-499, 2006
251. Advisory Committee for Reproductive Health Drugs Meeting. the safety
and efficacy of New Drug Application (NDA 21-945), proposed trade
name Gestiva, 17 alpha-hydroxyprogesterone caproate injection, 250
mg/mL, Adeza Biomedical, for the proposed indication prevention of
preterm delivery in women with a history of a prior preterm delivery.
Available at: http://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-
4227M1.pdf. Last accessed August 29, 2006
252. Christian MS, Brent RL, Calda P: Embryo–fetal toxicity signals for
17a-hydroxyprogesterone caproate in high-risk pregnancies: A review
of the non-clinical literature for embryo–fetal toxicity with progestins.
J Matern Fetal Neonatal Med 20:89-112, 2007
253. McDonald H, Brocklehurst P, Gordon A: Antibiotics for treating bac-
terial vaginosis in pregnancy. Cochrane Database Syst Rev
CD000262, 2007
254. Carey JC, Klebanoff MA, Hauth JC, et al: Metronidazole to prevent
preterm delivery in pregnant women with asymptomatic bacterial
vaginosis. National Institute of Child Health and Human Develop-
ment Network of Maternal-Fetal Medicine Units. N Engl J Med 342:
534-540, 2000
255. Carey JC, Klebanoff MA: What have we learned about vaginal infec-
tions and preterm birth? Semin Perinatol 27:212-216, 2003
256. Riggs MA, Klebanoff MA: Treatment of vaginal infections to prevent
preterm birth: a meta-analysis. Clin Obstet Gynecol 47:796-807,
2004
257. Odendaal HJ, Popov I, Schoeman J, et al: Preterm labour: is bacterial
vaginosis involved? S Afr Med J 92:231-234, 2002
258. Kekki M, Kurki T, Pelkonen J, et al: Vaginal clindamycin in preventing
preterm birth and peripartal infections in asymptomatic women with
158
bacterial vaginosis: a randomized, controlled trial. Obstet Gynecol
97:643-648, 2001
259. Lamont RF, Jones BM, Mandal D, et al: The efficacy of vaginal clinda-
mycin for the treatment of abnormal genital tract flora in pregnancy.
Infect Dis Obstet Gynecol 11:181-189, 2003
260. Kekki M, Kurki T, Kotomaki T, et al: Cost-effectiveness of screening
and treatment for bacterial vaginosis in early pregnancy among
women at low risk for preterm birth. Acta Obstet Gynecol Scand
83:27-36, 2004
261. Larsson PG, Fahraeus L, Carlsson B, et al: Late miscarriage and pre-
term birth after treatment with clindamycin: a randomised consent
design study according to Zelen. Br J Obstet Gynaecol 113:629-637,
2006
262. Morency AM, Bujold E: The effect of second-trimester antibiotic ther-
apy on the rate of preterm birth. J Obstet Gynaecol Can 29:35-44,
2007
263. Andrews WW, Goldenberg RL, Hauth JC, et al: Interconceptional
antibiotics to prevent spontaneous preterm birth: a randomized clin-
ical trial. Am J Obstet Gynecol 194:617-623, 2006
264. Espinoza J, Erez O, Romero R: Preconceptional antibiotic treatment to
prevent preterm birth in women with a previous preterm delivery.
Am J Obstet Gynecol 194:630-637, 2006
265. Briggs RM, Thompson WB Jr: Treatment of the incompetent cervix.
Obstet Gynecol 16:414-418, 1960
266. Seppala M, Vara P: Cervical cerclage in the treatment of incompetent
cervix. A retrospective analysis of the indications and results of 164
operations. Acta Obstet Gynecol Scand 49:343-346, 1970
267. Robboy MS: The management of cervical incompetence. UCLA expe-
rience with cerclage procedures. Obstet Gynecol 41:108-112, 1973
268. Crombleholme WR, Minkoff HL, Delke I, et al: Cervical cerclage: an
aggressive approach to threatened or recurrent pregnancy wastage.
Am J Obstet Gynecol 146:168-174, 1983
269. Lazar P, Gueguen S, Dreyfus J, et al: Multicentred controlled trial of
cervical cerclage in women at moderate risk of preterm delivery. Br J
Obstet Gynaecol 91:731-735, 1984
270. Rush RW, Isaacs S, McPherson K, et al: A randomized controlled trial
of cervical cerclage in women at high risk of spontaneous preterm
delivery. Br J Obstet Gynaecol 91:724-730, 1984
271. Final report of the Medical Research Council/Royal College of Obste-
tricians and Gynaecologists multicentre randomised trial of cervical
cerclage. MRC/RCOG Working Party on Cervical Cerclage. Br J Obstet
Gynaecol 100:516-523, 1993
272. Ayhan A, Mercan R, Tuncer ZS, et al: Postconceptional cervical cer-
clage. Int J Gynaecol Obstet 42:243-246, 1993
273. Golan A, Wolman I, Arieli S, et al: Cervical cerclage for the incompe-
tent cervical os. Improving the fetal salvage rate. J Reprod Med 40:
367-370, 1995
274. Olatunbosun OA, al Nuaim L, Turnell RW: Emergency cerclage com-
pared with bed rest for advanced cervical dilatation in pregnancy. Int
Surg 80:170-174, 1995
275. Guzman ER, Houlihan C, Vintzileos A, et al: The significance of trans-
vaginal ultrasonographic evaluation of the cervix in women treated
with emergency cerclage. Am J Obstet Gynecol 175:471-476, 1996
276. Kurup M, Goldkrand JW: Cervical incompetence: elective, emergent,
or urgent cerclage. Am J Obstet Gynecol 181:240-246, 1999
277. Althuisius SM, Dekker GA, van Geijn HP, et al: Cervical incompetence
S. Mazaki-Tovi et al.
prevention randomized cerclage trial (CIPRACT): study design and
preliminary results. Am J Obstet Gynecol 183:823-829, 2000
278. Althuisius SM, Dekker GA, Hummel P, et al: Final results of the
Cervical Incompetence Prevention Randomized Cerclage Trial
(CIPRACT): therapeutic cerclage with bed rest versus bed rest alone.
Am J Obstet Gynecol 185:1106-1112, 2001
279. Guzman ER, Ananth CV: Cervical length and spontaneous prematu-
rity: laying the foundation for future interventional randomized trials
for the short cervix. Ultrasound Obstet Gynecol 18:195-199, 2001
280. Novy MJ, Gupta A, Wothe DD, et al: Cervical cerclage in the second
trimester of pregnancy: a historical cohort study. Am J Obstet Gynecol
184:1447-1454, 2001
281. Althuisius SM, Dekker GA, van Geijn HP: Cervical incompetence: a
reappraisal of an obstetric controversy. Obstet Gynecol Surv 57:377-
387, 2002
282. To MS, Palaniappan V, Skentou C, et al: Elective cerclage vs. ultra-
sound-indicated cerclage in high-risk pregnancies. Ultrasound Obstet
Gynecol 19:475-477, 2002
283. Althuisius SM, Dekker GA, Hummel P, et al: Cervical incompetence
prevention randomized cerclage trial: emergency cerclage with bed
rest versus bed rest alone. Am J Obstet Gynecol 189:907-910, 2003
284. Berghella V, Bega G, Tolosa JE, et al: Ultrasound assessment of the
cervix. Clin Obstet Gynecol 46:947-962, 2003
285. Odibo AO, Elkousy M, Ural SH, et al: Prevention of preterm birth by
cervical cerclage compared with expectant management: a systematic
review. Obstet Gynecol Surv 58:130-136, 2003
286. To MS, Alfirevic Z, Heath VC, et al: Cervical cerclage for prevention of
preterm delivery in women with short cervix: randomised controlled
trial. Lancet 363:1849-1853, 2004
287. Belej-Rak T, Okun N, Windrim R, et al: Effectiveness of cervical cer-
clage for a sonographically shortened cervix: a systematic review and
meta-analysis. Am J Obstet Gynecol 189:1679-1687, 2003
288. Drakeley AJ, Roberts D, Alfirevic Z: Cervical stitch (cerclage) for pre-
venting pregnancy loss in women. Cochrane Database Syst Rev
CD003253, 2003
289. Drakeley AJ, Roberts D, Alfirevic Z: Cervical cerclage for prevention of
preterm delivery: meta-analysis of randomized trials. Obstet Gynecol
102:621-627, 2003
290. Rust OA, Atlas RO, Jones KJ, et al: A randomized trial of cerclage
versus no cerclage among patients with ultrasonographically detected
second-trimester preterm dilatation of the internal os. Am J Obstet
Gynecol 183:830-835, 2000
291. Higgins SP, Kornman LH, Bell RJ, et al: Cervical surveillance as an
alternative to elective cervical cerclage for pregnancy management of
suspected cervical incompetence. Aust N Z J Obstet Gynaecol 44:228-
232, 2004
292. Sakai M, Shiozaki A, Tabata M, et al: Evaluation of effectiveness of
prophylactic cerclage of a short cervix according to interleukin-8 in
cervical mucus. Am J Obstet Gynecol 194:14-19, 2006
293. Goldenberg RL, Klebanoff M, Carey JC, et al: Metronidazole treatment
of women with a positive fetal fibronectin test result. Am J Obstet
Gynecol 185:485-486, 2001
294. Shennan A, Crawshaw S, Briley A, et al: A randomised controlled trial
of metronidazole for the prevention of preterm birth in women posi-
tive for cervicovaginal fetal fibronectin: the PREMET Study. Br J Ob-
stet Gynaecol 113:65-74, 2006
Postpartum Hemorrhage:
A Recurring Pregnancy Complication
Michelle A. Kominiarek, MD,* and Sarah J. Kilpatrick, MD, PhD†

Postpartum hemorrhage (PPH) is a potentially life-threatening complication of both vaginal

and cesarean deliveries. Although many variables increase the chance for bleeding, a PPH
in a previous pregnancy is one of the greatest risk factors for recurrent PPH. A physiologic
explanation for this association is not known, but recurrent risk factors such as a retained
placenta or underlying medical disorders may account for the majority of recurrent PPH
cases. To reduce maternal morbidity and mortality, prevention of PPH in these patients is
critical. Steps to minimize hemorrhagic complications include the identification of high-risk
patients through a complete history, vigilant management of the third stage of labor, and
having uterotonic medications readily available in the delivery room. Patients with inherited
coagulopathies require individualized treatment, and their risks for bleeding extend beyond
the first 24 hours after delivery. Further studies are needed to determine whether the
administration of prophylactic measures such as prostaglandins decrease the PPH occur-
rence in high-risk patients.
Semin Perinatol 31:159-166 © 2007 Elsevier Inc. All rights reserved.

KEYWORDS postpartum hemorrhage, recurrence, risk factors, prevention, retained placenta,

coagulation disorders

A lthough the prevalence of postpartum hemorrhage

(PPH) varies between developing and developed coun-
tries, it is the leading cause of maternal morbidity and mor-
tality worldwide.1 The etiology of PPH falls into four main
categories: tone, tissue, trauma, and thrombosis disorders
(Table 1).
An estimated blood loss ⬎500 mL for a vaginal delivery
and ⬎1000 mL for a cesarean delivery defines early or pri-
mary PPH, which occurs within the first 24 hours after de-
livery. This affects 4% to 6% of pregnancies, and uterine
atony is the cause in 75% to 90% of cases.2,3 The subjective
description of blood loss at delivery limits the interpretation
of outcomes in any study of PPH. Comparisons of pre- and
postpartum hemoglobin or hematocrit may be more accu-
rate, and a decrease in hematocrit levels by 10% has also
defined PPH.2 Although a patient may meet blood loss crite-
ria for a PPH, blood transfusion rates are better estimates of
the hemorrhage severity. Postpartum anemia resulting in red
*Department of Obstetrics and Gynecology, Indiana University School of
Medicine, Indianapolis, IN.
†Department of Obstetrics and Gynecology, University of Illinois at Chi-
cago, Chicago, IL.
Address reprint requests to Michelle A. Kominiarek, MD, 550 North Uni-
versity Boulevard, Room 2440, Department of Obstetrics and Gynecol-
ogy, Indianapolis, IN 46202. E-mail: mkominia@iupui.edu
blood cell transfusion occurs in less than 1% and after a
cesarean delivery 1% to 7%.4
Late or secondary PPH is excessive vaginal bleeding occur-
ring between 24 hours and 6 weeks after delivery.5 Unlike the
quantitative definition of primary PPH, the definition of sec-
ondary PPH is more subjective and requires sufficient bleed-
ing to prompt the patient to seek medical attention. Second-
ary PPH is also referred to as persistent or delayed PPH and is
estimated to occur in 1% to 3% of all deliveries.6 Patients
usually present during the second postpartum week, and the
most common etiology is retained placenta fragments.
Although PPH occurs in women without risk factors, it is
often a predictable event. There are many risk factors sug-
gested for PPH (Table 2). These include an over-distended
uterus (multiple gestations, polyhydraminos, macrosomia),
primigravidity, chorioamnionitis, prolonged rupture of
membranes, fibroids, previous cesarean delivery, coagulation
disorders, anticoagulant therapy, labor induction and augmen-
tation, prolonged labors, preeclampsia, obesity, and general an-
esthetics.7-9 The relationship between grand multiparity (ⱖ5
vaginal births) and PPH has been disputed.2,3,8,10,11 In a univar-
iate analysis, delivery by a midwife was associated with a de-
creased risk of PPH compared with physician deliveries.2
One of the most important risk factors for PPH is a prior
PPH. However, in women without recurrent risk factors,

0146-0005/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. 159
doi:10.1053/j.semperi.2007.03.001
160
Table 1 Etiology of Postpartum Hemorrhage
Tone
Uterine atony
Uterine inversion
Tissue
Retained placenta or blood clots
Abnormal placentation (previa, accreta)
Connective tissue disorders (Ehlers-Danlos, Marfans)
Trauma
Lower genital tract lacerations
Uterine rupture
Thrombosis disorders
Coagulopathies
Inherited coagulation disorders
HELLP
DIC
Anticoagulant use
such as a previous twin gestation or chorioamnionitis, the
physiological explanation for the increased recurrence is un-
known. The focus of this article is to review data on the
recurrence of either primary or secondary PPH in future
pregnancies.
The Epidemiology
of Recurrent PPH
The objective of one of the earliest studies on recurrent PPH
was to determine whether a patient with a prior PPH was
more likely to hemorrhage during or after the third stage of a
subsequent labor. They included deliveries from 1936 to
1945 and defined PPH as an estimated blood loss ⬎600 mL.3
Of interest, cesareans, which were excluded from the analy-
sis, accounted for only 1.7% of the deliveries. Of the 12,243
women with vaginal births, the rate of PPH was 5.2%. How-
ever, the recurrence rate of PPH was 8.1%. In 68% (21/31) of
the repeated PPH cases, the cause was the same as the initial
hemorrhage, suggesting that recurrent risk factors may play a
role in PPH recurrence.3
In a study of recurring abnormalities of the third stage of
labor, 132 pregnancies with a known prior PPH were evalu-
ated.12 Twenty-three percent had a recurrent PPH (blood loss
⬎20 oz or required placenta extraction), and 22% had a
“potentially” abnormal third stage but precautions were
taken to prevent hemorrhage (placenta removed or given
ergometrine even though blood loss was ⬍20 oz). After one
PPH, there was a recurrence in 20/100 (20%) and in 7/25
(28%) after more than one PPH. Even if a normal third stage
accompanied a second pregnancy following a prior PPH, the
occurrence of PPH in the third pregnancy was still high, at
21%. There was a subset of 10 women whose risk factors for
PPH in the first pregnancy included nonrecurring complica-
tions such as general anesthesia, antepartum hemorrhage,
and multiple gestations. These women had a total of 17 sub-
sequent pregnancies without PPH.12
Changes in obstetrical practice, including routine use of
oxytocics and decreasing parity among women, prompted
M.A. Kominiarek and S.J. Kilpatrick
Hall and coworkers to study the recurrence risk for either
PPH (ⱖ500 mL blood loss at a singleton vaginal delivery) or
retained placenta (requiring manual removal) using a longi-
tudinal analysis which controlled for the patient’s reproduc-
tive history.11 The population included 6615 women who
delivered between 1967 and 1981. Although the original
paper did not reports statistics, for patients with two consec-
utive live births and a history of PPH in the first birth, the
odds ratio (OR) for a patient to have a subsequent PPH was
3.68 (95% CI 2.49-5.45). Interestingly, after a labor induc-
tion for the second birth, the risk of either recurrent PPH or
retained placenta was also significant at 19.6% (OR 2.89,
95% CI 2.89-5.28). Of 1106 women who had three consec-
utive live births, only one had a PPH three times. PPH oc-
curred in 13.5% in the second live birth in 375 women whose
first birth was preceded by an abortion. In summary, the
incidence of PPH and/or retained placenta in the next two
births was ⬎12% in the presence of a PPH and/or retained
placenta in the first birth. If there was no prior history of PPH
or retained placenta, the incidence of either one in the sub-
sequent pregnancy was ⬍6% unless there was an intervening
abortion.11 Although this study did not address pregnancy
complications or risk factors, patients with a prior PPH or
retained placenta were more likely to have a recurrence.
In a more recent case-control study of risk factors for PPH,
a previous PPH had an OR of 3.55 (95% CI 1.24-10.19) for
recurrent PPH (a hematocrit decrease of ⱖ10 points between
admission and postdelivery or by the need for blood transfu-
sion) in a multivariate analysis.2 A previous PPH was one of
the strongest predictors of recurrent PPH in their 17-factor
logistic regression model. An interesting aspect of the study
was their analysis of which hemorrhages might be predict-
able. A regression model of variables potentially known be-
fore the onset of labor, such as preeclampsia, parity, multiple
gestation, prior PPH, or previous cesarean delivery, derived
an adjusted OR for a previous PPH of 2.85 (95% CI 1.07-
7.60). Similar results were reported in a review of 19,476
deliveries at a tertiary care center. PPH (blood loss ⬎1000 mL
Table 2 Risk Factors for Postpartum Hemorrhage
Non-recurring
Primigravidity
Macrosomia
Polyhydraminos
Multiple gestations
Prolonged or augmented labors
Prolonged third stage
Chorioamnionitis
Antepartum hemorrhage
Operative deliveries
Recurring
Fibroids
Maternal obesity
Coagulation disorders
Previous cesarean
Specific medical/genetic disorders
ⴞGrand multiparity
Previous postpartum hemorrhage
Postpartum hemorrhage
Table 3 Recurrence Risk for Postpartum Hemorrhage Based
on Prior History and Risk Factors
Recurrence
Risk Factor Risk for PPH
Primary PPH3,11,12 8-28%
Secondary PPH14 19%†
Prior PPH treated with hypogastric artery 27%
ligation15
Prior PPH treated with uterine artery 0-100%
embolization16-18
Myomectomy as treatment for 0-1%
fibroids29,31
Uterine artery ligation as treatment for 6-19%
fibroids21,29,30,32,33
Von Willebrand disease46 80%
ⴱBaseline risks: primary PPH 4-6%, secondary PPH 1-3%.
†Risk is for recurrent secondary PPH.
and/or need for blood transfusion) occurred in 5.15% of
vaginal deliveries and a prior PPH had an OR of 2.2 (95% CI
1.7-2.9) for recurrent PPH.13
Although data are more limited, recurrent PPH has also
been described for secondary PPH. A retrospective study
from two hospitals in the United Kingdom identified 48 cases
of secondary PPH (0.73% incidence). Of the 32 multiparas, 6
(18.8%) also had a secondary PPH in a previous pregnancy.14
Over several decades, despite changing obstetrical care, a
previous PPH remains an important predictor of PPH in sub-
sequent deliveries. Clinicians should consider it as one of the
most important risk factors for PPH (Table 3).
Condition-Specific
Recurrence Risks for
Postpartum Hemorrhage
Previous Invasive Treatment for PPH
The primary management of PPH is medical: treatment with
uterotonic drugs. In most cases, this is successful; however,
surgical techniques to control bleeding, such as hypogastric
artery ligation, bilateral uterine artery ligation (O’Leary su-
tures), and the B-Lynch technique, are alternatives to hyster-
ectomy in cases of persistent bleeding. Arterial embolization
or balloon occlusion of radiographically identified bleeding
vessels is another nonsurgical option for continued hemor-
rhage. Patients requiring any of these treatments for either a
primary or secondary PPH were very likely to have suffered a
significant hemorrhage. The risk for recurrent PPH is of ut-
most concern in this group of patients.
Nizard and coworkers reported subsequent pregnancy
outcomes after bilateral hypogastric artery ligation in 43
women.15 Information was obtained either through chart re-
view or telephone interview. Of the 13 completed pregnan-
cies, two had a “threatened” PPH which was described as
“easily managed by manual evacuation of the placenta and
intravenous oxytocin,” and one patient had a PPH success-
fully treated with prostaglandins during a cesarean deliv-
161
ery.15 Although the numbers in this report are small, it is the
largest series of pregnancies reported after hypogastric artery
ligation, and a recurrence of 3/13 (27%) is significant.
Several studies have addressed the long-term effect of uterine
artery embolization (UAE) for the control of PPH on menses,
fertility, and future pregnancies. Thirteen full-term deliveries
after a previous bilateral UAE for a PPH were uncomplicated,
and no instances of recurrent PPH were reported.16,17
In both of these studies, the authors do not mention the
etiology or any high-risk factors for hemorrhage in the prior
pregnancy or if any prophylactic measures were taken to
prevent a recurrence. In contrast to these reassuring out-
comes, a separate study describes four patients who delivered
at term after a UAE for PPH in a prior pregnancy. Hemor-
rhage recurred in all of them, and two required a hysterec-
tomy for placenta accreta.18 The etiology for the prior PPH
was uterine atony in three cases and a placenta accreta in the
fourth. There are case reports of successful pregnancy out-
comes without hemorrhage after a B-lynch suture19 and a
B-lynch suture combined with hypogastric artery ligation.20
The small number of cases limits the interpretation of these
studies. The exact cause for the recurrent PPH is unclear, but
a devascularized myometrium after UAE may not allow the
uterus to adequately contract after a delivery.21 Other theo-
ries propose that a prior UAE may lead to abnormal implan-
tation and excessive trophoblast invasion in future pregnan-
cies.18 It may be reasonable to consider antenatal imaging in
these cases to assess the placental implantation site for evi-
dence of invasive placental disease. Although outcomes are
mixed, preparation for the recurrence of PPH and placenta
accreta is the best approach in these patients.
Fibroids
Fibroids may increase the chance for PPH. The mechanism
may be mediated through abnormal muscle contractility
leading to uterine atony. Although they have been cited as the
cause for many complications in pregnancy, including pre-
term labor, abruption, fetal growth restriction, dysfunctional
labor, and cesarean delivery, the studies regarding fibroids
and PPH are conflicting, where some show an increased
risk22-25 and others show no association.26-28
Although no investigations have directly evaluated the
PPH recurrence in the setting of uterine fibroids, a number of
studies have described PPH outcomes in patients treated with
either an interval myomectomy or UAE for symptomatic fi-
broids. In an analysis of 50 published cases of pregnancy after
UAE for fibroids, there were 2/23 (9%) occurrences of PPH.21
In a subsequent study, these authors compared pregnancy
outcomes in women treated with UAE to laparoscopic myo-
mectomy. The difference in the PPH rates did not reach sta-
tistical significance: 6% versus 1% (OR 6.3, 95% CI 0.6-71.8)
for the UAE and myomectomy groups, respectively.29 A sim-
ilar study surveyed women who became pregnant after a UAE
for fibroids. Of the 26 pregnancies, 16 continued beyond the
second trimester with a PPH rate of 19%.30 A review of 158
pregnancies after laparoscopic myomectomy reported no
cases of PPH, even though the cesarean delivery rate was
162
75%.31 Walker and coworkers described 56 completed preg-
nancies after UAE with 6 cases (18.2%) of PPH, which was
similar to the 3/18 (17%) rate of PPH described in the On-
tario Multicenter Trial, a large prospective study of women
undergoing UAE as an alternative to hysterectomy for symp-
tomatic fibroids.32,33
The recurrence of PPH in patients treated with either myo-
mectomy or UAE is difficult to interpret from these small
retrospective studies as the previous pregnancy outcomes
were not compared and PPH was not always defined. How-
ever, the available data suggest that the risk for PPH after
myomectomy is less than it is after UAE. Clearly, the removal
or treatment of fibroids before pregnancy does not eliminate
the risk of PPH, and in some instances, it appears to be
increased.
Retained Placenta
The incidence of retained placenta is 1% to 5.5%. The occur-
rence of PPH is significantly higher when there is a retained
placenta: 9.6% to 21.3% versus 2.3% to 3.5%.2,11 Retained
placenta is essentially another complication of the third stage
of labor, and many studies suggest that it is likely to recur in
future pregnancies. The medical records of 24,750 deliveries
over an 8-year period at a hospital in Norway were reviewed.
In summary, 165 women (0.6%) had a manual placenta re-
moval, and PPH occurred in 16 (10%).34 Of the 74 parous
women, 12 (16%) had a prior retained placenta. A similar
study of 134 patients with a retained placenta reported re-
currences in 23% to 32% of cases.35 In a case-control study of
113 women with a retained placenta, a prior retained pla-
centa was a risk factor for recurrence, OR 9.8 (95% CI 1.1-
85.5) in a logistic regression analysis.36 Although recurrence
of PPH has not been included in these reports, it is appropri-
ate to conclude that a history of retained placenta is a risk for
its recurrence and, therefore, PPH.
Uterine Inversion
Uterine inversion, a potentially life-threatening complication
of the third stage of labor, is associated with PPH in 94% of
cases.37,38 In most situations, appropriate management of the
third stage can prevent this occurrence. Because it compli-
cates few deliveries (about 1 in 2,500), the recurrence of
uterine inversion is difficult to quantify. A review of 56 preg-
nancies after a previous uterine inversion from various re-
ports suggested that it recurred in 33% of subsequent preg-
nancies.39 All recurrences were in those patients who did not
have surgery (Spinelli operation, Piccoli’s incision, combined
Piccoli-Borelius-Westermann method, Küstner operation,
Küstner-Borelius-Westermann operation, Hehrer’s method,
Duret’s Method, or Aveling repositor) to correct the inver-
sion. In contrast, a more recent review of 40 cases of uterine
inversion where PPH and blood transfusion rates were 65%
and 47.5%, respectively, reported no recurrences of uterine
inversion in 26 subsequent pregnancies.40 Although the rec-
ommended delivery route for patients with a prior uterine
inversion has never been described in the literature, recur-
rent uterine inversion is a rare event. If there are no contra-
M.A. Kominiarek and S.J. Kilpatrick
indications to vaginal delivery, then this should be the pre-
ferred route, but the placenta should be delivered without
excessive cord traction.
Von Willebrand Disease
A maternal coagulation disorder increases the risk for PPH.
Von Willebrand disease (VWD), the most common inherited
bleeding disorder, is found in 1% of the general population
regardless of ethnicity. Of the three categories, type 1 ac-
counts for 70% of all cases. Although factor VIII and von
Willebrand factor antigen (vWF:Ag) levels often improve in
pregnancy, women with VWD are at increased risk for PPH
because of the rapid decline in these levels after delivery.
Rates have been estimated as high as 16% to 29% for primary
PPH and 20% to 28% for secondary PPH,41-43 and transfusion
rates as high as 25% have been reported.44 PPH occurs more
commonly in type 2 and 3 patients and those with vWF:Ag
levels ⬍50% of normal at term.41,45
Of 75 women with type I VWD followed at 46 different
hemophilia treatment centers in the United States, 32% re-
ported PPH a total of 54 times, suggesting a high recurrence
rate in subsequent pregnancies.44 PPH recurred with succes-
sive pregnancies in 80% of patients who had type I VWD in
combination with PPH during the first birth.46
Kadir and coworkers described 67 women with VWD fol-
lowed at the Royal Free Hospital Hemophilia Centre from
1980 to 1996.44 The diagnosis of VWD was unknown in six
women with 11 pregnancies, and the diagnosis was later
established in two women when PPH occurred after an abor-
tion. In an analysis of 38 women with type I VWD, the diag-
nosis of VWD was unknown before presentation in a sub-
stantial number of cases, including 5 (13.1%) with PPH.47
This information leads one to question whether a patient’s
PPH is the consequence of an undiagnosed coagulation dis-
order such as VWD. The purpose of the study by Hundegger
and coworkers was to retrospectively evaluate patients with
PPH, defined as a drop in hemoglobin concentration of at
least 8% between delivery day and postpartum day 3, for type
1 VWD.48 Of the 3565 women who delivered in 1997, 14
women were eligible after excluding cesarean deliveries and
major birth injuries. These patients were contacted by phone
and returned for testing after stopping estrogen-containing
hormones for 2 months and aspirin and nonsteroidal antiin-
flammatory drugs for 1 week. Blood samples, collected on
days 5 to 7 of the menstrual cycle, were tested for vWF:Ag,
factors II, V, VII, VIII, IX, X, XI, and XII, prothrombin, acti-
vated partial thromboplastin time (aPTT), thrombin time,
fibrinogen, and for a complete blood count. None had abnor-
mal levels of vWF:Ag or other factor levels.48 Although the
numbers are small, this is the only study that evaluated pa-
tients for a coagulation disorder after having a PPH. The
prevalence of undiagnosed VWD in women with PPH is pres-
ently unknown.
It is critical that the obstetrician/gynecologist is aware of
the prevalence and clinical presentation of patients with
VWD. At the first prenatal visit or after a pregnancy-related
hemorrhage, it is necessary to obtain a bleeding history, es-
Postpartum hemorrhage
pecially with respect to menorrhagia and bleeding at the time
of surgical or dental procedures and injuries. A family history
of these occurrences is important to ascertain as well. Women
with unexplained significant menorrhagia should be tested
for VWD.49,50 In addition, acute postpartum or postoperative
hemorrhages that do not respond to customary treatment
should prompt an investigation of the patient’s coagulation
status (aPTT and PT). Prolonged values may be an indication
of an underlying bleeding disorder. Identifying a coagulation
disorder can improve morbidity from bleeding events and
avoid unnecessary surgery. Given the limited available data,
routine testing for VWD is currently not indicated in patients
whose bleeding history is only a primary PPH. It is not clear
whether VWD testing is of benefit for women having second-
ary PPH without evidence for retained placental fragments.
Future studies will hopefully provide more guidance in this
area.
Other Coagulation Disorders
Congenital coagulation disorders such as deficiencies in fac-
tors II, VII, and X are rare, but the obstetric experience of
these patients has been described in case series and literature
reviews. The majority of patients with deficiencies in either
factor II, VII, or X have excessive bleeding at delivery.51 Fac-
tor XI (Hemophilia C) deficiency is transmitted autosomally,
and the carrier rate is as high as 9% to 13% in the Ashkenazi
Jewish population.52,53 In 1 report, there were 3/14 (21%)
incidences of PPH in severely deficient women.54 In a sepa-
rate study, primary and secondary PPH complicated 4/25
(16%) and 6/25 (24%) of deliveries, respectively.42 Even car-
riers of hemophilia A (factor VIII deficiency) and B (factor IX
deficiency), have high rates of both primary (21.7%) and
secondary PPH (10.9%).55
Primary PPH has been reported in 2.1% to 7.7% of patients
treated with anticoagulants for either a thrombophilia or
thromboembolism during pregnancy.56,57 Immune thrombo-
cytopenic purpura is also associated with PPH in 24% to 27%
of cases.58,59
No study has addressed repeated PPH in these popula-
tions, including those with rare inherited coagulation disor-
ders. Assuming the conditions persist in subsequent preg-
nancies, recurrence is likely. Increased awareness among
clinicians of these less common causes is essential for optimal
outcome.
Connective Tissue Disorders
Compared with the general population, patients with con-
nective tissue disorders have higher occurrences of PPH. PPH
has been reported in up to 19% of patients with Ehlers-
Danlos syndrome, a disease characterized by abnormalities in
the metabolism and synthesis of collagen.60 The manifesta-
tions of Ehlers-Danlos syndrome, such as easy bruising and
bleeding tendencies, are attributed to poor connective tissue
support of the blood vessels and direct involvement of the
vessel wall, rather than defective platelet function or abnor-
mal coagulation.61 Consequently, uterine atony from inef-
fective contractions or lacerations of the perineum likely
163
explain the increased frequency of PPH. Other maternal
diseases associated with PPH include Gaucher (21-77%),
Osteogenesis Imperfecta (11%), and Marfans Syndrome (8-
21%).62-65 In patients with connective tissue disorders, the
treatment approach to PPH is similar in that uterotonic
agents are the first-line therapy. Uterine ruptures and inver-
sions in these patients may account for some of the instances
of PPH.61,64
Prevention of PPH Recurrence
PPH prevention remains an important issue in obstetrics. The
third stage of labor in women with a previous PPH history
should be managed vigilantly, with anticipation of a potential
hemorrhage. Patients should be appropriately counseled
about the potential for recurrence and its implications. Intra-
venous access during labor and sending a type and screen are
appropriate prophylactic measures. Management of the third
stage of labor includes administration of oxytocin after the
delivery of the fetus or placenta (the latter is a more common
practice in the United States) and expeditious placenta deliv-
ery. A study comparing the administration of oxytocin (20
units in 500 mL crystalloid intravenous bolus) either after the
delivery of the fetal shoulder or placenta showed no differ-
ence in PPH (5.4% versus 5.8%, OR 0.92, 95% CI 0.59-1.43)
or retained placenta (2.4% versus 1.6%, OR 1.49, 95% CI
0.72-3.08).66 At a cesarean, spontaneous delivery of the
placenta has been shown to decrease blood loss by 31%
compared with manual removal.67 Additional uterotonic
medications, such as misoprostol, 15-methyl PGF2␣,
methylergonovine, or dinoprostone, should be readily avail-
able in the delivery room.68 These recommendations are
summarized in Table 4.
One study investigated prostaglandin use in a double-
blinded randomized trial for women with a history of PPH,
defined as a blood loss ⬎1000 mL due to uterine atony after
a vaginal delivery.69 Exclusion criteria were preexisting coag-
ulation disorders, anticoagulation treatment, fibroids, multi-
ple pregnancies, hypertension, and an induction or augmen-
tation of labor. Patients were randomized either to the study
group (0.5 mg sulprostone after delivery of the shoulder fol-
lowed by placebo after placenta delivery) or control group
(5 U oxytocin after delivery of the shoulder followed by 0.2
mg ergometrine after placenta delivery). An additional inter-
vention in the third stage was “fundal pressure while holding
the lower segment of the uterus, after the first signs of pla-
Table 4 Steps to Prevent a Recurrent Postpartum Hemorrhage
Identify risk factors including bleeding history.
Provide intravenous access in labor.
Have blood products available (type and screen as an
initial measure).
Avoid an induction or augmentation of labor.
Vigilant management of the third stage of labor.
Have uterotonic medications readily available in the
delivery room.
Allow spontaneous delivery of the placenta at cesareans.
164
cental detachment.” The trial was stopped prematurely due
to concerns of the cardiovascular side effects of sulprostone,
but 69 cases were available for analysis. Although there was
no statistically significant difference between the 2 groups,
the rates of PPH (⬎500 mL blood loss) were high: 16/36
(44%) in the oxytocin/ergometrine group and 16/33 (47%)
in the sulprostone group.69 Although this study found no
benefit to sulprostone in a high-risk population, the conclu-
sion may have been different if enrollment had not been
stopped.
Autologous blood donation has been described for preg-
nant patients at high risk for hemorrhage.70-72 However, most
blood donated for these purposes is not transfused, and this
approach has not been shown to be cost effective in patients
without a placenta previa.73,74
There are no known preventive strategies for patients at
increased risk for a secondary PPH. Counseling patients on
how to recognize the signs and symptoms of excessive bleed-
ing may allow early diagnosis, but is unlikely to prevent
secondary PPH. Complete placental removal is the best pre-
vention strategy. Antenatal findings of an accessory placental
lobe may identify those patients who would benefit from
uterine exploration after delivery to confirm complete expul-
sion of placental tissue.
Patients with inherited coagulopathies require specialized
treatment during the peripartum. Bleeding risks in affected
individuals are difficult to predict given the wide variations in
clinical presentation. However, preparing for the recurrence
of PPH in these patients is the cornerstone of their medical
care. The risk for PPH is often directly correlated to the factor
level activity. Replacement of the specific deficient factor and
transfusion of other products, such as fresh frozen plasma or
DDAVP, can correct the problem, but transfusion of packed
red blood cells is still the treatment for acute anemia. Con-
sultation or comanagement with a hematologist or hemo-
philia treatment center and the hospital’s blood bank is ap-
propriate in these instances. In the event of an operative
delivery, meticulous hemostasis during surgery will also im-
prove outcomes.
Future Research
All further research on the topic of bleeding complications in
pregnancy should define PPH in a consistent manner so that
studies can be compared and generalized. A more objective
measurement of estimated blood loss, such as a comparison
of pre- and postpartum blood counts or calibrated drapes,
would be beneficial in prospective studies. Previous retro-
spective studies have identified the risk factors for PPH and
confirmed a significantly increased risk for recurrent PPH in
patients with a prior history. Determining an underlying
mechanism for recurrent PPH, such as a molecular or biolog-
ical marker, could identify those at risk and potentially give
insight to the prevention and treatment of PPH. It is possible
that a coagulation disorder, inherited or acquired, is respon-
sible for many cases of PPH without a clear cause. A more
comprehensive understanding of the frequency of these dis-
orders in cases of PPH is needed since these conditions re-
M.A. Kominiarek and S.J. Kilpatrick
quire special therapies. Randomized controlled trials of pro-
phylactic medications such as misoprostol for PPH in high-
risk patients are needed as well.
Conclusions
The key to management of PPH is early recognition and treat-
ment. The goals are to ultimately reduce maternal morbidity
and mortality. Predicting the risk of PPH is an essential part of
prenatal screening and assessment on labor and delivery and
is heavily dependent on an accurate history. During the
event, a cause either related to tone, tissue, trauma, or throm-
bosis should be identified and documented. Evidence shows
that a prior PPH increases the risk for recurrence, 8% to 28%
for primary PPH and 19% for secondary PPH. Although the
underlying pathophysiology is often unclear, repeated PPH
may be related to recurring identifiable risk factors. Prevention
of bleeding complications in the third stage centers on identifi-
cation of these risk factors and preparation for recurrence.
References
1. AbouZahr C: Global burden of maternal death and disability. Br Med
Bull 67:1-11, 2003
2. Combs CA, Murphy EL, Laros RK: Factors associated with postpartum
hemorrhage with vaginal birth. Obstet Gynecol 77:69-76, 1991
3. Doran JR, O’Brien SA, Randall JH: Repeated postpartum hemorrhage.
Obstet Gynecol 5:186-192, 1955
4. Jansen AJG, van Rhenen DJ, Steegers EAP, et al: Postpartum hemor-
rhage and transfusion of blood and blood components. Obstet Gynecol
Surv 60:663-671, 2005
5. Hoveyda F, MacKenzie IZ: Secondary postpartum haemorrhage: inci-
dence, morbidity and current management. Br J Obstet Gynaecol 108:
927-930, 2002
6. King PA, Duthie SJ, Dong ZG, et al: Secondary postpartum hemor-
rhage. Aust NZ J Obstet Gynaecol 29:394-398, 1989
7. Sheiner E, Sarid L, Levy A, et al: Obstetric risk factors and outcome of
pregnancies complicated with early postpartum hemorrhage: a popu-
lation-based study. J Matern Fetal Neo Med 18:149-154, 2005
8. Stones RW, Paterson CM, Saunders NJ: Risk factors for major obstetric
hemorrhage. Eur J Obstet Gynecol Reprod Biol 48:15-18, 1993
9. Brinsden PR, Clark AD: Postpartum haemorrhage after induced and
spontaneous labour. Br Med J 2:855-856, 1978
10. Tsu VD: Postpartum haemorrhage in Zimbabwe: a risk factor analysis.
Br J Obstet Gynaecol 100:327-333, 1993
11. Hall MH, Halliwell R, Carr-Hill R: Concomitant and repeated happen-
ings of complications of the third stage of labour. Br J Obstet Gynaecol
92:732-738, 1985
12. Dewhurst CJ, Dutton WAW: Recurrent abnormalities of the third stage
of labour. Lancet 273:764-767, 1957
13. Magann EF, Evans S, Hutchinson M, et al: Postpartum hemorrhage
after vaginal birth: an analysis of risk factors. Southern Med J 98:419-
422, 2005
14. Mongelli M: Secondary post-partum haemorrhage: a recurrent condi-
tion? Clin Exp Obstet Gynecol 19:97, 1992
15. Nizard J, Barrinque L, Frydman R, et al: Fertility and pregnancy out-
comes following hypogastric artery ligation for severe post-partum
haemorrhage. Hum Reprod 18:844-848, 2003
16. Descargues G, Tinlot FM, Douvrin F, et al: Menses, fertility and preg-
nancy after arterial embolization for the control of postpartum haem-
orrhage. Hum Reprod 19:339-343, 2004
17. Stancato-Pasik A, Mitty H, Richard HM, et al: Obstetric embolotherapy:
effect on menses and pregnancy. Radiology 204:791-793, 1997
18. Salomon LJ, De Tayrac R, Castaigne-Meary V, et al: Fertility and preg-
nancy outcome following pelvic arterial embolization for severe post-
partum haemorrhage. A cohort study. Hum Reprod 18:849-852, 2003
Postpartum hemorrhage
19. B-Lynch C, Coker A, Lawal AH, et al: The B-Lynch surgical technique
for the control of massive postpartum haemorrhage: an alternative to
hysterectomy? Five cases reported. Br J Obstet Gynaecol 104:372-375,
1997
20. Api M, Api O, Yayla M: Fertility after B-lynch suture and hypogastric
artery ligation. Fertil Steril 84:509, 2005
21. Goldberg J, Pereira L, Berghella V: Pregnancy after uterine artery em-
bolization. Obstet Gynecol 100:869-872, 2002
22. Qidwai GI, Caughey AB, Jacoby AF: Obstetric outcomes in women with
sonographically identified uterine leiomyomata. Obstet Gynecol 107:
376-382, 2006
23. Hasan F, Arumugam K, Sivanesaratnam V: Uterine leiomyomata in
pregnancy. Int J Gynecol Obstet 34:45-48, 1990
24. Winer-Muram HT, Muram D, Gilleison MS: Uterine myomas in preg-
nancy. J Can Assoc Radiol 35:168-170, 1984
25. Muram D, Gillieson MS, Walters JH, et al: Myomas of the uterus in
pregnancy: ultrasonographic follow-up. Am J Obstet Gynecol 138:16-
19, 1980
26. Roberts WE, Fulp KS, Morrison JC, et al: The impact of leiomyomas on
pregnancy. Aust NZ J Obstet Gynaecol 39:43-47, 1999
27. Vergani P, Ghidini A, Stobelt N, et al: Do uterine leiomyomas influence
pregnancy outcome. Am J Perinatol 11:356-358, 1994
28. Lev-Toaff AS, Coleman BG, Arger PH, et al: Leiomyomas in pregnancy:
a sonographic study. Radiology 164:375-380, 1987
29. Goldberg J, Pereira L, Berghella V, et al: Pregnancy outcomes after
treatment for fibromyomata: uterine artery embolization versus laparo-
scopic myomectomy. Am J Obstet Gynecol 191:18-21, 2004
30. Carpenter TT, Walker WJ: Pregnancy following uterine artery embo-
lisation for symptomatic fibroids: a series of 26 completed pregnancies.
Br J Obstet Gynaecol 112:321-325, 2005
31. Seracchioli R, Manuzzi L, Vianello F, et al: Obstetric and delivery out-
come of pregnancies achieved after laparoscopic myomectomy. Fertil
Steril 86:159-165, 2006
32. Walker WJ, McDowell SJ: Pregnancy after uterine artery emoblization
for leiomyomata: a series of 56 completed pregnancies. Am J Obstet
Gynecol 195:1266-1271, 2006
33. Pron G, Mocarski E, Bennett J, et al: Pregnancy after uterine artery
embolization for leiomyomata: the Ontario multicenter trial. Obstet
Gynecol 105:67-76, 2005
34. Tandberg A, Albrechtsen S, Iversen OE: Manual removal of the pla-
centa: incidence and clinical significance. Acta Obstet Gynecol Scand
78:33-36, 1999
35. VanBeekhuizen ME, Vierhout ME: Risk of recurrence of retained pla-
centa. Med Tijdschr Geneeskd 138:2149-2152, 1994
36. Titiz H, Wallace A, Voaklander DC: Manual removal of the placenta: a
case control study. Aust NZ J Obstet Gynaecol 41:41-44, 2001
37. Platt LD, Druzin ML: Acute puerperal inversion of the uterus. Am J
Obstet Gynecol 141:187-190, 1981
38. Watson P, Besch N, Bowes WA: Management of acute and subacute
puerperal inversion of the uterus. Obstet Gynecol 55:12-16, 1980
39. Miller NF: Pregnancy following inversion of the uterus. Am J Obstet
Gynecol 13:307-322, 1927
40. Baskett TF: Acute uterine inversion: a review of 40 cases. J Obstet
Gynaecol Can 24:953-956, 2002
41. Ramsahoye BH, Davies SV, Dasani H, et al: Obstetric management in
von Willebrand’s disease: a report of 24 pregnancies and a review of the
literature. Haemophilia 1:140-144, 1995
42. Kadir RA, Lee CA, Sabin CA, et al: Pregnancy in women with von
Willebrand’s disease or factor XI deficiency. Br J Obstet Gynaecol 105:
314-321, 1998
43. Greer IA, Lowe GDO, Walker JJ, et al: Haemorrhagic problems in
obstetrics and gynaecology in patients with congenital coagulopathies.
Br J Obstet Gynecol 98:909-918, 1991
44. Kirtava A, Crudder S, Dilley A, et al: Trends in clinical management of
women with von Willebrand disease: a survey of 75 women enrolled in
haemophilia treatment centres in the United States. Haemophilia 10:
158-161, 2004
45. Kujovich JL: Von Willebrand disease and pregnancy. J Thromb Hae-
most 3:246-253, 2005
165
46. Kouides PA, Phatak PD, Burkart P, et al: Gynaecological and obstetrical
morbidity in women with type I von Willebrand disease: results of a
patient survey. Haemophilia 6:643-648, 2000
47. Ragni MV, Bontempo FA, Hassett AC: von Willebrand disease and
bleeding in women. Haemophilia 5:313-317, 1999
48. Hundegger R, Husslein P, Berghammer P, et al: Postpartum bleeding
and von Willebrand’s disease. Arch Gynecol Obstet 266:160-162,
2002
49. American College of Obstetricians and Gynecologists Committee
Opinion #263. Von Willebrand’s disease in gynecologic practice, 2001
50. American College of Obstetricians and Gynecologists Committee
Opinion #329. Menstruation in girls and adolescents. Using the men-
strual cycle as a vital sign, 2006
51. Girolami A, Randi ML, Ruzzon E, et al: Pregnancy and oral contracep-
tives in congenital bleeding disorders of the vitamin K-dependent co-
agulation factors. Acta Haematol 115:58-63, 2006
52. Kadir RA, O’Connell NM, Economides DL, et al: Screening for factor XI
deficiency amongst pregnant women of Ashkenazi Jewish origin. Hae-
mophilia 12:625-628, 2006
53. Shpilherg O, Peretz H, Zivelin R, et al: One of the two common muta-
tions causing factor XI deficiency in Ashkenazi Jews (type 11) is also
prevalent in Iraqi Jews, who represent the ancient gene pool of Jews.
Blood 85:429-432, 1995
54. Bolton-Maggs PHB, Wan-Yin BY, McCraw AH, et al: Inheritance and
bleeding in factor XI deficiency. Br J Haemotol 69:521-528, 1988
55. Kadir RA, Economides DL, Braithwaite J, et al: The obstetric expe-
rience of carriers of haemophilia. Br J Obstet Gynaecol 104:803-
810, 1997
56. Maslovitz S, Many A, Landsberg JA, et al: The safety of low molecular
weight heparin therapy during labor. J Matern Fetal Neonat Med 17:
39-43, 2005
57. Rowan JA, McLintock C, Taylor RS, et al: Prophylactic and therapeutic
enoxaparin during pregnancy: Indications, outcomes, and monitoring.
Aust NZ J Obstet Gynecol 43:123-128, 2003
58. Borna S, Borna H, Zhazardoost S: Maternal and neonatal outcomes in
pregnant women with immune thrombocytopenic purpura. Arch Ira-
nian Med 9:115-118, 2006
59. Hwa HL, Wang TR, Huang SC, et al: Maternal and fetal outcome of
pregnant women with idiopathic thrombocytopenic purpura: retro-
spective analysis of 25 cases. J Formos Med Assoc 92:957-961, 1993
60. Lind J, Wallenburg HCS: Pregnancy and the Ehlers-Danlos syndrome:
a retrospective study in a Dutch population. Acta Obstet Gynecol Scand
81:293-300, 2002
61. Volkov N, Nisenblat V, Ohel G, et al: Ehlers-Danlos syndrome: insights
on obstetric aspects. Obstet Gynecol Surv 62:51-57, 2007
62. Rosnes JS, Sharkey MF, Veille JC, et al: Gaucher’s disease in pregnancy.
Obstet Gynecol Surv 51:549-558, 1996
63. Young BK, Gorstein F: Maternal osteogenesis imperfecta. Obstet Gy-
necol 31:461-470, 1968
64. Rahman J, al-Suleiman SA, Rahman MS, et al: Obstetric and gyneco-
logic complications in women with Marfan syndrome. J Reprod Med
48:723-728, 2004
65. Meijboom L, Drenthen W, Pieper PG, et al: Obstetric complications in
Marfan syndrome. Int J Card 110:53-59, 2006
66. Jackson KW, Allbert JR, Schemmer GK, et al: A randomized controlled
trial comparing oxytocin administration before and after placental de-
livery in the prevention of postpartum hemorrhage. Am J Obstet Gy-
necol 185:873-877, 2001
67. McCurdy C, Magann E, McCurdy C, et al: The effect of placental man-
agement at cesarean delivery on operative blood loss. Am J Obstet
Gynecol 167:1363, 1992
68. American College of Obstetricians and Gynecologists Practice Bulletin
#76. Postpartum hemorrhage, 2006
69. VanSelm M, Kanhai HHH, Keirse M: Preventing the recurrence of
atonic postpartum hemorrhage: a double-blind trial. Acta Obstet Gy-
necol Scand 74:270-274, 1995
70. Newton M, Mosey LM, Egli GE, et al: Blood loss during and immedi-
ately after delivery. Obstet Gynecol 17:9-18, 1961
166
71. McVay PA, Hoag RW, Hoag MS, et al: Safety and use of autologous
blood donation during the third trimester of pregnancy. Am J Obstet
Gynecol 160:1479-1488, 1989
72. Herbert WN, Owen HG, Collins ML: Autologous blood storage in
obstetrics. Obstet Gynecol 72:166-170, 1988
M.A. Kominiarek and S.J. Kilpatrick
73. Andres AL, Piacquadio KM, Resnik R, et al: A reappraisal of the need for
autologous blood donation in the obstetric patient. Am J Obstet Gy-
necol 163:1551-1552, 1990
74. Combs CA, Murphy EL, Laros RK: Cost-benefit analysis of autologous
blood donation in obstetrics. Obstet Gynecol 80:621-625, 1992
Thromboembolism in
Pregnancy: Recurrence and Its Prevention
Andra H. James, MD, MPH, Chad A. Grotegut, MD, Leo R. Brancazio, MD, and
Haywood Brown, MD

Fifteen to 25% of thromboembolic events in pregnancy are recurrent events. Women with
a history of thrombosis have a three- to fourfold increased risk of recurrence when they are
pregnant compared with when they are not. The risks are even higher postpartum. The rate
of recurrent venous thromboembolic events without anticoagulation is 2.4% to 12.2%,
whereas the rate with anticoagulation is 0% to 2.4%. Because the rates of recurrent
thromboembolism can be reduced with anticoagulation, women with a history of thrombo-
sis who are not on lifelong anticoagulation will likely require anticoagulation during
pregnancy, or at least during the postpartum period. Women who are already on lifelong
warfarin for the prevention of recurrent venous thromboembolism should be counseled
about the teratogenic effects of warfarin and offered the opportunity to be converted to
heparin before conception. During pregnancy, low-molecular-weight heparin, with fewer
side effects and a longer half-life, is generally preferred over unfractionated heparin.
Unfractionated heparin with its shorter half-life is generally preferred around the time of
delivery. Women on antiplatelet medication for prevention of arterial thromboembolism
may be converted to low-dose aspirin after conception and supplemented with low-dose
heparin or low-molecular-weight heparin during pregnancy. Because current recommen-
dations rely on case series and expert opinion, additional studies including randomized
trials might enhance our ability to prevent recurrent thromboembolism in pregnancy.
Semin Perinatol 31:167-175 © 2007 Elsevier Inc. All rights reserved.

KEYWORDS recurrent thromboembolism, venous thromboembolism, arterial thromboembo-

lism, deep vein thrombosis, pulmonary embolus, pregnancy

N ormal pregnancy is accompanied by an increase in clot-

ting factors.1,2 The resulting hypercoagulable state has
likely evolved to protect women from hemorrhage at the time
of miscarriage and childbirth. Indeed, in the developing
world, the leading cause of maternal death is still hemor-
rhage.3 In Western Europe and the United States, where
hemorrhage is successfully treated or prevented, the leading
cause of maternal death is thromboembolic disease.4 During
pregnancy, the risk of venous thromboembolism is increased
4-fold,5 and the risk of arterial thromboembolism, myocar-
dial infarction, and stroke is also increased 3- to 4-fold.6,7
Postpartum, the risk of venous thromboembolism is 20-fold
higher,5 and the risk of arterial thromboembolism (stroke) is
similarly elevated.8
Division of Maternal–Fetal Medicine, Department of Obstetrics and Gyne-
cology, Duke University Medical Center, Durham, NC.
Address reprint requests to Andra H. James, MD, MPH, Box 3967 DUMC,
Durham, NC 27710. E-mail: andra.james@duke.edu
The overall number of maternal deaths from thromboem-
bolism in pregnancy is approximately 3 per 1000 deliveries.
Two per 100,000 are due to arterial thrombosis and 1 per
100,000 are due to venous thrombosis.6,7,9 Although arterial
events account for more deaths, venous events are more com-
mon, accounting for 4 out of 5 thromboembolic events dur-
ing pregnancy.6,7,9 Eighty percent of these events are deep
vein thrombosis,9 and 20% are pulmonary emboli.9 The most
important risk factor for thrombosis during pregnancy is a
history of thrombosis.6,7,9,10
Epidemiology of
Recurrent Thrombosis
During pregnancy, the risk of thromboembolism is increased.
This is especially true for women with a history of thrombosis.
The risk of recurrent venous thromboembolism in pregnancy is
three- to fourfold higher compared with women not pregnant
(RR 3.5; 95% CI 1.6, 7.8),11 and the risk of a recurrent arterial

0146-0005/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. 167
doi:10.1053/j.semperi.2007.03.002
168 A.H. James et al.

Table 1 Rates of Recurrent Venous Thromboembolism (VTE) during Pregnancy and the Postpartum period with and without
Anticoagulation*
Rate of Recurrent VTE Rate of Recurrent VTE without
Study with Anticoagulation Anticoagulation
Badaracco and Vessey, 197491 6/30 (20%)† -
Tengborn et al., 198992
Pregnancy 3/20 (15%) 8/67 (12%)
Delivery and puerperium 2/57 (5%) 3/34 (11%)
Sanson et al., 199916 3/149 (1.5%)‡ -
Brill-Edwards et al., 200013
Pregnancy - 3/125 (2.4%)
Postpartum (95% CI: 0.2%, 6.9%)
Lepercq et al., 200117 3/125 (2.4%)§ -
Pabinger et al., 200514 7/574 (1.2%)¶ 8/197 (6.9%)
(95% CI: 1.6%, 10.6%)
De Stefano et al., 200615 0/87 (0%)# 19/155 pregnancies (12.2%)
(95% CI: 7.9%, 18.3%)
*When available, the rate in pregnancy compared to postpartum is specified.
†Anticoagulation consisted of heparin 5000 units subcutaneously twice daily.
‡Compiled from case series. Anticoagulation consisted of varying doses of varying low-molecular-weight heparins.
§Two of these events occurred in women who were not taking warfarin as prescribed and the third occurred in a woman 2 weeks after
anticoagulation was discontinued at 6 weeks postpartum.
¶357/574 (65%) received 20 mg of enoxaparin once daily and 217/574 (35%) received 40 mg of enoxaparin once daily.
#Anticoagulation consisted of heparin 5000 units subcutaneously two or three times daily or low-molecular-weight heparin 4000-5000
anti-factor X units/day.

thromboembolism is probably similarly increased. One study
found the relative risk of recurrent stroke to be 2.2 (95% CI 0.5,
17.5) during pregnancy and 9.7 (95% CI 1.2, 78.9) postpartum.12
Fifteen to 25% of thromboembolic events in pregnancy are
recurrent events. There are few data about the risk of recurrent
arterial events in pregnancy, but a study of 115 women with a
history of stroke (89 with a history of arterial ischemic stroke
and 26 with a history of cerebral vein thrombosis) found the
incidence of recurrent stroke during pregnancy to be 1.8%
(0.5%, 7.5%) and during the first 6 weeks postpartum to be
4.8% (0.6%, 35.9%). During pregnancy, most of the 115
women with a history of arterial thrombosis received antiplatelet
medication, and most of the women with a history of cerebral
vein thrombosis received no prophylaxis.12 Sanson and cowork-
ers found no recurrence of arterial thromboembolic events dur-
ing pregnancy among 8 women who received anticoagulation
with low-molecular-weight heparin.
There are several studies about the risk of recurrent venous
events in pregnancy (Table 1). In recent studies, the rate of
recurrent venous thromboembolism in women who did not
receive anticoagulation has been reported to range from 2.4% to
12.2%.13-15 In women who did receive anticoagulation, the rate
of recurrent venous thromboembolism has been reported to
range from 0% to 2.4%.13,16,17
Risk Factors for Recurrent
Thrombosis in Pregnancy
Although there are no data on the risk factors for recurrent
thrombosis in pregnancy, the risk factors are thought to be
the same as the overall risk factors for thrombosis. Aside from
a history of thrombosis, the most important risk factor for
venous thromboembolism is thrombophilia.9,10 From an
analysis of 14,335 records from the Nationwide Inpatient
Sample,9 other medical conditions that were statistically sig-
nificant risk factors for venous thromboembolism during
pregnancy were heart disease, sickle cell disease, lupus, obe-
sity, anemia, diabetes, hypertension, and smoking. Preg-
nancy and delivery complications that were associated with a
significantly increased risk of venous thromboembolism in-
cluded multiple gestation, hyperemesis, disorders of fluid,
electrolyte and acid-base balance, antepartum hemorrhage,
cesarean delivery, postpartum infection, postpartum hemor-
rhage, and transfusion (Table 2). In the same analysis, age
and race were also risk factors for venous thromboembolism.
The odds ratio (OR) for women age 35 and older was 2.1
(2.0, 2.3).9 When controlled for age, the OR for black women
was still 1.4 (1.2, 1.6).9 The risk factors for arterial thrombo-
embolism were similar to those for venous thromboembo-
lism, except for stroke, where hypertension OR ⫽ 6.1 (4.5,
8.1) and thrombocytopenia OR ⫽ 6.0 (1.5, 24.1) were more
important risk factors and myocardial infarction, where hy-
pertension OR ⫽ 11.7 (6.9, 21.2) and smoking OR ⫽ 6.2
(4.1, 9.5) were more important risk factors.
Thrombophilia is present in 20%18 to 40%15,19 of women
who experience venous thromboembolism during pregnancy
and the postpartum period. Both acquired and inherited
thrombophilia increase the risk, but it is not clear whether
thrombophilia increases the risk of recurrent venous events
during pregnancy and the postpartum period. In a systematic
review of the risk of recurrent venous thromboembolism in
individuals who were not pregnant, factor V Leiden and the
prothrombin gene mutation were found to confer a slightly
increased risk of recurrence with an OR for factor V Leiden of
Thromboembolism in pregnancy 169

Table 2 Medical Conditions and Complications of Pregnancy and Delivery Associated with an Increased Risk of Venous
Thromboembolism in Pregnancy9
Risk Factor Odds Ratio Confidence Interval
Medical conditions
Heart disease 7.1 6.2, 8.3
Sickle cell disease 6.7 4.4, 10.1
Lupus 8.7 5.8, 13.0
Obesity 4.4 3.4, 5.7
Anemia 2.6 2.2, 2.9
Diabetes 2.0 1.4, 2.7
Hypertension 1.8 1.4, 2.3
Smoking 1.7 1.4, 2.1
Complications of pregnancy and delivery
Multiple gestation 1.6 1.2, 2.1
Hyperemesis 2.5 2.0, 3.2
Fluid and electrolyte imbalance 4.9 4.1, 5.9
Antepartum hemorrhage 2.3 1.8, 2.8
Cesarean delivery 2.1 1.8, 2.4
Postpartum infection 4.1 2.9, 5.7
Postpartum hemorrhage 1.3 1.1, 1.6
Transfusion 7.6 6.2, 9.4

1.41 (1.14, 1.75) and for the prothrombin gene mutation of
1.72 (1.27, 2.31).20 In a separate study, protein C and S
deficiencies were found to confer only a slightly increased
risk of recurrence [OR 1.4 (0.9, 2.2)],21 but antithrombin
deficiency was found to confer approximately a twofold in-
creased risk of recurrence [OR 1.9 (1.0, 3.9)].21 This con-
firmed the findings of Christiansen and coworkers who also
found a twofold increased risk of recurrence with antithrom-
bin deficiency [OR 1.8 (0.9, 3.7)].22 Although homozygosity
for factor V Leiden, homozygosity for the prothrombin gene
mutation, and combined heterozygosity for both factors are
associated with a high risk of venous thromboembolism, it is
not clear whether they also confer an increased risk of recur-
rent thrombosis. Results are conflicting.22-24
Brill-Edwards and coworkers13 and Pabinger and co-
workers found that thrombophilia conferred an increased
risk of recurrent venous thromboembolism in pregnancy
and the postpartum period, but De Stefano and coworkers
did not.15 Nonetheless, any thrombophilic condition that
confers an increased risk of primary venous thromboem-
bolism above the background risk of recurrence in preg-
nancy of 2.4% to 12.2% will likely confer an increased risk
of recurrent thrombosis. This would be true for antithrom-
bin deficiency where the absolute risk of venous thrombo-
embolism in pregnancy has been reported to be as high as
40% to 68%,25-27 the antiphospholipid syndrome where
the absolute risk has been reported to be as high as 30%,28
and homozygosity for factor V Leiden where the risk has
been estimated to be 32%.29 Homozygosity, let alone het-
erozygosity, for the MTHFR C677T polymorphism does
not confer any increased risk of venous thromboembolism
in pregnancy29 and, therefore, would not be expected to
increase the risk of recurrent events.
Evaluation of the Woman
with a History of Thrombosis
Ideally, evaluation of the woman with a history of throm-
bosis should occur before conception, or at least early in
pregnancy. At the time of the evaluation, the clinician
obtains a history, reviewing any pertinent discharge sum-
maries, reports of imaging studies and laboratory reports,
and makes recommendations. In most cases, women can
be counseled that, although their history puts them at an
increased risk for recurrent thrombosis and, if they have
an underlying hypercoagulable state, an increased risk of
poor pregnancy outcome, these risks are manageable and
can be reduced with anticoagulation. Women with throm-
boembolic conditions that place them at a high risk of
maternal mortality may be best served by avoiding preg-
nancy. These conditions include mechanical heart
valves,30 chronic thromboembolic pulmonary hyperten-
sion, a history of recurrent thrombosis while fully antico-
agulated, and a history of myocardial infarction.
Usually, women with a history of thrombosis will re-
ceive anticoagulation during pregnancy. Women who are
on lifelong anticoagulation will be continued on full anti-
coagulation. They should be counseled about the terato-
genic effects of warfarin and offered the opportunity to be
converted to low-molecular-weight heparin before con-
ception. This can be done in collaboration with the phy-
sician who prescribes the patient’s anticoagulation.
Women who have not had a complete thrombophilia
workup should be offered appropriate testing. Whereas
the results of thrombophilia testing will not alter the gen-
eral recommendation for anticoagulation in pregnancy,
the results may alter the intensity of anticoagulation that is
prescribed.
170
Testing for Thrombophilia
Testing should include assays for both antiphospholipid an-
tibodies and inherited thrombophilia. Tests for inherited
thrombophilia should include assays for antithrombin (III),
protein C and protein S deficiency, as well as tests for factor V
Leiden and the prothrombin gene G20210A mutation. Since
protein S activity levels fall during pregnancy, a cutoff of 35%
is suggested.31,32 Antithrombin (III)33-38 and protein C39-42
levels do not change significantly during pregnancy, so lab-
oratory reference values can be used. Hyperhomocysteine-
mia is associated with thrombosis and possibly with poor
pregnancy outcome. Treatment of hyperhomocysteinemia is
with folic acid, vitamin B12, and vitamin B6.32 In the absence
of adequate folate levels, the methylene tetrahydrofolate re-
ductase (MTHFR) C677T polymorphism can result in ele-
vated homocysteine levels,43 but testing for the MTHFR
C677T polymorphism is not recommended, since even ho-
mozygosity for the polymorphism does not appear to be as-
sociated with an increased risk of thrombosis or poor preg-
nancy outcome.29 There is insufficient information on other
polymorphisms for genes in the folate metabolism pathway
to make specific testing recommendations. Even if the poly-
morphism were present, the treatment for hyperhomocys-
teinemia is folic acid, vitamin B12, and vitamin B6,32 which
can be adequately supplemented with prenatal vitamins. The
4G/5G PAI-1 polymorphism was associated with poor preg-
nancy outcome in one retrospective study,44 but has not been
studied sufficiently to be included in testing.
Tests for antiphospholipid antibodies include the lupus
anticoagulant, anticardiolipin antibodies, and anti-␤2 glyco-
protein I antibodies. The addition of anti-␤2 glycoprotein I
antibodies to the lupus anticoagulant and anticardiolipin an-
tibodies is recommended in an international consensus state-
ment to increase the sensitivity of the assays for the diagnosis
of the antiphospholipid syndrome.45
In summary, the recommended tests are:
● Lupus anticoagulant,
● Anticardiolipin antibodies,
● Anti-␤2 glycoprotein I antibodies,
● Activated protein C resistance with factor V Leiden if
abnormal,
● Prothrombin G20210A polymorphism,
● Protein C,
● Protein S, and
● Antithrombin (III).
Rationale for
Thromboprophylaxis in Women
with a History of Thrombosis
Pregnancy increases the risk of thrombosis fourfold,5 includ-
ing women who have a history of thrombosis.11 Women who
are not on lifelong anticoagulation will likely require antico-
agulation during pregnancy, or, at a minimum, during the
postpartum period. Although there are no randomized trials
of anticoagulation versus placebo for the prevention of recur-
A.H. James et al.
rent thrombosis in pregnancy, the risk of recurrent thrombo-
embolism is significantly reduced in women who receive
thromboprophylaxis.13,14,16,17
Women with a history of recurrent thrombosis will likely
be on lifelong anticoagulation and, because of warfarin’s ef-
fects on the fetus, will require conversion from warfarin to
unfractionated or low-molecular-weight heparin.
Options for
Anticoagulation
during Pregnancy
Unique aspects of anticoagulation in pregnancy include both
maternal and fetal issues. During pregnancy, there is an in-
crease in blood volume of 40% to 50%46 and an increase in
the volume of distribution. An increase in glomerular filtra-
tion46 results in increased renal excretion of drugs eliminated
by this route. Additionally, there is an increase in protein
binding of heparin. Since 45% of pregnancies are unin-
tended,47 many women do not realize they are pregnant dur-
ing the critical period for organogenesis, which is the 4th to
8th weeks after conception.48 Warfarin taken during this pe-
riod is associated with a 14.6% to 56% reported risk of mis-
carriage,49-55 and carries up to a 30% risk of congenital anom-
alies.49-51,53,55-58 Placental transfer of warfarin later in
pregnancy can result in fetal bleeding58,59 or still-
birth.49,51,53,54 Long-term sequelae include a 14% reported
risk of adverse neurological outcome60 and a 4% reported
risk of low intelligence quotient (IQ).60
The preferred agents for anticoagulation in pregnancy are
heparin compounds.61 Neither heparin62-64 nor low-molecu-
lar-weight heparin63,64 crosses the placenta, and both are
considered safe in pregnancy.17,65 Disadvantages of unfrac-
tionated heparin include the necessity of parenteral adminis-
tration, a 2% risk of major bleeding,65 a 2% to 36% risk of
reduced bone density,66-68 a 2% risk of vertebral fracture,69
and a risk of heparin-induced thrombocytopenia (HIT).61
Although the risk of HIT, a life- and limb-threatening com-
plication of heparin therapy, is low in pregnancy, and may be
lower than in nonpregnant patients,70 the actual risk is un-
known.61
There are few comparative studies in pregnancy, but in
nonpregnant patients, low-molecular-weight heparin has
been associated with fewer side effects than unfractionated
heparin.61 Although parenteral administration is still re-
quired, potential advantages of low-molecular-weight hepa-
rin over unfractionated heparin are less bleeding, a more
predictable response, a lower risk of HIT, a longer half-life,
and maybe less bone loss.61 However, in a recently completed
randomized trial of low-dose unfractionated heparin versus
enoxaparin for thromboprophylaxis in pregnancy, the inci-
dence of clinically significant bone loss was 2% to 2.5% and
was no different in women who took unfractionated heparin
compared with those who took enoxaparin.68 Another study
found that bone loss in women who took low-molecular-
weight heparin was approximately 4%, no different than
bone loss in controls.71 A definite advantage of enoxaparin,
Thromboembolism in pregnancy
Table 3 Protocols for Thromboprophylaxis in Pregnancy61,93
Bates et al., 200461
Unfractionated Heparin
Mini-dose “low dose” 5000 U sc q 12 hrs
Moderate-dose “low dose” q 12 hrs to target anti-factor Xa level of
0.1-0.3 U/ml
Adjusted dose “full dose” q12 hrs to target mid-interval aPTT in
therapeutic range
Low-Molecular-Weight Heparin
Prophylactic dose “low dose” Enoxaparin 40 mg qd
Dalteparin 5000 U qd
Tinzaparin 4500 U qd
Weight-adjusted dose “full dose” Enoxaparin 1 mg/kg bid or 1.5 mg/kg qd
Dalteparin 100 U/kg q 12 hrs or 200 U/kg
1 24 hrs
Tinzaparin 175 mg U/kg qd
and probably other low-molecular-weight heparins, over un-
fractionated heparin is less bruising at injection sites.72 A
disadvantage of low-molecular-weight heparin is that it is
more expensive. Also, its longer half-life may be a problem at
the time of delivery.
Long-term therapy with fondaparinux, a new selective fac-
tor Xa inhibitor, may result in less bone loss than either
unfractionated or low-molecular-weight heparin,73 but data
on the use of fondaparinux in pregnancy are limited. Al-
though Lagrange and coworkers74 observed no transplacen-
tal passage of fondaparinux using a perfused cotyledon
model, Dempfle and coworkers75 found transplacental pas-
sage of fondaparinux in five women who took it for 1 to 101
days because of heparin allergy. Antifactor Xa levels in um-
bilical cord plasma of newborns, however, were found to be
only one-tenth the concentration of maternal plasma, a con-
centration well below that required for effective anticoagula-
tion.75 Nonetheless, at the present time, there are insufficient
data to justify the routine use of fondaparinux in pregnancy,
but fondaparinux is probably still the anticoagulant of choice
in cases of severe cutaneous allergies or heparin-induced
thrombocytopenia in pregnancy.75,76
Protocols for Anticoagulation
in Pregnancy for Women
with a History of Thrombosis
Protocols for prevention of recurrent venous thromboembo-
lism are presented in Table 3. Full-dose (adjusted dose) an-
ticoagulation is recommended61,77 for women with either a
need for life-long anticoagulation or antiphospholipid syn-
drome with a history of thrombosis. Full-dose (adjusted
dose) or an intermediate or moderate dose is recom-
mended61,77 for women with either antithrombin (III) defi-
ciency or homozygosity for the factor V Leiden mutation, the
prothrombin gene G20210A mutation, or compound het-
erozygosity for both mutations. Low-dose anticoagulation is
recommended32,61 for women with a history of unprovoked
171
Duke Protocol93
5000 U sc q 12hrs <8 weeks
7500 U sc q 12 hrs 8-28 weeks
10,000 U sc q 12 hrs >28 weeks
q 8 or12 hrs to target mid-interval aPTT in
therapeutic range
Enoxaparin 40 mg qd or 30 mg bid before
28 weeks then
Enoxaparin 40 mg bid after 28 weeks
Enoxaparin 1 mg/kg bid with target of
antifactor Xa level of 0.5-1.0
thrombosis. Although in one series women with transient
risk factors had a rate of recurrence similar to that of other
women with a history of thrombosis,14 close observation (as-
sessment of signs and symptoms of thrombosis at routine
prenatal visits) may be an option for women with a history of
thrombosis in the setting of transient risk factors such as
injury or immobility.61 Nonetheless, if these women do not
receive anticoagulation during pregnancy, they should be
considered for thromboprophylaxis during the first 2 to 6
weeks postpartum.
There are few protocols for thromboprophylaxis of arterial
thromboembolism. Currently, there is no consensus regard-
ing the best protocol for women with a history of stroke78 or
myocardial infarction. Outside of pregnancy, most of these
women are on an antiplatelet agent. It is our practice to dis-
continue full-dose antiplatelet agents and prescribe aspirin
81 mg per day along with low-dose unfractionated or low-
molecular-weight heparin to counteract the hypercoagulabil-
ity of pregnancy.
Initiating Anticoagulation
during Pregnancy
Normal pregnancy is accompanied by increased concentra-
tions of factors VII, VIII, X, and von Willebrand factor and by
pronounced increases in fibrinogen.1 Factors II, V, and IX are
relatively unchanged.1 Free protein S, the active, unbound
form, is decreased during pregnancy secondary to increased
levels of its binding protein, the complement component
C4b.1 Plasminogen activator inhibitor type 1 (PAI-1) levels
are increased fivefold.1 Levels of PAI-2, produced by the pla-
centa, increase dramatically during the third trimester.2
These changes, which may not return to baseline until more
than 8 weeks postpartum,1 begin with conception. So does
the risk of thrombosis.10,14,79
Women on lifelong anticoagulation should be converted
from warfarin to low-molecular-weight heparin before preg-
nancy or as soon as possible after conception. The problem
172 A.H. James et al.

with conversion before pregnancy is the inconvenience and incision at the time of cesarean delivery. A vertical midline
discomfort of parenteral administration of heparins and the incision, which is made in a watershed area and does not
risks associated with their long-term use. The problem with involve dissection of the rectus muscles off of the fascia, may
conversion after conception is that the half-life of warfarin is be associated with less bleeding.
36 to 42 hours80 and it may remain in the maternal circula-
tion for several days, increasing the risk of miscarriage and
congenital anomalies. Only a few women are candidates for Postpartum Management
warfarin rather than heparins during pregnancy. Candidates
Pneumatic compression devices are left in place until the
include women with mechanical heart valves30 and certain
patient is ambulatory and until anticoagulation is restarted
other unusual conditions.
after delivery. To minimize bleeding complications, resump-
Women who are not on lifelong anticoagulation, but are
tion of anticoagulation should be postponed until 12 hours
candidates for thromboprophylaxis in pregnancy, should
after vaginal delivery, 12 hours after epidural removal, or 24
start soon after conception. An exception is women who will
hours after cesarean delivery. After the risk of postpartum
be undergoing ovulation induction. Because hormone ther-
hemorrhage has lessened (2 or more weeks after delivery),
apy, including clomiphene, increases the risk of thrombo-
unless a woman prefers to remain on unfractionated or low-
sis,81 these women should begin anticoagulation at the time
molecular-weight heparin, she may be bridged to warfarin
they start ovulation induction.
for the remainder of the 6-week postpartum period. Women
Because HIT manifests within the first 5 to 15 days of
who have had a thrombotic event during the current preg-
exposure to heparins,82 platelet counts may be monitored for
nancy should remain on warfarin for at least another 3 to 6
the first 2 to 3 weeks after initiation of therapy. Although
months after delivery. Women on lifelong anticoagulation
platelet counts usually drop by 10% in pregnancy83 and
will remain on warfarin indefinitely. Although warfarin is
thrombocytopenia affects up to 10% of all pregnancies,83 HIT
contraindicated during pregnancy, it is not contraindicated
still must be considered in women who develop thrombocy-
during breastfeeding. In a study of the transfer of warfarin
topenia after starting heparin or low-molecular-weight hep-
into breast milk, less than 25 ng of warfarin was detected per
arin.
mL.86 The American Academy of Pediatrics Committee
on Drugs supports breastfeeding for women who take
warfarin.87
Management At the present time, since there are no data about whether
at the Time of Delivery fondaparinux enters breast milk, fondaparinux should not be
used routinely in women who are breastfeeding, but
Women are often converted from low-molecular-weight hep-
fondaparinux is an option for women who are not breastfeed-
arin to unfractionated heparin at 36 to 37 weeks of gestation
ing. Fondaparinux, a selective factor Xa inhibitor, may be
or sooner if there is preterm labor, preeclampsia, fetal (intra-
used until a woman is bridged to warfarin. For women who
uterine) growth restriction, oligohydramnios, or other evi-
have to be fully anticoagulated for only 6 weeks postpartum,
dence of imminent delivery. The purpose of converting
an advantage of fondaparinux over warfarin is that it does not
women to the shorter-acting unfractionated heparin has less
require monitoring. In addition, it requires only daily, as
to do with any risk of bleeding at the time of delivery, but
opposed to twice-daily, dosing.
rather the rare possibility of an epidural or spinal hematoma
Women who are not breastfeeding and who will be on
with regional anesthesia.84 Due to this possibility, anesthesi-
lifelong anticoagulation should be allowed to take estrogen-
ologists usually will not place a regional anesthetic if a
containing contraceptives, but these are contraindicated for
woman has received low-molecular-weight heparin within
the woman who will discontinue anticoagulation at 6 weeks
12 to 24 hours. Because of the benefits of regional analgesia
postpartum. Although progestins may increase the levels of
and anesthesia over other analgesia and anesthesia for labor
certain coagulation factors, progestin-only contraceptives
and delivery,84 every effort should be made to ensure that a
have not been found to increase the risk of thrombosis and
woman has not received low-molecular-weight heparin
are, therefore, generally allowed.88
within 12 to 24 hours of needing a regional anesthetic. De-
pending on the risk of thrombosis, unfractionated heparin
should be held for 6 to 24 hours before delivery. Should a
woman go into labor while taking unfractionated heparin,
Fetal Surveillance
the heparin will usually clear within 6 hours. Reversal of Hypercoagulability, as manifested by a history of thrombo-
heparin is rarely required and is not indicated for low-dose embolism, may alter normal hemostasis and increase the like-
heparin. Although the use of pneumatic compression devices lihood of poor pregnancy outcome, including abruption,
for the prevention of pregnancy-related thrombosis has not stillbirth, fetal growth restriction, and preeclampsia.29 Al-
been studied, extrapolating from perioperative data,85 the though anticoagulation may improve pregnancy outcome,89
placement of pneumatic compression devices in labor or be- a plan for fetal surveillance should still be implemented.90
fore cesarean delivery is recommended. In the woman who is This would include periodic ultrasounds for fetal growth,
being aggressively anticoagulated, consideration should be fetal testing in the last month or two of pregnancy, and con-
given to entering the abdomen through a vertical midline sideration of delivery by 39 weeks gestation.
Thromboembolism in pregnancy
Implications for
Family Members
Family members should be informed about any inherited
thrombophilia and what the specific condition is (such as
factor V Leiden or protein S deficiency). Family members
who inherit the same genes may be at an increased risk of
developing venous thromboembolism. Obviously, first-de-
gree relatives are at greater risk compared with extended
family members, but extended family members may also
benefit from the information. Family members should in-
form their health care providers and together they can decide
whether testing for thrombophilia is indicated.
Knowledge Gaps
and Future Research
Although there are several case series, there are no random-
ized trials of thromboprophylaxis for the prevention of recur-
rent venous thromboembolism in pregnant women. Guide-
lines rely on expert opinion. Randomized trials would be
helpful. As pointed out, even though arterial thromboembo-
lism may result in more deaths, there is even less information
about thromboprophylaxis for the prevention of recurrent
arterial thromboembolism. Even case series would be help-
ful. Since these events are rare, registries may be required.
Summary
The risk of recurrent venous and arterial thromboembolism
is high during pregnancy. The rate of recurrent venous
thromboembolism in women not receiving anticoagulation
has been reported to range from 2.4% to 12.2%. In women
receiving anticoagulation, the rate of recurrent venous
thromboembolism ranges from 0% to 2.4%. Women with a
history of arterial thromboembolism probably experience
similar reductions in the rate of recurrence with anticoagula-
tion. Therefore, anticoagulation with one of the various hep-
arin compounds is generally recommended in pregnancy
even for women who are not on lifelong anticoagulation.
Women who are taking warfarin can be offered the opportu-
nity to be converted to low-molecular-weight heparin before
conception. To minimize bleeding complications, resump-
tion of anticoagulation should be postponed until 12 to 24
hours after delivery. After the risk of postpartum hemorrhage
has subsided, women may be bridged to warfarin. Because
current recommendations rely on case series and expert
opinion, additional studies including randomized trials
might enhance our ability to prevent recurrent thromboem-
bolism in pregnancy.
References
1. Bremme KA: Haemostatic changes in pregnancy. Best Pract Res Clin
Haematol 16:153-168, 2003
2. Medcalf RL, Stasinopoulos SJ: The undecided serpin. The ins and outs
of plasminogen activator inhibitor type 2. FEBS J 272:4858-4867, 2005
3. Postpartum hemorrhage. From the Prevention of Postpartum Hemor-
rhage Initiative Web Site. Office of Health, Infectious Diseases and
173
Nutrition, Bureau for Global Health, USAID. Available at:
http://www.pphprevention.org/pph.php. Last accessed January 28,
2007.
4. Chang J, Elam-Evans LD, Berg CJ, et al: Pregnancy-related mortality
surveillance: United States, 1991–1999. MMWR Surv Summ 52:1-8,
2003
5. Heit JA, Kobbervig CE, James AH, et al: Trends in the incidence of
venous thromboembolism during pregnancy or postpartum: a 30-year
population-based study. Ann Intern Med 143:697-706, 2005
6. James AH, Bushnell CD, Jamison MG, et al: Incidence and risk factors
for stroke in pregnancy and the puerperium. Obstet Gynecol 106:509-
516, 2005
7. James AH, Jamison MG, Biswas MS, et al: Acute myocardial infarction
in pregnancy: a United States population-based study. Circulation 113:
1564-1571, 2006
8. Kittner SJ, Stern BJ, Feeser BR, et al: Pregnancy and the risk of stroke.
N Engl J Med 335:768-774, 1996
9. James AH, Jamison MG, Brancazio LR, et al: Venous thromboembolism
during pregnancy and the postpartum period: incidence, risk factors,
and mortality. Am J Obstet Gynecol 194:1311-1315, 2006
10. James AH, Tapson VF, Goldhaber SZ: Thrombosis during pregnancy
and the postpartum period. Am J Obstet Gynecol 193:216-219, 2005
11. Pabinger I, Grafenhofer H, Kyrle PA, et al: Temporary increase in the
risk for recurrence during pregnancy in women with a history of ve-
nous thromboembolism. Blood 100:1060-1062, 2002
12. Lamy C, Hamon JB, Coste J, et al: Ischemic stroke in young women: risk
of recurrence during subsequent pregnancies. French Study Group on
Stroke in Pregnancy. Neurology 55:269-274, 2000
13. Brill-Edwards P, Ginsberg JS, Gent M, et al: Safety of withholding
heparin in pregnant women with a history of venous thromboembo-
lism. Recurrence of Clot in This Pregnancy Study Group. N Engl J Med
343:1439-1444, 2000
14. Pabinger I, Grafenhofer H, Kaider A, et al: Risk of pregnancy-associated
recurrent venous thromboembolism in women with a history of venous
thrombosis. J Thromb Haemost 3:949-954, 2005
15. De Stefano V, Martinelli I, Rossi E, et al: The risk of recurrent venous
thromboembolism in pregnancy and puerperium without antithrom-
botic prophylaxis. Br J Haematol 135:386-391, 2006
16. Sanson BJ, Lensing AW, Prins MH, et al: Safety of low-molecular-
weight heparin in pregnancy: a systematic review. Thromb Haemost
81:668-672, 1999
17. Lepercq J, Conard J, Borel-Derlon A, et al: Venous thromboembolism
during pregnancy: a retrospective study of enoxaparin safety in 624
pregnancies. Br J Obstet Gynaecol 108:1134-1140, 2001
18. Dilley A, Austin H, El-Jamil M, et al: Genetic factors associated with
thrombosis in pregnancy in a United States population. Am J Obstet
Gynecol 183:1271-1277, 2000
19. Gerhardt A, Scharf RE, Beckmann MW, et al: Prothrombin and factor V
mutations in women with a history of thrombosis during pregnancy
and the puerperium. N Engl J Med 342:374-380, 2000
20. Ho WK, Hankey GJ, Quinlan DJ, et al: Risk of recurrent venous throm-
boembolism in patients with common thrombophilia: a systematic re-
view. Arch Intern Med 166:729-736, 2006
21. De Stefano V, Simioni P, Rossi E, et al: The risk of recurrent venous
thromboembolism in patients with inherited deficiency of natural an-
ticoagulants antithrombin, protein C and protein S. Haematologica
91:695-698, 2006
22. Christiansen SC, Cannegieter SC, Koster T, et al: Thrombophilia, clin-
ical factors, and recurrent venous thrombotic events. J Am Med Assoc
293:2352-2361, 2005
23. De StefanoV, Martinelli I, Mannucci PM, et al: The risk of recurrent
deep venous thrombosis among heterozygous carriers of both factor V
Leiden and the G20210A prothrombin mutation. N Engl J Med 341:
801-806, 1999
24. Lindmarker P, Schulman S, Sten-Linder M, et al: The risk of recurrent
venous thromboembolism in carriers and non-carriers of the G1691A
allele in the coagulation factor V gene and the G20210A allele in the
prothrombin gene. DURAC Trial Study Group. Duration of Anticoag-
ulation. Thromb Haemost 81:684-689, 1999
174
25. Pabinger I, Schneider B: Thrombotic risk in hereditary antithrombin
III, protein C, or protein S deficiency. A cooperative, retrospective
study. Gesellschaft fur Thrombose- und Hamostaseforschung (GTH)
Study Group on Natural Inhibitors. Arterioscler Thromb Vasc Biol
16:742-748, 1996
26. Conard J, Horellou MH, Van Dreden P, et al: Thrombosis and preg-
nancy in congenital deficiencies in AT III, protein C or protein S: study
of 78 women. Thromb Haemost 63:319-320, 1990
27. Hellgren M, Tengborn L, Abildgaard U: Pregnancy in women with
congenital antithrombin III deficiency: experience of treatment with
heparin and antithrombin. Gynecol Obstet Invest 14:127-141, 1982
28. Krnic-Barrie S, O’Connor CR, Looney SW, et al: A retrospective review
of 61 patients with antiphospholipid syndrome. Analysis of factors
influencing recurrent thrombosis. Arch Intern Med 157:2101-2108,
1997
29. Robertson L, Wu O, Langhorne P, et al: Thrombophilia in pregnancy: a
systematic review. Br J Haematol 132:171-196, 2006
30. James AH, Brancazio LR, Gehrig TR, et al: Low-molecular-weight hep-
arin for thromboprophylaxis in pregnant women with mechanical
heart valves. J Matern Fetal Neonatal Med 19:543-549, 2006
31. Rhee E, Beckman M, Dowling N, et al: Protein S levels in normal
pregnancy. Am J Obstet Gynecol 193:S174, 2005
32. Lockwood CJ: Inherited thrombophilias in pregnant patients: detection
and treatment paradigm. Obstet Gynecol 99:333-341, 2002
33. Hellgren M, Blomback M: Studies on blood coagulation and fibrinolysis
in pregnancy, during delivery and in the puerperium. I. Normal con-
dition. Gynecol Obstet Invest 12:141-154, 1981
34. Stirling Y, Woolf L, North WR, et al: Haemostasis in normal pregnancy.
Thromb Haemost 52:176-182, 1984
35. Dahlman T, Hellgren M, Blomback M: Changes in blood coagulation
and fibrinolysis in the normal puerperium. Gynecol Obstet Invest 20:
37-44, 1985
36. Gerbasi FR, Bottoms S, Farag A, et al: Increased intravascular coagula-
tion associated with pregnancy. Obstet Gynecol 75:385-389, 1990
37. Sanchez-Luceros A, Meschengieser SS, Marchese C, et al: Factor VIII
and von Willebrand factor changes during normal pregnancy and pu-
erperium. Blood Coagul Fibrinolysis 14:647-651, 2003
38. Wickstrom K, Edelstam G, Lowbeer CH, et al: Reference intervals for
plasma levels of fibronectin, von Willebrand factor, free protein S and
antithrombin during third-trimester pregnancy. Scand J Clin Lab In-
vest 64:31-40, 2004
39. Faught W, Garner P, Jones G, et al: Changes in protein C and protein S
levels in normal pregnancy. Am J Obstet Gynecol 172:147-150, 1995
40. Cerneca F, Ricci G, Simeone R, et al: Coagulation and fibrinolysis
changes in normal pregnancy. Increased levels of procoagulants and
reduced levels of inhibitors during pregnancy induce a hypercoagula-
ble state, combined with a reactive fibrinolysis. Eur J Obstet Gynecol
Reprod Biol 73:31-36, 1997
41. Clark P, Brennand J, Conkie JA, et al: Activated protein C sensitivity,
protein C, protein S and coagulation in normal pregnancy. Thromb
Haemost 79:1166-1170, 1998
42. Kjellberg U, Andersson NE, Rosen S, et al: APC resistance and other
haemostatic variables during pregnancy and puerperium. Thromb
Haemost 81:527-531, 1999
43. Jacques PF, Bostom AG, Williams RR, et al: Relation between folate
status, a common mutation in methylenetetrahydrofolate reductase,
and plasma homocysteine concentrations. Circulation 93:7-9, 1996
44. Glueck CJ, Phillips H, Cameron D, et al: The 4G/4G polymorphism of
the hypofibrinolytic plasminogen activator inhibitor type 1 gene: an
independent risk factor for serious pregnancy complications. Metabo-
lism 49:845-852, 2000
45. Miyakis S, Lockshin MD, Atsumi T, et al: International consensus state-
ment on an update of the classification criteria for definite antiphos-
pholipid syndrome (APS). J Thromb Haemost 4:295-306, 2006
46. Gordon M: Maternal physiology in pregnancy, in Gabbe S, Niebyl J,
Simpson J (eds): Normal and Problem Pregnancies (ed 4). New York,
NY, Churchill Livingstone, 2002, pp 63-92
47. Naimi TS, Lipscomb LE, Brewer RD, et al: Binge drinking in the pre-
A.H. James et al.
conception period and the risk of unintended pregnancy: implications
for women and their children. Pediatrics 111:1136-1141, 2003
48. Moore K: Organogenetic period: the fourth to eighth weeks, in The
Developing Human: Clinically Oriented Embryology (ed 6). Philadel-
phia, PA, WB Saunders Company, 1998, pp 83-106
49. Nassar AH, Hobeika EM, Abd Essamad HM, et al: Pregnancy outcome
in women with prosthetic heart valves. Am J Obstet Gynecol 191:1009-
1013, 2004
50. Chan WS, Anand S, Ginsberg JS: Anticoagulation of pregnant women
with mechanical heart valves: a systematic review of the literature. Arch
Intern Med 160:191-196, 2000
51. Blickstein D, Blickstein I: The risk of fetal loss associated with Warfarin
anticoagulation. Int J Gynaecol Obstet 78:221-225, 2002
52. Vural KM, Ozatik MA, Uncu H, et al: Pregnancy after mechanical mitral
valve replacement. J Heart Valve Dis 12:370-376, 2003
53. Sadler L, McCowan L, White H, et al: Pregnancy outcomes and cardiac
complications in women with mechanical, bioprosthetic and ho-
mograft valves. Br J Obstet Gynaecol 107:245-253, 2000
54. Cotrufo M, De Feo M, De Santo LS, et al: Risk of warfarin during
pregnancy with mechanical valve prostheses. Obstet Gynecol 99:35-
40, 2002
55. Schaefer C, Hannemann D, Meister R, et al: Vitamin K antagonists and
pregnancy outcome. A multi-centre prospective study. Thromb Hae-
most 95:949-957, 2006
56. Iturbe-Alessio I, Fonseca MC, Mutchinik O, et al: Risks of anticoagulant
therapy in pregnant women with artificial heart valves. N Engl J Med
315:1390-1393, 1986
57. Srivastava AK, Gupta AK, Singh AV, et al: Effect of oral anticoagulant
during pregnancy with prosthetic heart valve. Asian Cardiovasc Thorac
Ann 10:306-309, 2002
58. Meschengieser SS, Fondevila CG, Santarelli MT, et al: Anticoagulation
in pregnant women with mechanical heart valve prostheses. Heart 82:
23-26, 1999
59. Chen WW, Chan CS, Lee PK, et al: Pregnancy in patients with pros-
thetic heart valves: an experience with 45 pregnancies. Q J Med 51:
358-365, 1982
60. Wesseling J, Van Driel D, Heymans HS, et al: Coumarins during preg-
nancy: long-term effects on growth and development of school-age
children. Thromb Haemost 85:609-613, 2001
61. Bates SM, Greer IA, Hirsh J, et al: Use of antithrombotic agents during
pregnancy: the Seventh ACCP Conference on Antithrombotic and
Thrombolytic Therapy. Chest 126:627S-644S, 2004 (suppl)
62. Flessa HC, Kapstrom AB, Glueck HI, et al: Placental transport of hep-
arin. Am J Obstet Gynecol 93:570-573, 1965
63. Harenberg J, Schneider D, Heilmann L, et al: Lack of anti-factor Xa
activity in umbilical cord vein samples after subcutaneous administra-
tion of heparin or low molecular mass heparin in pregnant women.
Haemostasis 23:314-320, 1993
64. Schneider D, Heilmann L, Harenberg J: [Placental transfer of low-mo-
lecular weight heparin]. Geburtshilfe Frauenheilkd 55:93-98, 1995
65. Ginsberg JS, Kowalchuk G, Hirsh J, et al: Heparin therapy during
pregnancy. Risks to the fetus and mother. Arch Intern Med 149:2233-
2236, 1989
66. Dahlman TC, Sjoberg HE, Ringertz H: Bone mineral density during
long-term prophylaxis with heparin in pregnancy. Am J Obstet Gy-
necol 170:1315-1320, 1994
67. Barbour LA, Kick SD, Steiner JF, et al: A prospective study of heparin-
induced osteoporosis in pregnancy using bone densitometry. Am J
Obstet Gynecol 170:862-869, 1994
68. Casele H, Haney EI, James A, et al: Bone density changes in women who
receive thromboprophylaxis in pregnancy. Am J Obstet Gynecol 195:
1109-1113, 2006
69. Dahlman TC: Osteoporotic fractures and the recurrence of thrombo-
embolism during pregnancy and the puerperium in 184 women un-
dergoing thromboprophylaxis with heparin. Am J Obstet Gynecol 168:
1265-1270, 1993
70. Fausett MB, Vogtlander M, Lee RM, et al: Heparin-induced thrombo-
cytopenia is rare in pregnancy. Am J Obstet Gynecol 185:148-152,
2001
Thromboembolism in pregnancy
71. Carlin AJ, Farquharson RG, Quenby SM, et al: Prospective observa-
tional study of bone mineral density during pregnancy: low molecular
weight heparin versus control. Hum Reprod 19:1211-1214, 2004
72. Casele H, Haney E: Bruising in women undergoing thromboprophy-
laxis in pregnancy. Am J Obstet Gynecol 193:S81, 2006
73. Matziolis G, Perka C, Disch A, et al: Effects of fondaparinux compared
with dalteparin, enoxaparin and unfractionated heparin on human os-
teoblasts. Calcif Tissue Int 73:370-379, 2003
74. Lagrange F, Brun JL, Vergnes MC, et al: Fondaparinux sodium does not
cross the placental barrier: study using the in-vitro human dually per-
fused cotyledon model. Clin Pharmacokinet 41:47-49, 2002 (suppl 2)
75. Dempfle CE: Minor transplacental passage of fondaparinux in vivo.
N Engl J Med 350:1914-1915, 2004
76. Mazzolai L, Hohlfeld P, Spertini F, et al: Fondaparinux is a safe alter-
native in case of heparin intolerance during pregnancy. Blood 108:
1569-1570, 2006
77. ACOG. Thromboembolism in Pregnancy. American College of Obste-
trician and Gynecologists, 2000:1-9
78. Coppage KH, Hinton AC, Moldenhauer J, et al: Maternal and perinatal
outcome in women with a history of stroke. Am J Obstet Gynecol
190:1331-1334, 2004
79. Ray JG, Chan WS: Deep vein thrombosis during pregnancy and the
puerperium: a meta-analysis of the period of risk and the leg of presen-
tation. Obstet Gynecol Surv 54:265-271, 1999
80. Ansell J, Hirsh J, Poller L, et al: The pharmacology and management of
the vitamin K antagonists: the Seventh ACCP Conference on Anti-
thrombotic and Thrombolytic Therapy. Chest 126:204S-233S, 2004
(suppl)
81. Stewart JA, Hamilton PJ, Murdoch AP: Thromboembolic disease asso-
ciated with ovarian stimulation and assisted conception techniques.
Hum Reprod 12:2167-2173, 1997
82. Warkentin TE, Levine MN, Hirsh J, et al: Heparin-induced thrombo-
175
cytopenia in patients treated with low-molecular-weight heparin or
unfractionated heparin. N Engl J Med 332:1330-1335, 1995
83. McCrae KR, Bussel JB, Mannucci PM, et al: Platelets: an update on
diagnosis and management of thrombocytopenic disorders. Hematol-
ogy (Am Soc Hematol Educ Program) 282-305, 2001
84. Horlocker TT: Low molecular weight heparin and neuraxial anesthesia.
Thromb Res 101:141-154, 2001
85. Baker WH, Mahler DK, Foldes MS, et al: Pneumatic compression de-
vices for prophylaxis of deep venous thrombosis (DVT). Am Surg 52:
371-373, 1986
86. Orme ML, Lewis PJ, de Swiet M, et al: May mothers given warfarin
breast-feed their infants? Br Med J 1:1564-1565, 1977
87. American Academy of Pediatrics Committee on Drugs: Transfer of
drugs and other chemicals into human milk. Pediatrics 108:776-789,
2001
88. Cardiovascular disease and use of oral and injectable progestogen-only
contraceptives and combined injectable contraceptives. Results of an
international, multicenter, case-control study. World Health Organiza-
tion Collaborative Study of Cardiovascular Disease and Steroid Hor-
mone Contraception. Contraception 57:315-324, 1998
89. Kupferminc MJ, Eldor A, Steinman N, et al: Increased frequency of
genetic thrombophilia in women with complications of pregnancy.
N Engl J Med 340:9-13, 1999
90. James A, Brancazio L, Ortel T: Thrombophilia in pregnancy: maternal
and fetal implications. Curr Womens Health Rev 2:51-59, 2006
91. Badaracco MA, Vessey MP: Recurrence of venous thromboembolic dis-
ease and use of oral contraceptives. Br Med J 1:215-217, 1974
92. Tengborn L, Bergqvist D, Matzsch T, et al: Recurrent thromboembo-
lism in pregnancy and puerperium. Is there a need for thromboprophy-
laxis? Am J Obstet Gynecol 160:90-94, 1989
93. James AH, Brancazio LR, Ortel TL: Thrombosis, thrombophilia, and
thromboprophylaxis in pregnancy. Clin Adv Hematol Oncol 3:187-
197, 2005
Recurrent Gestational Diabetes: Risk
Factors, Diagnosis, Management, and Implications
Joseph N. Bottalico, DO

Gestational diabetes mellitus (GDM) should be regarded as a sentinel event in a woman’s

life that presents challenges and disease prevention opportunities to all providers of health
care for women of reproductive age. Prediabetic risk factors are rising in prevalence and
include dietary and lifestyle habits, which when superimposed on genetic predisposition
contribute to the rising prevalence of type 2 diabetes and GDM. There is growing evidence
that treatment of GDM matters, with a continuum of adverse pregnancy outcome risks
proportional to degrees of maternal glucose intolerance. GDM in an index pregnancy
increases the risk of recurrent GDM in subsequent pregnancies, and recurrence rates of up
to 70% have been reported. GDM recurrence rates are influenced by maternal health
characteristics and past pregnancy history. The risk of later metabolic syndrome and type
2 diabetes is increased in women with a history of GDM and women should be screened
for postpartum glucose intolerance. Opportunities to prevent recurrent GDM and later type
2 diabetes require attention to risk factors and plasma glucose status with identification of
impaired fasting glucose or impaired glucose tolerance.
Semin Perinatol 31:176-184 © 2007 Elsevier Inc. All rights reserved.

KEYWORDS gestational diabetes, recurrence, diabetes mellitus-type 2, diabetes risk factors,

prevention, metabolic syndrome, preconception care

G estational diabetes mellitus (GDM) is defined as any

degree of glucose intolerance with onset or first recog-
nition during pregnancy. The definition of GDM does not
an increased incidence of GDM. It is thus becoming more
common to care for women who have had a previous preg-
nancy complicated by GDM.
preclude the possibility that unrecognized glucose intoler-
ance may have existed before the pregnancy, and the defini-
tion applies whether insulin, oral antidiabetic agents, or di- The Epidemiology of
etary modification is used for treatment. Approximately 7% Gestational Diabetes Recurrence
of all pregnancies in the United States are complicated by
Given that most of the risk factors for GDM persist or become
gestational diabetes resulting in more than 200,000 cases
worse in subsequent pregnancies, it is not surprising that
annually,1 but the prevalence ranges from 1% to 14% of all
GDM has a high recurrence rate of 35.6% to 70%. The fact
pregnancies depending on the population studied and the
that a wide range of recurrence rates have been reported in
diagnostic tests employed.
various studies is, in part, due to the variability of GDM
Gestational diabetes is often considered to be type 2 dia-
screening methods and the use of different diagnostic thresh-
betes unmasked by pregnancy. The two entities share com-
old values for various glucose tolerance tests. It is clear from
mon risk factors, a number of which are increasing in prev-
the literature, however, that a diagnosis of GDM confers an
alence, such as obesity and advancing maternal age. These
elevated risk of recurrent GDM in subsequent pregnancies in
factors, combined with more universal screening, have led to
addition to an increased risk of later type 2 diabetes mellitus.
Table 1 summarizes studies reporting rates of recurrence for
Division of Maternal Fetal Medicine, Department of Obstetrics and Gyne- GDM.
cology, UMDNJ-School of Osteopathic Medicine, Stratford, NJ. Philipson and Super2 examined the recurrence of glucose
Address reprint requests to Joseph N. Bottalico, DO, Department of Obstet- intolerance in 36 women with an index pregnancy compli-
rics and Gynecology, Division of Maternal Fetal Medicine, UMDNJ-
School of Osteopathic Medicine, University Doctors Pavilion-Suite cated by GDM. Oral or intravenous glucose tolerance tests
3500, 42 East Laurel Road, Stratford, NJ 08084-1504. E-mail: bottaljn were used to document glucose intolerance or gestational
@umdnj.edu diabetes. They reported that 55% (20 of 36) of women de-

176 0146-0005/07/$-see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2007.03.006
Recurrent gestational diabetes 177

Table 1 Summary of Literature on Recurrence of Gestational Diabetes Including Diagnostic Criteria, Risk Factors, and Outcomes
Author Complications
(Country- Data Recurrence Risk Factors for with
Year) Years Diagnostic Criteria Rate Recurrence Recurrence
Philipson2 1979-1987 100 g OGTT (C/C criteria) or 55% (20/36) -BMI > 30 kg/m2 -More large for
USA-1999 IVGTT (25-28 weeks) -Obesity gestational age
births
-More macrosomia
Gaudier3 1983-1990 50 g screen (>135 mg/dl) @ 52% (47/90) -BMI > 35
USA-1992 24-28 weeks. If screen ⴙ, -Insulin required in
100 g OGTT (105/190/165/ index pregnancy
145 mg/dl) -Previous baby > 4kg
Foster-Powell9 1990-1996 75 g 2-hour OGTT (100/180/ 70% (82/117) -Maternal age
Australia- 145 mg/dl) -Insulin required in
1998 index pregnancy
-Pre-pregnancy BMI
-Weight gain between
pregnancies
Spong4 1988-1992 50 g screen (>140 mg/dl) @ 68% (111/164) -Earlier GDM in index -Higher birth
USA-1998 24-26 weeks. If screen ⴙ, pregnancy weight
100g OGTT (105/190/165/ -Insulin required in -More infants
145 mg/dl) index pregnancy >4kg
-Hospital admission in
index pregnancy
Major5 1992-1996 50g screen (>140 mg/dl) @ 69% (54/78) -BMI > 30 in index
USA-1998 24-28 weeks. If screen ⴙ, pregnancy
100g OGTT (105/190/165/ -GDM Dx < 24 weeks
145 mg/dl) in index pregnancy
-Insulin required in
index pregnancy
-Weight gain > 15 lbs
between pregnancies
-Pregnancy interval <
24 months
MacNeill6 1980-1996 50g screen (>140 mg/dl). If 35.6% (232/651) -Birth weight >4 kg
Canada- screen ⴙ, 100g OGTT index pregnancy
2001 (105/190/165/145 mg/dl) -Pre-pregnancy weight
in subsequent
pregnancy

veloped gestational diabetes in a subsequent pregnancy. The
women with consecutive pregnancies complicated by GDM
were heavier and delivered larger neonates than the women
who did not develop recurrent GDM. In 1992, Gaudier and
coworkers3 conducted a retrospective review of 90 women
whose index pregnancies were complicated by GDM and
whose subsequent pregnancies were managed at the same
institution. There were 52% (47) who had a recurrence of
GDM in their subsequent pregnancy. These 47 women had
an increased BMI (32.8 kg/m2 versus 28.9 kg/m2, P ⬍ 0.03)
and more large for gestational age (LGA) neonates (38% ver-
sus 14%; P ⬍ 0.05). A greater number also required insulin
during their index pregnancy (38% versus 19%; P ⬍ 0.05)
than those who did not have a recurrence of GDM. They
concluded that women with a history of GDM who have a
BMI greater than 35 kg/m2, whose previous newborn was
LGA, and who required insulin during the previous preg-
nancy are at increased risk for recurrence of GDM.
Spong and coworkers4 evaluated the influence of maternal
and neonatal factors on the recurrence of GDM in 164 pre-
dominantly Hispanic women whose index pregnancy was
complicated by GDM. The diagnosis of GDM was based on
the National Diabetes Data Group (NDDG) criteria using a
100-g oral glucose tolerance test. There were 68% (111) with
a recurrence of GDM. Women with recurrence had GDM
diagnosed earlier, frequently required insulin (25% versus
8%, P ⬍ 0.05), and had more hospital admissions in their
index pregnancy compared with women without a recur-
rence of GDM. Infants of women with recurrence were
heavier and had an increased incidence of macrosomia (26%
versus 10%, P ⬍ 0.05).
Major and coworkers5 reported on 78 women with GDM
in a previous pregnancy. Universal screening was performed
using a 50-g oral glucose load. Those with a value of 140
mg/dL or greater were then given the 100-g oral glucose
tolerance test (OGTT) using the threshold criteria of the Na-
tional Diabetes Data Group (fasting of 105 mg/dL, 1 hour of
190 mg/dL, 2 hours of 165 mg/dL, and 3 hours of 145 mg/
178
dL). GDM recurrence was found in 69% (54) of women.
Recurrence of GDM was more common with an index preg-
nancy parity ⱖ1, BMI ⱖ30 kg/m2, a GDM diagnosis at ⱕ24
gestational weeks in the first pregnancy, and insulin require-
ment in the first pregnancy. A weight gain of ⱖ15 lbs and an
interval between pregnancies of ⱕ24 months had the stron-
gest association with recurrence of GDM.
MacNeill and coworkers6 published a retrospective longi-
tudinal study in 2001 of a predominantly white cohort of 651
women in Nova Scotia diagnosed with GDM during a preg-
nancy that occurred between 1980 and 1996 and who had at
least one subsequent pregnancy during that time period. The
screening method employed was a 50-g 1-hour glucose load.
A value of ⱖ140 mg/dL was considered a positive screen and
was followed by a 3-hour oral glucose tolerance test with
100 g of glucose that required more than one glucose over the
threshold values for a positive test (fasting ⱖ95mg/dL, 1
hour ⱖ190 mg/dL, 2 hours ⱖ165 mg/dL, and 3 hours 145
mg/dL). These criteria combine elements from the current
ADA endorsed Carpenter and Coustan7 threshold values for
the 100-g glucose 3-hour OGTT (fasting ⱖ95mg/dL, 1-hour
ⱖ180 mg/dL, 2-hour ⱖ155 mg/dL, and 3-hour 140 mg/dL)
and the National Diabetes Data Group8 values (fasting
ⱖ105mg/dL, 1 hour ⱖ190 mg/dL, 2 hours ⱖ165 mg/dL,
and 3 hours 145 mg/dL), which also require more than one
abnormal value for a positive test. The rate of recurrence of
GDM in the subsequent pregnancy was found to be 35.6%.
Multivariate regression models showed that infant birth
weight in the index pregnancy and maternal prepregnancy
weight before the subsequent pregnancy were predictive of
recurrent GDM.
A 1998 study by Foster-Powell and Cheung9 through a
diabetes service in New South Wales, Australia reported a
retrospective review of 540 women with GDM managed be-
tween 1990 and 1996. There was a GDM recurrence rate of
70% using a 2-hour 75-g OGTT for diagnosis with modified
WHO threshold values. Finally, Danilenko-Dixon and col-
leagues10 in 2000 reported that perinatal outcomes in women
with previous gestational diabetes but with normal glucose
tolerance tests during a subsequent pregnancy were not im-
proved with regard to birth weight, macrosomia, route of
delivery, and neonatal complications.
Unfortunately, these studies on the recurrence of GDM
suffer from the limitations of having no formal proof that
some of the women did not have undiagnosed type 2 diabe-
tes, impaired fasting glucose, or impaired glucose tolerance
using current ADA criteria before the subsequent pregnancy.
Increasing Prevalence
of Pre-Diabetic Risk
Factors in the United States
Since GDM may very well be a “tip of the iceberg” phenom-
enon for many women, it is important to consider the epide-
miologic landscape affecting the first occurrence of GDM as
well as the risks for recurrent GDM in subsequent pregnan-
cies and the longer term risk of type 2 diabetes.
J.N. Bottalico
Excessive weight is an important public health concern in
the United States, as well as other affluent societies. Pleis and
coworkers11 reported that, by the end of 2000, 34% of adult
Americans were overweight and another 27% were obese.
This represented an increase of 75% compared with 1980
statistics. These data showed that, at the end of 2000, more
than 50% of the adults in the United States were either over-
weight or obese. United States data from 1997 and 1998 for
women aged 18 to 24 and 25 to 44 revealed an estimated
prevalence of overweight (BMI ⱖ 25 kg/m2) or obese (BMI ⱖ
30 kg/m2) of over 30% for the 18 to 24 age group and over
40% for the 25 to 44 group.12 An increased prevalence of
obesity in U.S. adolescents has also been documented and
associated with declining levels of physical activity.13 The
links between obesity, insulin resistance, and type 2 diabetes
mellitus are well known, and the long-term complications of
obesity are numerous. The strong association between in-
creased BMI and higher risks for GDM has been clearly es-
tablished.
There is also growing recognition of the importance of the
metabolic syndrome as a multiplex risk factor for cardiovas-
cular disease and type 2 diabetes. In women, the metabolic
syndrome is defined by the presence of three or more of the
following criteria: abdominal obesity (waist circumference
⬎88 cm or 34.7 inches), elevated triglycerides (ⱖ150 mg/
dL), high-density lipoprotein (⬍50 mg/dL), high blood pres-
sure (ⱖ130/85 mm Hg), and elevated fasting glucose (110
mg/dL).14 It should be noted that the current definition of
impaired fasting glucose is 100 to 125 mg/dL.1 The estimated
prevalence of the metabolic syndrome in women is 24%,
with prevalence increasing with age as reported by Ford and
coworkers using data from the National Health and Nutrition
Survey (NHANES III).15 For 4549 female subjects reported
by Ford, metabolic syndrome prevalence was about 6% in
those 20 to 29 years of age, 14% in those 30 to 39 years of age,
20% in those 40 to 49 years of age, and ⬎30% for women
older than 50 years of age. As with obesity, the pathophysi-
ologic features of the metabolic syndrome are likely to be
associated with a variety of pregnancy complications, includ-
ing GDM.
United States
Diabetes Prevalence:
Diagnosed and Undiagnosed
National estimates on diabetes prevalence have been pub-
lished by the Centers for Disease Control and Prevention
(CDC) in Atlanta.16 The total prevalence of frank diabetes
mellitus among women age 20 years or older in the United
States in 2005 was 9.7 million, or 8.8% of all women in this
age group. The prevalence of diabetes by race and ethnicity
among people 20 years of age or older in the United States in
2005 was an estimated 8.7% prevalence for all non-Hispanic
whites, 13.3% for non-Hispanic blacks, and about 9.5% of
Hispanic/Latino Americans. The rates are also higher for
American-Indians, Alaskan natives, Asian Americans, and
Pacific Islanders. Many of these women will have DM iden-
Recurrent gestational diabetes
tified for the first time in pregnancy and be classified as GDM.
However, if not tested after delivery, a second pregnancy may
be incorrectly classified as recurrent GDM instead of preges-
tational DM. These epidemiologic trends suggest that diabe-
tes, GDM, and recurrent GDM will likely complicate a greater
number of pregnancies in the next few decades.
In a cross-sectional sample of U.S. adults over the age of 40
tested between 1988 and 1994, 33.8% had an impaired fast-
ing glucose (IFG; which is currently defined as a plasma
glucose of 100-125 mg/dL after an overnight fast). A total of
15.4% had impaired glucose tolerance (IGT), currently de-
fined as 140 to 199 mg/dL after a 2-hour oral glucose toler-
ance test with 75 g of oral glucose solution.16 When percent-
ages were applied to the entire U.S. population in 2000, an
estimated 41 million adults had prediabetes. Data are not
readily available for the reproductive age female population
with regard to the prevalence of prediabetes, although in-
creasing overweight, obesity, and ethnicity trends suggest
that a rising prevalence may be occurring.
Diagnosis of GDM
GDM is a condition that lacks international consensus con-
cerning the method of choice for screening and specific cri-
teria for diagnosis. The Fourth International Workshop-Con-
ference on Gestational Diabetes in 1998 recommended a
screening strategy based on risk assessment for detecting ges-
tational diabetes and that risk assessment for GDM should be
undertaken at the first prenatal visit.7 Women can then be
classified as either low-risk, average-risk, or high-risk. High-
risk women should be screened for GDM as soon as feasible
during pregnancy. If high-risk women are found not to have
GDM at initial screening, they should be retested between 24
and 28 weeks of gestation.1 Risk factors most consistently
linked with GDM include a previous macrosomic infant, obe-
sity, suspected glucose intolerance when not pregnant, glu-
cosuria, a strong immediate family history of type 2 diabetes
or GDM, history of unexplained fetal demise and, especially,
women with a history of GDM in a prior pregnancy (Table 2).
A diagnosis of GDM is based on a positive OGTT (ⱖ2 abnor-
mal values) most commonly performed after an abnormal
1-hour plasma glucose screen with a 50-g oral glucose load (the
“two-step” approach). Diabetes mellitus in pregnancy can also
be diagnosed if the fasting plasma glucose is ⱖ126 mg/dL or a
casual plasma glucose is ⱖ200 mg/dL, but these criteria may be
less reliable since they are mostly applicable to nonpregnant
adults. Guidelines issued by the Fourth International Workshop
Conference on Gestational Diabetes Mellitus,7 the American Di-
abetes Association (ADA-2004),1 and American College of Ob-
stetricians and Gynecologists17 in 2001 lean toward recom-
mending the use of the Carpenter-Coustan criteria for the
diagnostic 3-hour, 100-g glucose OGTT. However, these orga-
nizations also recognize the alternative use of the single-step,
2-hour, 75-g glucose OGTT in certain high prevalence popula-
tions (threshold values of 95 mg/dL fasting, 180 mg/dL at 1
hour, and 155 mg/dL at 2 hours). ACOG also acknowledges that
expert panels have supported both the Carpenter-Coustan and
the National Diabetes Data Group criteria and report that there
179
Table 2 Risk Factors for Gestational Diabetes Mellitus and
Recurrence
Previous history of gestational diabetes
Previous diagnosis of GDM before 24 weeks
Insulin requirement in previous pregnancy
Previous GDM and weight gain of >15 lbs between
pregnancies
Previous GDM and interval between pregnancies <24
months
Previous history of macrosomia (birth weight >9 lbs or
4100 grams)
Previous history of adverse pregnancy outcome (not
clearly attributable to a condition other than diabetes
during pregnancy)
Ethnic group with an elevated risk of gestational and type
2 diabetes
Hispanic
African
Native American
South or East Asian
Pacific Island Ancestry
First degree relative with diabetes
Advanced maternal age
Obesity (BMI >30-35 kg/m2)
Glucosuria
Metabolic syndrome
Insulin resistance (eg, PCOS)
are “no data from clinical trials to determine which is superior.”
Nevertheless, it is important to remember that, similar to other
screening tests, those for GDM may have problems with repro-
ducibility.18
As with other high-risk groups, ADA guidelines for the detec-
tion of GDM indicate that glucose testing for women with a
history of prior GDM should occur “as soon as feasible,” with
re-screening, between 24 and 28 weeks if the initial screen is
negative. Maser and coworkers19 evaluated medical records for
60 women enrolled in a GDM management program that pre-
sented with 2 subsequent pregnancies with GDM to determine
whether more specific guidelines for detection are needed. Over
half (55%) of these women required insulin during both preg-
nancies, and 16.7% (10) required insulin during the second
enrollment for GDM, but not the first. For those subjects who
required insulin during both pregnancies, 88% (29 of 33) were
started earlier during the subsequent pregnancy (21.6 ⫾ 8.4
weeks of gestation versus 31.5 ⫾ 2.7 weeks of gestation, P ⬍
0.001). During the subsequent pregnancy, approximately one-
half of the women requiring insulin needed it before 24 weeks,
whereas a third required it by week 15. Therefore, it seems
reasonable to perform the initial screen by 15 weeks in women
with a previous history of GDM.
Gestational
Diabetes Management,
General and Recurrent
Despite the debate over screening strategies, there is a clear
association between maternal carbohydrate intolerance and
180
perinatal complications. The rates of excessive fetal growth
and neonatal morbidity rise with the degree of maternal hy-
perglycemia. The Toronto Tri-Hospital Gestational Diabetes
Project was a prospective study on the impact of increasing
maternal carbohydrate intolerance on both maternal and fe-
tal outcomes.20 Women with GDM were compared with a
cohort of 3637 women with singleton pregnancies that did
not have GDM. The study found a direct relationship be-
tween OGTT values and multiple adverse outcomes, includ-
ing preeclampsia, macrosomia, and operative delivery in
women without frank GDM. Saks and coworkers21 found a
positive relationship between OGTT results and fetal birth
weight in approximately 3500 pregnant women undergoing
screening. Langer and Mazze,22 in a large prospective study
designed to determine optimal levels of glycemic control for
treatment of women with GDM, demonstrated in 246
women with GDM that the women who achieved the lowest
range of blood glucose values throughout pregnancy had a
significantly lower incidence of LGA and macrosomic in-
fants. In 1994, Langer and coworkers23 compared intensive
to conventional therapy in 2500 women with GDM. Women
in the intensive therapy group had a significantly lower inci-
dence of macrosomic and LGA infants. These infants also had
lower rates of admission to the neonatal intensive care unit,
fewer metabolic complications, and less need for respiratory
support. Langer and coworkers24 compared 555 gravidas
with GDM diagnosed after 37 weeks with 1110 subjects
treated for GDM and 1110 nondiabetic subjects matched
from the same delivery year for obesity, parity, ethnicity, and
gestational age at delivery. They found a composite adverse
outcome rate of 59% for untreated, 18% for treated, and 11%
for nondiabetic subjects. A 2- to 4-fold increase in metabolic
complications and macrosomia/LGA was found in the un-
treated group with no difference between nondiabetic and
treated subjects. A 2- to 3-fold higher morbidity rate for the
untreated groups was found compared with the other
groups. They also concluded that untreated GDM confers
significant risks of perinatal morbidity at all disease severity
levels.
The Australian Carbohydrate Intolerance Study (ACHOIS)
was a large randomized multicenter trial for the treatment of
gestational diabetes.25 The criteria used in this study for the
diagnosis of GDM were based on the 75-g OGTT between 24
and 34 weeks gestation. Those with values below 140 mg/dL
(7.8 mmol/L) after an overnight fast and between 140 and
198 mg/dL (7.8-11.0 mmol/L) at 2 hours were eligible for
randomization. The 490 women assigned to the intervention
group had premeal glucose levels below 99 mg/dL and 2-
hour postprandial levels that did not exceed 126 mg/dL. The
510 women assigned to the control group received routine
care that was consistent with care provided in other facilities
in which screening for GDM was not standard. The rate of
serious perinatal complications (which was defined as death,
shoulder dystocia, bone fracture, and nerve palsy) was sig-
nificantly lower among infants of the women in the interven-
tion group (self-monitoring of blood glucose levels, individ-
ualized medical nutrition therapy counseling and insulin);
however, more infants of women in the intervention group
J.N. Bottalico
were admitted to the neonatal ICU. Women in the interven-
tion group had a higher rate of induction of labor than
women in the routine care group, although the rates of ce-
sarean delivery were similar at 31% and 32%, respectively. At
3 months postpartum, follow-up data were available for 573
women and revealed lower rates of depression and better
quality of life scores, consistent with improved health status
in the intervention group.
The above data suggest that making a diagnosis of GDM
and identifying effective interventions have the potential to
reduce morbidities associated with GDM and improve preg-
nancy outcomes. However, it is not clear which management
strategies might be most effective for women with recurrent
GDM. It seems likely given the probable greater degree of
glucose intolerance and onset or diagnosis earlier in gestation
that a need for more aggressive use of medications (oral an-
tidiabetic agents or insulin) should be anticipated.
Prevention of
Gestational Diabetes Recurrence
There are limited data examining interventions to prevent
recurrence of GDM. Medication interventions to prevent
GDM have been studied in women with polycystic ovary
syndrome (PCOS). Affected women are characteristically
obese, have insulin resistance and hyperinsulinemia, all of
which are risk factors for primary (and probably recurrent)
GDM.26,27 Metformin increases insulin sensitivity and re-
duces insulin resistance. It has been found to be a safe and
effective treatment for the metabolic and endocrine abnor-
malities in PCOS. Glueck and coworkers28 reported that, in
33 women with PCOS who received metformin during preg-
nancy, GDM developed in 1 of 33 (3%) versus 8 of 12 (67%)
of their previous pregnancies without metformin. Among the
39 women with a history of PCOS who did not take met-
formin, GDM developed in 14 of 60 (23%) of pregnancies.
When all live births were combined, GDM occurred in 22 of
70 pregnancies (31%) in women who did not take metformin
versus 1 of 33 pregnancies (3%) in those who did take met-
formin. The authors concluded that, in women with PCOS,
the use of metformin was associated with a 10-fold reduction
in the rate of GDM. The effect was probably achieved by
reducing insulin resistance and insulin secretion, thus reduc-
ing the secretory demands imposed on pancreatic beta cells
by insulin resistance in pregnancy. In light of the limited
available information, it is not clear whether medication in-
terventions after a pregnancy complicated by GDM will pre-
vent recurrence, but at the minimum, it seems reasonable to
recommend lifestyle changes such as increased physical ac-
tivity and weight reduction if overweight or obese.
Contribution of GDM
to Glucose Tolerance Status
There is epidemiologic evidence associating GDM with insu-
lin resistance, glucose intolerance, and type 2 diabetes.29 The
development of overt diabetes mellitus appears to require an
Recurrent gestational diabetes
associated defect in insulin secretion. There may be a finite
level of pancreatic “beta cell reserve” that is further depleted
with recurring GDM. Insulin resistance is another significant
factor for many women who eventually develop GDM.
Verma and coworkers30 examined the prevalence of the
insulin resistance syndrome (IRS) among women with a his-
tory of GDM compared with controls over a period of 11
years post delivery. They reported that 27.2% of women with
prior GDM versus only 8.2% of controls developed IRS by 11
years after delivery. Prepregnancy obesity was an important
contributor to this increased risk. Kousta and coworkers31
reported on normoglycemic women (34 with previous GDM
and 44 with no previous GDM) who were given insulin-
modified IV glucose tolerance tests. They found that post-
GDM women were more obese than controls, had evidence of
insulin resistance, and had higher fasting triglycerides.
Lauenborg and colleagues32 estimated the prevalence of the
metabolic syndrome by three different criteria (WHO 1999,
NCEP 2001, and the European Group for the Study of Insu-
lin Resistance 2002) among Danish women with previous
GDM. A cohort of women were followed for a median of 9.8
years (6.4-17.2 years) after their pregnancy. Outcome mea-
sures included BMI, glucose tolerance, blood pressure, lipid
profile, and insulin resistance, and they found that the prev-
alence of the metabolic syndrome was three times higher in
the prior GDM group in comparison to the control group.
Similar findings were reported by Albareda and coworkers33
in 2005 based on their study in a Spanish population.
It is possible that recurrent episodes of heightened insulin
resistance, such as with recurrent GDM, place high demands
on the pancreas and contribute to an eventual decline in beta
cell function that leads to type 2 diabetes in high-risk indi-
viduals. Peters and coworkers34 studied 666 Latino women
with a history of GDM. Among the 87 (13%) who completed
an additional pregnancy, the rate ratio of type 2 diabetes
increased significantly in comparison to women without an
additional pregnancy. Although the longevity of beta cell
function may be genetically determined, some individuals
may respond to repeated demands on pancreatic insulin se-
cretion (as seen in normal pregnancy, obesity, and polycystic
ovarian disease) in a way that eventually exhausts beta cell
reserve leading to the development of frank diabetes mellitus.
Interestingly, for the nonpregnant population, decreasing in-
sulin resistance through diet and exercise or medications
such as metformin or rosiglitazone has been shown to reduce
the risk of subsequent type 2 diabetes or delay its onset.35-37
Postpartum and
Long-Term Management
after Gestational Diabetes
The definition of GDM encompasses a fairly wide spectrum
of disease. The degree of glucose intolerance and the time of
onset varies, ranging from transient mild hyperglycemia lim-
ited to pregnancy to unrecognized pregestational diabetes to
pregestational metabolic syndrome (insulin resistance) with
or without features of PCOS. Although data are lacking, it is
181
likely that women with GDM who were most likely to have
had unrecognized pregestational diabetes in their index preg-
nancy include: those in whom GDM was diagnosed before 24
weeks (especially the first trimester), those who required in-
sulin before 20 weeks, and those with initial fasting plasma
glucose levels of ⱖ126 mg/dL (fasting glucose criterion for
nonpregnant diabetes mellitus). Other risk factors associated
with an increased risk of resistant glucose intolerance after
pregnancy include obesity, high-risk ethnic group, and type
2 diabetes in a first-degree relative.
In a systematic literature review, Kim and coworkers38
found that, after a pregnancy with GDM, rates of overt dia-
betes ranged from 2.6% to 70% in studies with follow up
from 6 weeks to 28 years. The incidence of type 2 diabetes
increased most in the first 5 years after the pregnancy with
GDM and seemed to plateau after 10 years. The Fourth In-
ternational Workshop-Conference on Gestational Diabetes
recommended that women diagnosed with GDM undergo
evaluation with the 75-g OGTT test at 6 to 12 weeks after
delivery.7 The American Diabetes Association in their 2004
position statement on gestational diabetes mellitus recom-
mends that “reclassification of maternal glycemic status
should be performed at least 6 weeks after delivery and ac-
cording to the guidelines of the expert committee” referenced
above.1 If glucose levels are normal postpartum, reassess-
ment of glycemia should be undertaken at a minimum of
3-year intervals. All women with impaired fasting glucose
(IFG) or impaired glucose tolerance (IGT) in the postpartum
period should be tested for diabetes annually. These patients
should receive intensive medical nutrition therapy and
should be placed on an individualized exercise program
because of their very high risk for the development of
diabetes.1 A summary of these recommendations together
with the author’s suggested evaluation plan after a preg-
nancy with GDM is provided in Figure 1.
Unfortunately, studies have shown that rates of postpar-
tum glucose tolerance testing compliance in women diag-
nosed with GDM have been less than optimal. Russel and
coworkers39 retrospectively studied a cohort of 344 women
with GDM from 2001 to 2004. They found that less than
one-half (45%) of women in the cohort with GDM under-
went postpartum glucose testing. More than one-third (36%)
of women who did have postpartum testing were found to
have persistent abnormal glucose tolerance. They found no
independent relationship between most demographic char-
acteristics and postpartum testing. Postpartum testing was
strongly associated only with the attendance at the postpar-
tum visit as shown by the 54% postpartum testing rate com-
pared with 17% of women who did not attend their postpar-
tum visit. Therefore, postpartum visits are a critical link to
compliance with follow-up testing.
These data highlight the importance of postpartum and
preconception care to allow further assessment of modifiable
risk factors for women with previous GDM, whether or not
they are considering another pregnancy. If not feasible for
those with subsequent pregnancies, then early prenatal care
to allow timely GDM screening and management is appro-
priate.
182 J.N. Bottalico

Figure 1 Suggested evaluation plan for women with a previous history of gestational diabetes.
Recurrent gestational diabetes
Diabetes Prevention
in Women with Previous GDM
The TRIPOD study demonstrated that the drug troglitazone
improved glucose tolerance after GDM in high-risk Hispanic
women.36 Treatment with troglitizone delayed or prevented
the onset of type 2 diabetes in treated women compared with
controls, with a 55% reduction in the average annual diabetes
incidence rates over a median follow-up period of 30
months. The proposed mechanism of this protective effect
was the preservation of pancreatic beta cell function which
appeared to be mediated by a reduction in the secretory
demands placed on the beta cells by chronic insulin resis-
tance.
The Diabetes Prevention Program (DPP) study published
in 200235 randomly assigned 3234 nondiabetic adults with
elevated fasting and postload plasma glucose concentrations
and randomized groups to either a lifestyle modification pro-
gram with at least 150 minutes of physical activity per week
or metformin (850 mg twice daily) or placebo. The average
follow up was 2.8 years, and the incidence of diabetes was
4.8, 7.8, and 11.0 cases per 100 person years in the lifestyle,
metformin, and placebo groups, respectively. Lifestyle inter-
vention reduced the incidence of type 2 diabetes by 58% and
metformin by 31% as compared with placebo. Of the 2191
women randomized into the 3-arm trial of the DPP, 353 gave
a history of GDM. The women with a history of GDM were
younger but had no other differences in parity, weight, level
of carbohydrate tolerance, or degree of insulin resistance
compared with those without such a history. Despite these
similarities in cohorts, a history of GDM conferred a 74%
increased hazard rate to develop diabetes compared with
those without such history.
More recently, the DREAM study37 included 5269 adults
aged 30 years or more who had either impaired fasting glu-
cose or impaired glucose tolerance. This trial included 1536
women treated with rosiglitazone with 1584 female controls
given a placebo. Histories of GDM were positive in 9.1% and
9.3% of these two subgroups of women, respectively. A total
of 11.6% of all persons in the rosiglitizone group (306/2635)
and 26.0% given placebo (686/2634) developed the compos-
ite primary outcome that included diabetes (hazard ratio
0.40, 95% CI 0.35-0.46, P ⬍ 0.0001). The mean ages in the
risiglitazone and placebo groups were 54.6 and 54.8 years,
respectively.
These landmark trials illustrate that persons at high risk for
the development of type 2 diabetes, which includes women
with histories of GDM, may benefit from some combination
of lifestyle interventions and drug therapy to reduce the risk
of eventual type 2 diabetes. Potential problems with medica-
tion side effects and lack of confirmatory studies, however,
limit full consideration of their use at the current time.
Future Direction
The concept of gestational diabetes mellitus being an issue
only for obstetricians and gynecologists needs to be replaced
183
with the idea that GDM is a “tip of the iceberg” phenomenon.
GDM is often the culmination of years of unrecognized and
unmodified diabetes risk factors that lead to overt and occult
clinical manifestations during pregnancy. It is clear that an
index case of gestational diabetes increases the risks of not
only recurrent gestational diabetes in subsequent pregnan-
cies, but also type 2 diabetes later in life for many women. We
also know that recurrent episodes of GDM further increase
the risk of eventual type 2 diabetes.
Although lifestyle interventions and insulin sensitizing
drugs can prevent or delay type 2 diabetes mellitus, there are
limited data on prevention of recurrent GDM and adverse
obstetric outcomes. Considering the possible fetal program-
ming effects of GDM on the offspring (albeit through incom-
pletely understood mechanisms and with a clear need for
further research), the concept of “diabetes begets diabetes”
has also emerged,40 inviting strategies to break this cycle.
Challenges for the future include development of strategies
to prevent the first episode of gestational diabetes. After an
index pregnancy with GDM, the prevention of recurrent
GDM may be possible through interventions that address
potentially modifiable risk factors, such as weight and BMI,
PCOS, and insulin resistance. Small studies involving the
drug metformin have suggested a reduction in the risk of
subsequent GDM, but data are insufficient to make wide-
spread recommendations endorsing this strategy and further
studies will be necessary to address safety and efficacy issues.
Other candidate medications deserve further study. Other
knowledge gaps include the lack of a definition of the meta-
bolic syndrome in pregnancy leading to the notion that GDM
may be a manifestation of the metabolic syndrome during
pregnancy. Further studies are also needed to address the
optimal screening strategy to detect recurrent GDM in sub-
sequent pregnancies.
Finally, given the rising prevalence of prediabetic risk fac-
tors, concerns are mounting that, without effective interven-
tion strategies, the incidence of gestational diabetes as well as
type 2 diabetes will continue to increase. Gestational diabetes
mellitus for many women represents only one stage in a con-
tinuum of risks that presents many challenges and preventa-
tive opportunities to health care systems. Further under-
standing of specific risks as well as their complex interactions
and rates of progression may allow the identification of effec-
tive strategies to break the cycle with the goals of not only
improving pregnancy outcomes but also reducing longer
term health risks for women and their children.
Acknowledgments
The author would like to express his gratitude to Naomi Spina
for her expert assistance in the preparation of this manuscript
and John Smulian, MD, MPH, for his valuable editorial contri-
butions.
References
1. American Diabetes Association. Position Statement, Gestational Diabe-
tes Mellitus. Diabetes Care, Vol. 27, Supplement I, January 2004.
2. Philipson EH, Super DM: Gestational diabetes mellitus: does it recur in
184
subsequent pregnancy? Am J Obstet Gynecol 160:1324-1329,
discussion 1329-1331, 1989
3. Gaudier FL, Hauth JC, Poist M, et al: Recurrence of gestational diabetes
mellitus. Obstet Gynecol 80:755-758, 1992
4. Spong CY, Guillermo L, Kuboshige J, et al: Recurrence of gestational
diabetes: identification of risk factors. Am J Perinatol 15:29-33, 1998
5. Major CA, DeVeciana M, Weeks J, et al: Recurrence of gestational
diabetes: who is at risk? Am J Obstet Gynecol 179:1038-1042, 1998
6. MacNeill S, Dodds L, Hamilton D, et al: Rates and risk factors for
recurrence of gestational diabetes. Diabetes Care 24:659-662, 2001
7. Metzger BE, Coutsan DR: Summary and recommendations of the
Fourth International Workshop-Conference on Gestational Diabetes
Mellitus. The Organizing Committee. Diabetes Care 21:B161-B167,
1998 (suppl 2)
8. National Diabetes Data Group: Classification and diagnosis of diabetes
mellitus and other categories of glucose intolerance. Diabetes 28:1039-
1057, 1979
9. Foster-Powell KA, Cheung NW: Recurrence of gestational diabetes.
Austr NZ J Obstet Gynecol 38: 384-387, 1998
10. Danilenko-Dixon D, Annamalai A, Mattson L, et al: Perinatal outcomes
in consecutive pregnancies discordant for gestational diabetes. Am J
Obstet Gynecol 182:80, 2000
11. Pleis JR, Senson V, Schiller JS: Summary Health Statistics for US Adults:
National Health Interview Survey, 2000. National Center for Health
Statistics. Vital Health STAT 10, 2003
12. Schoenborn CA, Adams PF, Barnes PM: Body weight status of adults.
United States, 1997-98. Advance data from vital and health statistics,
no. 330, National Center for Health Statistics, 2002
13. Kimm S, Glynn NW, Kriska AM, et al: Decline in physical activity in
black girls and white girls during adolescence. N Engl J Med. 347:709,
2002
14. Third report of the national cholesterol education program (NCEP)
Expert panel on detection, evaluation, and treatment of high blood
cholesterol adults (Adult Treatment Panel III) final report. Circulation
106: 3143-3421, 2002
15. Ford E, Giles W, Dietz W: Prevalence of the metabolic syndrome
among US adults: findings from the third National Health and Nutri-
tion Examination Survey. J Am Med Assoc 287:356-359, 2002
16. Centers for Disease Control and Prevention. National Diabetes Fact
Sheet. United States, 2005
17. American College of Obstetricians and Gynecologists. ACOG Practice
Bulletin, No. 30, Gestational diabetes, September 2001
18. Catalano PM, Avallone D, Drago N, et al: Reproducibility of the oral
glucose tolerance test in pregnant women. Am J Obstet Gynecol 169:
874-881, 1993
19. Maser R, Lenhard MJ, Henderson BC, et al: Detection of subsequent
episodes of gestational diabetes mellitus, a need for specific guidelines.
J Diabetes Complications 18:86-90, 2004
20. Sermer M, Naylor CD, Gare DJ, et al: Impact of increasing carbohydrate
intolerance on maternal-fetal outcomes in 3637 women without GDM.
The Toronto Tri-Hospital Gestational Diabetes Project. Am J Obstet
Gynecol 173:146-156, 1995
21. Sacks DA, Greenspoon JS, Abu-Fadil S, et al: Towards universal criteria
for gestational diabetes: the 75 gram glucose tolerance test in preg-
nancy. Am J Obstet Gynecol 172:607-614, 1995
J.N. Bottalico
22. Langer O, Mazze R: The relationship between large-for-gestational-age
infants and glycemic control in women with gestational diabetes. Am J
Obstet Gynecol 159:1478-1483, 1988
23. Langer O, Rodriguez DA, Xenakis EM, et al: Intensified versus conven-
tional management of gestational diabetes. Am J Obstet Gynecol 170:
1036-1047, 1994
24. Langer O, Yogev Y, Most O, et al: Gestational diabetes: the conse-
quences of not treating. Am J Obstet Gynecol 192:989-997, 2005
25. Crowther C, Hiller J, Moss J, et al: Effect of treatment of gestational
diabetes mellitus on pregnancy outcomes. N Engl J Med 352:2477-
2486, 2005
26. Radon P, McMahon MJ, Meyer WR: Impaired glucose tolerance in
pregnant women with polycystic ovary syndrome. Diabetologia 94:
194-197, 1999
27. Mikola M, Hiilesmaa V, Halttunen M, et al: Obstetric outcome in women
with polycystic ovarian syndrome. Hum Reprod 16:226-229, 2001
28. Glueck M, Wang P, Kobayashi S, et al: Metformin therapy throughout
pregnancy reduces the development of gestational diabetes in women
with polycystic ovary syndrome. Fertil Steril 77:520-525, 2002
29. Hanna F, Peters JR: Screening for gestational diabetes; past, present and
future. Diabet Med 19:351-358, 2002
30. Verma A, Boney C, Tucker R, et al: Insulin resistance syndrome in
women with prior history of gestational diabetes mellitus. J Clin Endo-
crinol Metab 87:3227-3235, 2002
31. Kousta E, Lawrence N, Godsla I, et al: Insulin resistance and beta cell
function in normoglycemic European women with a history of GDM.
Clin Endocrinol 59:289-229, 2003
32. Lauenborg J, Mathiesen E, Hansen T, et al: The prevalence of the
metabolic syndrome in a Danish population of women with previous
gestational diabetes is 3-fold higher than in the general population.
J Clin Endocrinol Metab 90:4004-4010, 2005
33. Albareda M, Caballero A, Badell G, et al: Metabolic syndrome at follow
up in women with and without gestational diabetes in index pregnancy.
J Metab Clin Exp 54:1115-1121, 2005
34. Peters RK, Kjos SL, Xiang A, et al: Long term diabetogenic effect of
single pregnancy in women with previous gestational diabetes mellitus.
Lancet 347:227-230, 1996
35. Diabetes Prevention Program Research Group: Reduction in the inci-
dence of type 2 diabetes with lifestyle intervention or metformin.
N Engl J Med 346:393-403, 2002
36. Buchanan T, Xiang A, Peters RK, et al: Preservation of pancreatic beta-
cell function and prevention of type 2 diabetes by pharmacological
treatment of insulin resistance in high-risk Hispanic women. Diabetes
51:2796-2803, 2002
37. Gerstein H, Yusuf S, Bosch J, et al: Effect of rosiglitazone on the fre-
quency of diabetes in patients with impaired glucose tolerance or im-
paired fasting glucose: a randomized controlled trial. Lancet 368:1096-
1105, 2006
38. Kim C, Newton K, Knopp RH: Gestational diabetes and the Incidence of
type 2 diabetes: a systematic review. Diabetes Care 25:1862-1868, 2002
39. Russell M, Phipps M, Olson C, et al: Rates of postpartum glucose testing
after gestational diabetes mellitus. Obstet Gynecol 8:1456-1462, 2006
40. Van Assche F, Holemas K, Aerts L: Long term consequences for off-
spring of diabetes during pregnancy. Br Med Bull 60:173-182, 2001
After Shoulder Dystocia:
Managing the Subsequent Pregnancy and Delivery
Edith D. Gurewitsch, MD,*,† Tara L. Johnson, BS, BM,† and Robert H. Allen, PhD†

Among risk factors for shoulder dystocia, a prior history of delivery complicated by
shoulder dystocia is the single greatest risk factor for shoulder dystocia occurrence, with
odds ratios 7 to 10 times that of the general population. Recurrence rates have been
reported to be as high as 16%. Whereas prevention of shoulder dystocia in the general
population is neither feasible nor cost-effective, intervention efforts directed at the partic-
ular subgroup of women with a prior history of shoulder dystocia can concentrate on
potentially modifiable risk factors and individualized management strategies that can
minimize recurrence and the associated significant morbidities and mortality.
Semin Perinatol 31:185-195 © 2007 Elsevier Inc. All rights reserved.

KEYWORDS prior shoulder dystocia, history of shoulder dystocia, recurrence, brachial plexus
palsy, injury prevention, risk management

T he occurrence of shoulder dystocia is largely considered

unpredictable. Epidemiologically, although diabetics’
infants weighing more than 4 kg at birth are disproportion-
ately at higher risk for shoulder dystocia compared with av-
erage weight newborns,1-5 nearly half of shoulder dystocia
events occur in nonmacrosomic infants of otherwise healthy
women.2,6 Although both antepartum and intrapartum risk
factors associated with occurrence of shoulder dystocia are
known,1,2 a substantial number of mother–infant pairs who
actually experience shoulder dystocia during delivery have
none of these risk factors, whereas many more deliver un-
eventfully despite having several risk factors.7 However,
among risk factors for shoulder dystocia, a history of shoul-
der dystocia in a prior delivery carries a recurrence risk of
10% to 16%.8-10 Akin to the single greatest predictor of pre-
term delivery being a history of preterm delivery in a previous
pregnancy, a prior history of delivery complicated by shoul-
der dystocia is indeed the single greatest risk factor for shoul-
*Department of Gynecology and Obstetrics, Division of Maternal Fetal Med-
icine, The Johns Hopkins University School of Medicine, Baltimore, MD.
†Department of Biomedical Engineering, The Johns Hopkins University
School of Medicine, Baltimore, MD.
Some of the research reported in this review was funded by a grant from the
Centers for Disease Control’s National Center for Injury Prevention and
Control: Grants for Traumatic Injury Biomechanics Research Program
04047: #CE00433-03. The contents of the article are the sole opinions of
the authors and do not represent the opinions of the NCIPC.
Address reprint requests to Edith D. Gurewitsch, MD, The Johns Hopkins
Hospital, 600 North Wolfe Street, Phipps 217, Baltimore, MD 21287.
E-mail: egurewi@jhmi.edu
der dystocia recurrence, with odds ratios 7 to 10 times that of
the general population.8-10 Table 1 provides a summary of
studies describing recurrence risks.8-11
Unfortunately, the pathogenesis of shoulder dystocia is
multivariate, screening for “at-risk” individual pregnancies is
poorly predictive (positively or negatively) of its actual oc-
currence, and thus effective interventions for prevention are
few. However, although avoidance of shoulder dystocia in
the general population is neither feasible nor cost-effec-
tive,12-14 concentrating intervention efforts on the particular
subgroup of women with a prior history of shoulder dystocia
has distinct merit. First, the occurrence of shoulder dystocia
in a previous pregnancy indicates the need for a targeted
evaluation. Second, review of the details of a woman’s spe-
cific shoulder dystocia experience can elucidate potentially
modifiable conditions and circumstances amenable to inter-
vention in a subsequent pregnancy. Third, even if shoulder
dystocia recurs, complications may be minimized by individ-
ualized management aimed at reducing or controlling those
factors that predispose to significant morbidity and mortality
arising from shoulder dystocia. In focusing on the women
with a prior history of shoulder dystocia, this review will
concentrate on those aspects of shoulder dystocia and injury
pathophysiology that are knowable and hence modifiable.
It is axiomatic that birth remains a moderately hazardous
process and that certain unintended and unavoidable out-
comes will occur even when complications are anticipated
and managed appropriately. Importantly, it is the untoward
outcomes of the condition and not necessarily the condition
itself that we wish to prevent. Indeed, avoidance of shoulder

0146-0005/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. 185
doi:10.1053/j.semperi.2007.03.009
186 E.D. Gurewitsch, T.L. Johnson, and R.H. Allen

Table 1 Summary of the Literature that Investigates Recurrence of Shoulder Dystocia Among Cohorts of Women with a Recorded History of Shoulder Dystocia in a Prior
dystocia recurrence per se should neither be expected nor set

SD Recurrence Rate/

Failed Trial of Labor

Cesarean Rate for
as a goal. However, its outcome may be significantly im-

13.8%/unknown
proved if those factors that increase the risk for harm are

12.2%/12.8%
11.9%/9.5%

16.7%/9.6%
prepared for and managed. As with any emergency, logical
evidence-tested response to shoulder dystocia— either be-
fore it occurs or once in progress—is directly correlated with
outcome, whether it occurs for the first time or is recurrent.
Unfortunately, fully tested and evidence-validated ap-
proaches to management specifically of the subsequent preg-
nancy and delivery of a woman with a prior history of shoul-
with History of SD (RR)
Recurrence Rate of SD

der dystocia do not exist. Nevertheless, empiric modification

Among All Subjects

of delivery method or of intrapartum management for

11.5% (RR-6.3)
9.8% (RR-17)

15.1% (RR-10)

women with a history of prior shoulder dystocia appears to

— (RR-7)

be commonplace8,10,11; however, without targeted emphasis

on modifiable risk factors, such strategies have had little im-
pact on either recurrence or morbidity.10,11 Our goal is to
propose a reasonable and logical approach to the management
of a subsequent pregnancy and delivery after a shoulder dys-
tocia based on interpretation of the available literature.
Proportion with Cesarean

Recurrence Prevention
Starts Immediately After
for History of SD

the Initial Shoulder Dystocia

5/51 (9.8%)

7/73 (9.6%)
4/78 (5.1%)
N (%)

Preventive strategies for the next possible shoulder dystocia

—

occurrence begin with the proper management of the after-

math of the index event. The incidence of shoulder dystocia
is increasing.1,15,16 This may be due to better diagnoses, better
documentation, or physical factors such as increasing birth
weight and obesity. The same is true for shoulder dystocia-
associated brachial plexus injury.17 Fortunately, the majority
Pregnancy after SD

of shoulder dystocia events are inconsequential in terms of

Proportion Having

51/203 (25.1%)
101/747 (13.5%)
73/602 (12.1%)
78/385 (20.2%)

untoward outcome. Still, up to 27% of shoulder dystocia will

be complicated by some maternal and/or fetal injury, with
N (%)

significant proportion (up to 10%) having attendant perma-

nent sequelae.18 Whether the original shoulder dystocia
event was mild, moderate, or severe, the occurrence of shoul-
der dystocia at any delivery is worthy of documentation and
evaluation.
Background

Documentation
Rate of SD

Abbreviations: SD, shoulder dystocia; RR, relative risk.

0.85%

Regardless of outcome, details of the shoulder dystocia— even

2.0%
1.5%
1.9%

merely that it occurred—must be communicated to the mother

and, by way of documentation in the medical record, to the next
obstetrician who will care for her. Ideally, each participant in the
delivery’s emergency response should author a note about the
Gurewitsch, et al.11 (1993-2004)

event itself and their role. However, there is no substitute for the
Ginsberg, et al.10 (1993-1999)

primary delivering clinician’s giving a comprehensive account-

Study (Time Period)

Lewis, et al.9 (1983-1992)

Smith, et al.8 (1980-1985)

ing of each aspect of the management and its results. Items

important to document are listed in Table 2.
Acker proposed a shoulder dystocia intervention form 15
years ago that was in keeping with the idea that this degree of
detail and documentation is not only important, but should be
standardized.19 The merits of documenting all of this informa-
Delivery

tion from risk management and medicolegal perspectives are

reviewed elsewhere.20-22 However, the relevance of such detail
to assessment of recurrence risk should not be underestimated.
After shoulder dystocia 187

Table 2 Documentation Suggested after a Delivery Compli- functional births characterized by fetopelvic disproportion,
cated by a Shoulder Dystocia That May Help with Manage- there is a continuum of obstruction wherein delivery of the
ment of a Subsequent Pregnancy fetal trunk is impeded following completed (or near com-
Second stage of labor details pleted) delivery of the fetal head. Whereas the most common
Duration definition of shoulder dystocia requires the presence of a
Time spent pushing bony impaction preventing spontaneous delivery of the fetal
Time the head was on the perineum prior to initiating trunk, its pathogenesis derives from variable contributions of
traction both size and positional incompatibilities between fetal
Total head to body delivery time shoulder and maternal pelvic dimensions. Some shoulder
Details of any operative interventions
dystocia events are caused mainly by positional misalignment
Type (forceps or vacuum)
Indications
of only marginally incompatible shoulder and pelvic dimen-
Station initiated sions (usually of a normal-sized infant and normal-sized pel-
Asynclitism (if present) vis). Others arise from a significant shoulder-to-pelvis size
Rotation of the head (if performed) incompatibility necessarily producing a “tight fit” between
Anesthesia details either a large-for-gestational age infant (most common) and a
Use of any prophylactic positioning or maneuvers normal-to-large pelvic cavity or a normal-sized infant and a
Position of head and side of restitution (manual or reduced-capacity pelvis (least common).
spontaneous) In a normal delivery, a winding, forward-progressing mo-
Timing and type of episiotomy with extensions tion occurs as the head and body traverse the birth canal. It is
How and when shoulder dystocia was recognized (eg, this rotational-type motion that accomplishes delivery of the
turtle sign, with first attempt at traction)
shoulders following emergence of the head through the in-
Maneuvers (eg, prophylactic McRoberts’) and traction
prior to diagnosis
troitus. This is effectively an anatomical requirement im-
Evidence for compound presentation posed by the typical arrangement of the bony boundaries of
Other procedures the pelvic inlet, midpelvis, and pelvic outlet, which is akin to
Nuchal cord management threads of a screw. Thus, just after delivery of the head, the
Suctioning of oropharynx shoulders often must come to lie in an oblique orientation
Meconium management relative to the maternal pelvis before they can to descend into
Personnel present the midpelvis and deliver through the pelvic outlet. Shoulder
Description of each maneuver performed dystocia occurs when the shoulders retain the anteroposte-
Maneuver documentation rior orientation they had assumed on the head’s initial entry
Type and sequence of maneuvers (usually in occiput transverse position) into the pelvic inlet
Who performed which maneuvers
and are unable to (or have yet to) rotate spontaneously to
Traction direction and orientation of head and thorax
Effectiveness of each maneuver
occupy the oblique diameter of the pelvis. Subsequently, the
Fetal response to each maneuver shoulders fail to deliver from behind the maternal pubic sym-
Final successful maneuver physis.
Timing of management choices Positional misalignments resulting in shoulder dystocia
Clear descriptions of right versus left shoulder and may also be produced by incomplete entry to the hollow of
anterior versus posterior shoulder (eg, which was the sacrum by the posterior shoulder as the head delivers.
initially anterior, which was manipulated directly, This may occur when there is a compound presentation with
which delivered first) the posterior arm beneath the posterior shoulder, from rela-
Birth weight tive lordosis of the maternal lumbosacral spine or from a
Apgar scores prominent sacral promontory impeding descent of the pos-
Arterial and venous cord gas
terior shoulder. The anterior shoulder then “rides high” and
Infant injury (if any)
Maternal injury (if any)
impacts behind the pubic symphysis. Another cause is insuf-
ficient time allotted to permit spontaneous shoulder rotation
to the normal oblique orientation relative to the pelvis. This
can occur following precipitous delivery of the head pro-
Each aspect provides potential clues to the pathogenesis of that duced either by increased compliance of pelvic tissues or else
particular shoulder dystocia and, regardless of any retrospective by instrumented deliveries. This can even occur simply by
assessment of the specific management’s propriety or prudence, too-hasty application of traction to the head immediately on
thorough review of the precise sequence of events may identify its emergence from the birth canal (eg, “to keep the momen-
potentially modifiable contributors to recurrence and outcome tum going”) without awaiting the next contraction. It is also
for that particular patient. noteworthy that shoulder dystocia is disproportionately
more common among anomalous or stillborn fetuses, sug-
Relating Delivery gesting that physiologic negotiation of the pelvic inlet and
Details to Pathophysiology outlet is indeed a dynamic process, facilitated by normal fetal
Shoulder dystocia results from heterogeneous processes that responsiveness.16 It is likely that any of these antecedents to a
produce the same clinical effect. Among impaired or dys- given shoulder dystocia can lead to an “accidental” or dynam-
188
ically determined misalignment of otherwise compatible fetal
shoulder and maternal pelvic dimensions. This latter situa-
tion is probably associated with a lower recurrence risk com-
pared with shoulder dystocias from other causes. For these
women, a recurrence may best be prevented by avoiding
instrumented deliveries in the future or by patiently allowing
the fetal head to spontaneously rotate to the oblique diame-
ter, before traction is applied to the head and neck.
More severe shoulder dystocia occurs when the anterior
shoulder becomes tightly impacted behind the pubic sym-
physis. In the most severe cases, the posterior shoulder is
simultaneously impacted on the sacral promontory. The
most common cause for this type of shoulder dystocia is a
large-for-gestational age or macrosomic fetus, whose shoul-
der width is typically 14 cm or more.23 Less commonly, the
maternal pelvis may be contracted or have a greater trans-
verse dimension at the pelvic outlet than the obstetric conju-
gate, as in the platypelloid pelvis. Acquired deformities of the
pelvis, such as coccygeal fracture from either trauma or a
previous delivery, may also cause such difficulty in delivery
of the shoulders. It is these types of shoulder dystocia
events—those encountered in significantly size-discrepant
mother–infant dyads—that are associated more often with
untoward outcome.24 It is also these types of shoulder dysto-
cia that would be more likely to recur in subsequent deliver-
ies. The approach to such women in the next pregnancy
would focus on careful monitoring of fetal growth antenatally
and timely delivery for some; others with narrow or reduced
pelvic capacity may be appropriately managed with planned
cesarean birth. We return to these strategies later in this re-
view.
The apparent simplicity of the above distinction between
positionally determined and size-determined pathogenesis of
the index shoulder dystocia is misleading. The contributions
of positional misalignment and true fetopelvic disproportion
to the occurrence of shoulder dystocia at a given delivery in a
given woman are variable and are by no means mutually
exclusive. A grand multipara who experiences shoulder dys-
tocia after a precipitous second stage labor and delivery of an
infant comparably sized to those she has delivered several
times before without incident may have been caused by an
acquired pelvic deformity that prevented normal occupancy
of the hollow of the sacrum by the infant’s posterior shoulder.
Thus, an apparent dynamically determined positional mis-
alignment was also impacted on by narrowed pelvic dimen-
sions. Similarly, an unanticipated finding of a randomized
controlled trial of forceps versus vacuum delivery was that
shoulder dystocia followed the vacuum deliveries more often
than it followed forceps deliveries.25 One explanation for this
outcome was that the vacuum may be more apt than forceps
to be successfully applied to the head of a macrosomic infant
already maximally occupying the pelvic cavity since, unlike
with forceps, the vacuum instrument itself does not have to
be accommodated between the head and the pelvic sidewalls.
Thus, shoulder dystocias seemingly attributable to insuffi-
cient time for shoulder rotation following instrumented as-
sistance with delivery of the head often also involve true size
E.D. Gurewitsch, T.L. Johnson, and R.H. Allen
discrepancy between a large-for-gestational-age fetus and
normal maternal pelvic capacity.
Retrospective Evaluation
of Pelvic Capacity and Infant Biometry
The contour of the pelvis undergoes modification and expan-
sion during pregnancy and delivery by a progressive laxity
that develops in the cartilage between the pubic rami and
within the sacroiliac joints. Thus, the prospective de novo
assessment of the likelihood of shoulder dystocia by tradi-
tional clinical or even medical image-derived pelvimetry per-
formed in either a nullipara or someone who previously has
had uneventful deliveries is bound to have a low yield. It is
also probable that the simple assessment of pelvic diameters
as done in traditional pelvimetry may be too crude an assess-
ment of pelvic capacity where propensity toward shoulder
dystocia is concerned. It is unknown whether volumetric
(three-dimensional) or surface-rendered (topographical)
analysis of bony contours rather than geometric (two-dimen-
sional) assessment could better differentiate women with
otherwise “normal” or “adequate” pelves who nonetheless
may have a predilection for shoulder dystocia from similar-
sized pelves of women who are unlikely to have shoulder
dystocia.
Similarly, not all fetuses of the same weight, even when
large-for-gestational age, are equally predisposed to shoulder
dystocia. The notion of macrosomia refers not simply to an
arbitrary weight cut-off, but rather a disproportionately large
fetal trunk relative to the head. Thus, anthropomorphic mea-
surements of an infant whose delivery was complicated by
shoulder dystocia may also yield some insight into pathogen-
esis.
Table 3 depicts the results of traditional and novel pelvim-
etry and corresponding infant biometry performed within 24
hours of delivery on three mother–infant pairs who experi-
enced shoulder dystocia.26 Based on clinical history alone
without benefit of postpartum pelvimetry, it would be rea-
sonable to surmise that patient 1 must have a “borderline”
pelvis where large-for-gestational-age fetuses are concerned.
She was unable to deliver a 10-lb baby at all, and a baby
weighing just less than 9 lbs experienced shoulder dystocia
during delivery. Patient 2, on the other hand, by clinical
judgment and without benefit of retrospective pelvic and
fetal biometry, could have been judged to be at reduced risk
for developing shoulder dystocia based on her documented
compliance with blood sugar management and ultrasound-
estimated fetal weight that was in a reasonable range.27 Yet, of
the three shoulder dystocia cases, hers was the most severe.
Patient 3 was only modestly compliant with management of
her blood sugar, as demonstrated by sonographic evidence of
accelerated fetal growth by the time she reached term. How-
ever, given the extensive history of her “tested pelvis” for
presumably similarly “macrosomic” (trunk-to-head dispro-
portionate) infants in the past and the relatively mild nature
of the shoulder dystocia she experienced in the context of her
precipitous delivery, it might be reasonable to suspect that
positional misalignment resulting from precipitous delivery
After shoulder dystocia 189

Table 3 Clinical and Computerized Tomographic Pelvimetric Data from Mother–Infant Dyads Examined Within 24 Hours of
Delivery Complicated by Shoulder Dystocia
Case 1 Case 2 Case 3
Clinical presentation VBAC, prior c-sec for CPD Primigravida, insulin-requiring Grand grand multipara
Prior infant 4318 g GDM, euglycemic during (10th delivery),
BMI 46.9, non-diabetic, pregnancy, BMI 34.5, 33-lb recurrent insulin
28-lb wt gain, EFW wt gain, EFW 3900 g, requiring GDM, largest
3800 g, 39-wk NSVD induction at 39 wk, NSVD prior infant 3973 g, no
after 27-min second after 70-min second stage prior history shoulder
stage dystocia, 3476-g sono
EFW @ 37 wk,
precipitous delivery on
arrival to hospital at 38
wks
Shoulder dystocia severity Head-to-body interval 70 Head-to-body interval 2 Head-to-body interval 45
seconds minutes seconds
Required McRoberts’, Required McRoberts’, Required McRoberts’ and
posterior Rubins’ and suprapubic pressure, and suprapubic pressure
Modified Woods’ Screw Woods’ Screw
Immediate neonatal outcome Apgars 9/9, cord pH 7.3, Apgars 7/9, no neonatal Apgars 8/9, temporary
facial bruising, no complications Erb’s palsy
fractures or neurapraxia
Birth weight (g) 3933 3613 4,880
Bisacromial width (cm) 14.33 14.83 14.67
Largest transverse diameter 15.76 12.09 11.72
(normal > 12 cm)
Sacral promontory to top of 11.63 10.41 11.21
pubic symphysis (normal
>11cm)
Interspinous distance (normal 12.47 10.57 11.18
>10 cm)
Intertuberous distance (cm) 14.71 13.36 13.53
Symphyseal separation (cm) 1.82 0.62 0.64
Right/left sacroiliac joint 0.49/0.42 0.34/0.48 0.58/0.62
space (cm)
Volume (cm3)* 1205 714 1463
Surface area (cm2)* 2141 1650 2690
*Novel pelvimetry was derived using 3D Doctor™ and reconstructing CT images in Matlab™ via intensity-based segmentation, stacking, and
surface-fitting of a mesh to the images. Results were validated by comparing 3D Doctor™ measurements against those derived by the
radiologist interpreting the CT scans.

was a greater factor in her shoulder dystocia pathogenesis
than true fetopelvic disproportion.
It is noteworthy that all three infants had similar bisacro-
mial widths. Babies 1 and 3 had proportionate upper and
lower body anthropomorphic dimensions, whereas Baby 2
had markedly asymmetric shoulder girth despite normal
overall body weight and ponderal index, the latter of which is
consistent with well-controlled gestational diabetes.28 Retro-
spectively, the traditionally derived sonographic estimation
of fetal weight of Baby 2 obtained before delivery overesti-
mated the actual birth weight, yet did not fully detect this
shoulder width asymmetry that perhaps might have been
detectable by additional nonstandardized means.29-32
Anecdotally, patient 1 had a subsequent pregnancy that
was scheduled for a repeat cesarean section at 39 weeks to
avoid recurrent shoulder dystocia. However, she presented
only a few hours before her scheduled operation already in
rapidly progressive labor. She successfully delivered vagi-
nally without shoulder dystocia a 3945-g infant, similar to the
previous child who developed shoulder dystocia. Interest-
ingly, the pelvimetric assessment following her initial shoul-
der dystocia delivery was consistent with a low recurrence
risk since it suggested that a true fetopelvic disproportion was
not evident. In light of the retrospective evaluation of pelvic
capacity and infant biometry following this patient’s shoulder
dystocia delivery, it is more probable that dynamic positional
misalignment was more contributory to the pathogenesis of
shoulder dystocia and her 27-minute second stage was more
significant in producing this than was any presumed discrep-
ancy in fetal shoulder and maternal pelvic dimensions based
on her prior cesarean delivery indication.
By contrast, the shoulder dystocia deliveries of patients 2
and 3 were more likely to have resulted from size discrepancy
than from positional misalignment of otherwise compatible
bony dimensions between mother and fetus. In the case of
patient 2, postpartum CT pelvimetry obtained after her index
190
Figure 1 Postpartum CT pelvimetry following shoulder dystocia. CT
images were obtained from a grand grand multiparous (para 9)
woman immediately following delivery, which was complicated by
shoulder dystocia. (A) Largest transverse diameter. (B) Anteropos-
terior diameter (sacral promontory to top of pubic symphysis); im-
age shows marked angulation of sacrococcygeal joint consistent
with healed fracture. (C) Interspinous diameter. (D) Intertuberous
diameter. Acquired pelvic deformity, likely sustained during earlier
delivery, probably contributed to “high-riding” anterior shoulder
resulting in shoulder dystocia.
shoulder dystocia event revealed a reduced pelvic capacity,
suggesting that she and her infant were size incompatible.
Given these findings, it would seem reasonable to propose
that recurrence of shoulder dystocia would be likely in this
patient, and she would be a good candidate for a scheduled
elective cesarean delivery in her next pregnancy.
Patient 3’s postpartum CT evaluation (Fig. 1) shows a
rather capacious pelvic cavity by standard measurements.
Given the clinical history alone, it would appear as though
the shoulder dystocia was more likely “sporadic” and attrib-
utable to positional misalignment in this patient. Even
though her infant was large-for-gestational age, it was not
“macrosomic” as defined by trunk-to-head disproportion (or
even by criteria for diabetic gravida given in the 2002 ACOG
Practice Bulletin on Shoulder Dystocia). Indeed, her antena-
tal estimated fetal weight was at the 72nd percentile. Based
on this, it might have been reasonable to surmise that recur-
rence of shoulder dystocia based on fetopelvic size discrep-
ancy would be relatively low in this patient, and potentially
could be modified further with improved diabetic manage-
ment to avoid excess neonatal adiposity.
However, a surprise finding of an acquired pelvic defor-
mity from a healed coccygeal fracture (likely sustained at the
delivery that immediately preceded the index shoulder dys-
tocia delivery) suggests a different pathogenesis for shoulder
E.D. Gurewitsch, T.L. Johnson, and R.H. Allen
dystocia. The sharp angulation of the sacrococcygeal joint
(Fig. 1b) likely impeded normal occupancy of the hollow of
the sacrum by the posterior shoulder in the index delivery.
This, in turn, would have caused the anterior shoulder to be
displaced forward and cephalad and become lodged behind
the pubic symphysis in an anteroposterior orientation. Such
a sacrococcygeal deformity could potentially reduce the effi-
cacy of first-line shoulder dystocia maneuvers that still main-
tain the shoulders in the anteroposterior orientation.33 Addi-
tionally, given the borderline small transverse diameter of her
pelvic inlet, the anteroposterior orientation is perhaps more
naturally predisposed to being the “path of least resistance”
for fetal descent in this patient. Thus, the combination of her
acquired deformity and her anthropoid-type pelvic architec-
ture makes her likely to experience recurrent shoulder dys-
tocia in future deliveries. A planned cesarean delivery for
future pregnancy should be considered. If a vaginal delivery
is planned, then antenatal management should focus on bet-
ter antenatal control of fetal growth and, with awareness of
the potential interference by the pelvic deformity, the deliv-
ering clinician can opt to prioritize rotational type maneuvers
as initial management for any recurrent shoulder dystocia,
which could reduce the risk of injury.34
Patient Counseling
It is often counterintuitive or seemingly premature to attempt
to counsel a patient regarding the possible pathogeneses of a
just-experienced shoulder dystocia or to prognosticate either
about its possible recurrence or about the long-term outcome
of any associated injuries. Nevertheless, it is important to
explain, in a candid and honest manner, what transpired,
what are the possible causes, and what might be anticipated
in the future and to begin to involve the patient actively in her
own and her child’s future care. Perhaps precisely because
there are so many unknowns about exact pathogeneses, risk
factors, prognostic indicators, and future management plans,
it is critically important to educate the woman whose delivery
was complicated by shoulder dystocia about the often unpre-
dictable and unpreventable nature of the complication, en-
sure her understanding that it is a significant issue as far as
future childbearing is concerned, and elicit the patient’s pref-
erences and priorities when planning future deliveries.
Until more information is amassed through epidemiolog-
ical and clinical studies, it is reasonable to encourage the
patient’s cooperation in investigating possible causes and
commitment to compliance with proposed management
schema that would aim to ameliorate potentially modifiable
contributors to risk. However, the inability to guarantee a
particular outcome or to entirely avoid risk in any chosen
mode of delivery should always be explained clearly. De-
pending on a particular patient’s degree of risk aversion, she
should be encouraged to consider how willing she would be
to maintain a flexible, dynamic, and evolving plan for deliv-
ery throughout the next pregnancy and perhaps even during
her next trial of labor. Knowledge of the occurrence of shoul-
der dystocia, even if otherwise uneventful in terms of diffi-
culty of management or associated morbidity, is important
After shoulder dystocia 191

Table 4 Comparison of Risk Factors Between Mild and Severe Shoulder Dystocia56
Mild Shoulder Severe Shoulder
Dystocia Dystocia*
N Value** N Value** P value
Maternal height (cm) 266 162.9 ⴞ 6.7 143 162.7 ⴞ 6.8 0.82
Maternal weight (kg) 274 87.4 ⴞ 18.4 148 93.7 ⴞ 22.0 0.002
Weight gain (>15.9 kg) 250 100 (40.0) 138 81 (58.7) 0.0004
Second stage abnormality 279 125 (44.8) 154 61 (39.6) 0.30
Prolonged second stage 279 43 (15.4) 154 23 (14.9)
Precipitous second stage 279 82 (29.3) 154 38 (24.6)
Operative vaginal delivery 290 93 (32.1) 170 62 (36.4) 0.34
Forceps 290 36 (12.4) 170 13 (7.6)
Vacuum 290 47 (16.2) 170 38 (22.3)
Combined 290 10 (3.4) 170 11 (6.5)
*Severe shoulder dystocia defined as have met at least one of the following three criteria: 1) head-to-body interval >90 seconds; 2) use of either
deliberate proctoepisiotomy or direct manipulation of the fetus (eg, rotational maneuvers, delivery of the posterior arm); and/or 3) evidence
of neonatal depression at birth (5-minute Apgar <7 and/or arterial cord pH <7.1).
**Mean ⴞ SD or N (%).

for the empowerment of both the patient and the obstetrician with shoulder dystocia management techniques that could
who will deliver her next child. reduce necessary traction at any delivery.34,42,43

The Interval Period: Preconceptual

Before the Next Pregnancy
Follow-Up of Infant Status
If the infant had sustained an injury at the index shoulder
dystocia delivery, whether skeletal or neurologic, the im-
portance of follow up of the infant’s condition must be
stressed to the patient (to optimize long-term outcome18),
as well as to the delivering clinician. Not only is ongoing
sensitive and caring communication with the family sig-
nificant from a risk management perspective,35,36 the in-
formation is also invaluable to management of the subse-
quent pregnancy and delivery. Parental input is extremely
important in this process.
For the delivering clinician, knowledge of whether an
infant that was discharged from the newborn nursery with
an as-yet unresolved brachial plexus palsy eventually re-
covers completely or requires surgical intervention and
remains with a permanent deficit is critical to retrospective
assessment of the management of the index shoulder dys-
tocia. Whereas many brachial plexus injuries of a tempo-
rary or even mild permanent nature (eg, restricted to the
upper plexus with only mild functional deficit in the
shoulder’s active range of motion) may have myriad etiol-
ogies (including malpositioning in utero),37 shoulder dys-
tocia-associated brachial plexus injuries involving all
nerve roots from C5 to C8/T1 and/or avulsion of any nerve
root from the spinal cord must have involved some degree
of externally applied lateral traction of sufficient magni-
tude and rate to produce an injury of such an extent.38-41
Setting aside whether the degree of traction applied was
within the standard of care, the contribution of externally
applied traction to the eventual outcome cannot, and
should not, be denied. Rather, it behooves the clinician to
learn from the experience, and familiarize him/herself
Management of Maternal Risk Factors
Among women with a history of shoulder dystocia in a pre-
vious pregnancy, predictors of recurrence seem to vary. Sig-
nificant differences, as well as lack thereof between women
with and without recurrent shoulder dystocia, have been
found for such variables as parity at index delivery (eg, prior
successful delivery without shoulder dystocia), maternal
weight or diabetic status, operative delivery, and length of
second stage.8-10 However, a consistent correlation has been
found between subsequent shoulder dystocia and high birth
weight in the subsequent pregnancy, as well as comparative
birth weight with the index pregnancy, especially in diabetic
pregnancies.44
The most recognized antepartum risk factors for shoulder
dystocia are also the same risk factors for fetal macrosomia.
Aside from a history of shoulder dystocia in a prior preg-
nancy, other risk factors include maternal obesity, weight
gain during pregnancy of more than 35 pounds, gestational
diabetes and pregestational diabetes without vascular com-
plications, and postdatism.21 As shown in Table 4, severe
compared with mild shoulder dystocia is more likely to be
associated with obese gravidas weighing more than 200
pounds or who gain excessive weight during pregnancy. If a
clinician is fortunate enough to have a motivated patient with
a history of shoulder dystocia who wishes to reduce the risk
of fetal macrosomia before her next pregnancy, recommen-
dation of weight reduction may be the single intervention
with the greatest impact.
Screening for occult diabetes is also reasonable. Some
women with a history of a false-positive glucose challenge
test may well be predisposed to macrosomia, suggesting
some degree of impaired glucose tolerance not yet manifested
as overt diabetes.45 In most instances, these women likely
have some degree of a metabolic syndrome or excess adipose
192
tissue that contributes to hyperinsulinemia, a precursor to
overt diabetes. Proper nutrition and exercise are well estab-
lished as effective modifiers of this effect. A commitment to
sustained lifestyle changes may improve future pregnancy
outcome, as well as the woman’s long-term health status
overall.
Antenatal Management
of the Subsequent Pregnancy
Eliciting the History and
Assessing Patient-Specific Recurrence Risk
Just as it is important for the delivering clinician who man-
aged a given patient’s shoulder dystocia to carefully docu-
ment and communicate to the patient the details of the event, so
too should any practitioner meeting an obstetric patient for
the first time specifically attempt to elicit a history of shoulder
dystocia in a prior pregnancy. The major antepartum (listed
above) and intrapartum risk factors for shoulder dystocia
should be assessed. Intrapartum risk factors include opera-
tive vaginal delivery and abnormal second-stage length, ei-
ther prolonged or precipitous. Even if there is no history of
gestational diabetes, the patient should be asked to recall
whether she had a false-positive glucose challenge test45 or
perhaps had not been screened. If the infant whose delivery
was complicated by shoulder dystocia had weighed more
than 4 kg at birth, this is reason enough to perform an early
glucose screen at registration. A specific discussion of nutri-
tion and monitored weight gain is warranted, especially if the
previous infant was large-for-gestational age. Vigilance for
impaired glucose tolerance leading to accelerated fetal
growth, with dietary modification and flexible medical ther-
apy as needed,46,47 should be a mainstay of antenatal man-
agement throughout the next pregnancy of any such patient,
especially one with a history of prior shoulder dystocia.
For those women whose early glucose screen is negative, it
is important to rescreen at the appropriate gestational age
(26-28 weeks). For those with a false-positive 1-hour 50-g
glucose screen (normal 3-hour glucose tolerance test) early in
gestation, repeat “screening” in the early third trimester
should be by the diagnostic 3-hour test rather than the
1-hour screening test. This is based on the principle that a
false-positive screening test may not be sensitive enough,
when repeated in a given patient, to consistently detect the
condition being screened for.
Patients who have a normal glucose screening test at 26 to
28 weeks who later develop either clinical or sonographic
evidence of accelerated fetal growth should be considered for
retesting again at 30 to 34 weeks since there may be delayed
detection of up to 15% of gestational diabetics. For those
women with a history of shoulder dystocia who, in the sub-
sequent pregnancy, manifest one abnormal value on the
3-hour glucose tolerance test obtained after an abnormal glu-
cose screen at 26 to 28 weeks, retesting should probably
occur at 30 to 34 weeks, regardless of growth parameters by
that stage. If there is any maternal or fetal suggestion of glu-
E.D. Gurewitsch, T.L. Johnson, and R.H. Allen
cose intolerance, aggressive management of diet and blood
glucose is warranted.
For those women with a history of shoulder dystocia who
are diagnosed with gestational diabetes in a subsequent preg-
nancy, it is especially important to monitor blood glucose
levels at several time points each day. A low threshold for
initiating oral hypoglycemic or insulin therapy may be ap-
propriate in these gravidas as well, especially if there is evi-
dence of accelerated fetal growth while on diet despite report
of normal blood glucose levels.47
Assessment of Fetal Growth
It is well established that the margin for error for ultrasound
estimation of fetal weight is too large to be relied on heavily
for predicting delivery complications.48 However, when
there has been a previous shoulder dystocia (similar to cases
with gestational diabetes), serial ultrasound measurements of
the trajectory of fetal growth are often more informative than
a single growth estimation for assessing the need for inter-
vention. Particular attention should be given to evidence of
asymmetrical growth using ponderal indices.
The most common way to assess for accelerated truncal
growth is the head circumference-to-abdominal circumfer-
ence ratio.49 If below 0.9 near term, the risk for shoulder
dystocia may be increased, even when the overall estimated
fetal weight has not surpassed the 90th percentile.
For the gestational diabetic apparently well managed on
diet alone, there is some evidence to suggest that empiric
initiation of insulin therapy once the abdominal circumfer-
ence exceeds the 75th percentile may curtail further acceler-
ated fetal growth.46 Although not studied prospectively, this
may be reasonable in a gestational diabetic with a history of a
previous shoulder dystocia who desires to have a subsequent
vaginal delivery.
Planning the Delivery: Mode and Timing
The practice of inducing labor for “impending macrosomia”
has no proven benefit. Such practices increase the rate of
cesarean delivery performed for failed induction without im-
pacting the incidence of shoulder dystocia.50-52 This lack of
evidentiary support for early “elective” inductions and the
persistent inability to shrink the margin of error in ultra-
sound estimation of fetal weight14 led the American College
of Obstetricians and Gynecologists in 2002 to revise their
Practice Bulletin entitled “Shoulder Dystocia,” raising the cut-
offs for estimated fetal weight above which primary cesarean
section without trial of labor may be offered, to 4500 g for the
diabetic gravida and to 5000 g for the nondiabetic gravida.
However, these recommendations may not apply for some
women. There is still some evidence that lower estimated
fetal weight thresholds for cesarean birth may be appropriate,
particularly in women with “preexisting” predilection for
shoulder dystocia.53,54 Although this evidence is not specific
to the woman with a history of shoulder dystocia, these
women may benefit the most from lower thresholds. Contin-
ued research is needed to more appropriately individualize
intrapartum management for such women.
After shoulder dystocia
Regardless of the specific estimated fetal weight cut-off
used to offer a primary cesarean section, only a small percent-
age of parturients will ever meet these criteria. What then can
be said about the strategy of elective induction of labor in an
attempt to ensure a lower birth weight than would result
from expectant management and, thereby, potentially avoid
shoulder dystocia? Whereas ineffective as a strategy when
applied to the general population, this may have merit in the
gravida with a history of prior shoulder dystocia. First, since
she is already parous, her risk of failed induction is signifi-
cantly lower compared with her nulliparous counterpart.
Second, postdatism is among the potentially modifiable an-
tepartum risk factors for shoulder dystocia that would be
eliminated by elective induction at term. Third, the risk of
recurrence of shoulder dystocia correlates with similar or
greater birth weight at subsequent delivery compared with
the index shoulder dystocia delivery.10 Finally, and most im-
portantly, it is the severe shoulder dystocia, which is more
likely to occur in obese gravida with macrosomic infants,55
that is most predictive of subsequent injury,56 and that we
would most wish to prevent or mitigate. However, these se-
vere shoulder dystocias occur in the same type of patient in
whom complications of cesarean delivery are also more likely
to occur. Therefore, a strategy of early induction of labor at
term, before development of substantial trunk-to-head size
discrepancy, may present a balanced alternative to elective
primary cesarean delivery in these women.
Anticipating
Shoulder Dystocia Recurrence
Simulation-Based Training and Rehearsal
Since the exact threshold for permanent injury in in vivo
shoulder dystocia is not known, the goal in shoulder dystocia
management should be to reduce uterine force and clinician
traction as much as possible. Maternal pushing and uterine
forces can only be controlled in a limited way; these also have
limited contribution to injury.57 Therefore, training and on-
going research must focus on how clinician-applied traction
might be reduced.43 This is especially important for shoulder
dystocia management because the very natural, unconscious
response when attempting to deliver the fetus once first at-
tempts have failed is to increase traction on subsequent at-
tempts.33,43,58 This training can be accomplished through
simulation-based training and with drills.
Already addressed in other fields of medicine, obstacles to
comparative research and provider training within the clinical
setting are best overcome by use of medical simulation.59,60 For
surgically oriented skills, including vaginal delivery techniques,
there is no substitute for mechanical simulation to allow haptic
feedback and biofidelic learning for the student obstetric pro-
vider.61,62 Real-time measurement of actual clinician-applied
forces during simulated shoulder dystocia deliveries—where as-
sociated mechanical fetal response can be measured prospec-
tively in a fetal model—may enable clinicians to self-assess more
accurately the magnitude, direction, and rate of traction they
apply during delivery.63
193
Simulation-based experimentation has also proven the hy-
pothesis that rotational maneuvers to resolve shoulder dys-
tocia require less applied force than McRoberts’ positioning.
Indeed, brachial plexus stretch is also reduced by a factor of
three with use of Rubin’s maneuver as an initial approach to
shoulder dystocia management.34 The comparative advan-
tage of fetal maneuvers for reducing brachial plexus strain
was also predicted computationally.64 Clinicians are enjoined
not to fear fetal manipulation, but to familiarize themselves
with the techniques by availing themselves of simulation-
based training and even to practice routine assessment of fetal
shoulder position by direct palpation at every delivery.65
The likelihood of favorable outcome of shoulder dystocia
is maximized by preparation and coordination of a well-re-
hearsed response by all members of the health care team.
Such resource utilization and management is best ensured by
systematic rehearsal.66 Communication and continuous feed-
back to team members regarding effectiveness of interven-
tions or lack thereof is essential to this effort. Otherwise,
cross-purposeful actions of two or more team members can,
albeit unintentionally, increase the risk for injury. Important
components of shoulder dystocia management include a
continuous assessment of the success or failure of each ma-
neuver, employing an alternative maneuver within approxi-
mately 30 seconds of a previous failed maneuver,67 and main-
taining a calm and unhurried approach by the primary
clinician. Each of these elements, as well as how and when to
communicate with the family during and after a shoulder
dystocia, can be rehearsed during drills until they progress
smoothly.
Conclusion
Considered one of the greatest fears of obstetric providers,
associated with considerable risk for injury to both mother
and fetus and fraught with potential liability for the clinician,
severe shoulder dystocia is an emergency that no one would
care to relive. Thus, after a woman has experienced the com-
plication, managing the risk of its recurrence in a subsequent
delivery is desirable and prudent. Indeed, unlike other spo-
radically occurring and unpredictable complications of preg-
nancy, recurrence of shoulder dystocia is not infrequent. Yet
shoulder dystocia’s definitive prevention, namely cesarean
delivery, while expedient and facile is also costly and poten-
tially risky,54,68 especially in the obese and diabetic gravida.
Because many women choose to attempt a vaginal birth after
a shoulder dystocia, it is important to use what information
there is in the literature to form a rational and reasonable
management plan for risk modification and for management
of a shoulder dystocia event should it recur. At least some of
the risk of shoulder dystocia recurrence indeed may be quan-
tifiable and potentially modifiable during subsequent preg-
nancies of individual women with a history of shoulder
dystocia. Importantly, avoidance of shoulder dystocia recur-
rence per se should neither be expected nor used as a mea-
sure of success in management. As with other medical and
obstetric conditions at higher risk for morbidity and mortal-
ity, it is the untoward outcomes of shoulder dystocia and not
194
necessarily shoulder dystocia itself that we wish to prevent.
Thus, circumstances and conditions that increase the risk of
injury from shoulder dystocia should be targeted, and if there
is recurrence, the goal becomes the atraumatic resolution of
the shoulder dystocia.69
Acknowledgments
The authors wish to thank Dr. Elliot Fishman of The Johns
Hopkins University School of Medicine’s Department of Ra-
diology for his assistance with interpretation of the CT pel-
vimetry.
References
1. Acker DB, Sachs BP, Friedman EA: Risk factors for shoulder dystocia.
Obstet Gynecol 66:762-768, 1985
2. Benedetti TJ, Gabbe SG: Shoulder dystocia: a complication of fetal
macrosomia and prolonged second stage of labor with midpelvic deliv-
ery. Obstet Gynecol 52:526-529, 1978
3. Berard J, Dufour P, Vinatier D, et al: Fetal macrosomia:risk factors and
outcome: a study of the outcome concerning 100 cases ⬎4500 g. Eur J
Obstet Gynecol Reprod Biol 77:51-59, 1998
4. Hassan AA: Shoulder dystocia: risk factors and prevention. Aust NZ J
Obstet Gyn 28:107-109, 1988
5. Nesbitt T, Gilbert W, Herrchen B: Shoulder dystocia and associated risk
factors with macrosomic infants born in California. Am J Obstet Gy-
necol 179:476-480, 1998
6. Acker DB, Sachs BP, Friedman EA: Risk factors for shoulder dystocia in
the average-weight infant. Obstet Gynecol 67:614-618, 1986
7. Geary M: Risk factors and fetal outcome in cases of shoulder dystocia
compared with normal deliveries of a similar birthweight. Br J Obstet
Gynaecol 104:121-122, 1997
8. Smith RB, Lane C, Pearson JF: Shoulder dystocia: what happens at the
next delivery? Br J Obstet Gynecol 101:713-715, 1994
9. Lewis D, Raymond RC, Perkins MB, et al: Recurrence rate of shoulder
dystocia. Am J Obstet Gynecol 172:1369-1371, 1995
10. Ginsberg NA, Moisidis C: How to predict recurrent shoulder dystocia.
Am J Obstet Gynecol 184:1427-1430, 2001
11. Gurewitsch E, Landsberger E, Jain A, et al: Does knowledge of prior
shoulder dystocia affect management and outcome of subsequent de-
liveries? Am J Obstet Gynecol 193:S42, 2005
12. Blickstein I, Ben-Arie A, Hagay ZJ: Antepartum risks of shoulder dys-
tocia and brachial plexus injury for infants weighing 4200 g or more.
Gynecol Obstet Invest 45:77-80, 1998
13. Nagey DA: Can shoulder dystocia be prevented? Am J Obstet Gynecol
163:1095-1096, 1990
14. Rouse DJ, Owen J, Goldenberg RL, et al: The effectiveness and costs of
elective cesarean delivery for fetal macrosomia diagnosed by ultra-
sound. J Am Med Assoc 276:1480-1486, 1996
15. Spong CY, Beall M, Rodrigues D, et al: An objective definition of shoul-
der dystocia: prolonged head to body delivery intervals and/or the use
of ancillary obstetric maneuvers. Obstet Gynecol 86:433-440, 1995
16. Gurewitsch ED, Johnson E, Hamzehzadeh S, et al: Risk factors for
brachial plexus injury with and without shoulder dystocia. Am J Obstet
Gynecol 194:486-492, 2006
17. Bager B: Perinatally acquired brachial plexus palsy: A persisting chal-
lenge. Acta Paediatr 86:1214-1219, 1997
18. Waters PM: Comparison of the natural history, the outcome of micro-
surgical repair, and the outcome of operative reconstruction in brachial
plexus palsy. J Bone Jt Surg 81A:649-659, 1999
19. Acker DB: A shoulder dystocia intervention form. Obstet Gynecol 78:
150-151, 1991
20. Peleg D, Powell S: Shoulder dystocia: prediction, prevention, manage-
ment, and defense. Postgraduate obstetrics and gynecology 18:1-6,
1998
21. Dildy GA, Clark SL: Shoulder dystocia: risk identification. Clin Obstet
Gynecol 43:265-282, 2000
E.D. Gurewitsch, T.L. Johnson, and R.H. Allen
22. Gross TL, Sokol RJ, Williams T, et al: Shoulder dystocia: a fetal-physi-
cian risk. Am J Obstet Gynecol 15:1408-1414, 1987
23. Verspyck E, Goffinet F, Hellot MF, et al: Newborn shoulder width: a
prospective study of 2222 consecutive measurements. Br J Obstet Gy-
necol 106:589-593, 1999
24. Gurewitsch ED, Donithan M, Stallings S, et al: Episiotomy versus fetal
manipulation in managing severe shoulder dystocia: a comparison of
outcomes. Am J Obstet Gynecol 191:911-916, 2004
25. Bofill JA, Rust OA, Devidas M, et al: Shoulder dystocia and operative
vaginal delivery. J Matern Fetal Med 6:220-224, 1997
26. Johnson T, Allen R, Fishman E, et al: Use of traditional and novel CT
pelvimetry distinguish between different types of shoulder dystocia. J
Soc Gynecol Invest 13:117A, 2006
27. Sokol RJ, Blackwell SC: ACOG practice bulletin: shoulder dystocia.
Number 40, November 2002. Int J Gynecol Obstet 80:87-92, 2003
28. Rosenn B, Miodovnik M, Combs CA, et al: Preconception management
of insulin-dependent diabetes: improvement of perinatal outcome. Ob-
stet Gynecol 1991:846-849, 1991
29. Klaij FA, Geirsson RT, Nielsen H, et al: Humerospinous distance mea-
surements: accuracy and usefulness for predicting shoulder dystocia in
delivery at term. Ultrasound Obstet Gynecol 12:115-119, 1998
30. Cohen BF, Penning S, Ansley D, et al: The incidence and severity of
shoulder dystocia correlates with a sonographic measurement of asym-
metry in patients with diabetes. Am J Perinatol 16:197-201, 1999
31. Riska A, Lain H, Voutilainen P, et al: Estimation of fetal shoulder width
by measurement of the humerospinous distance by ultrasound. Ultra-
sound Obstet Gynecol 7:272-274, 1996
32. Mintz MC, Landon MB, Gabbe SG, et al: Shoulder soft tissue width as a
predictor of macrosomia in diabetic pregnancies. Am J Perinatol 6:240-
243, 1989
33. Gurewitsch ED, Allen RH: Fetal manipulation for managment of shoul-
der dystocia. Fetal Matern Med Rev 17:239-280, 2006
34. Gurewitsch E, Kim E, Yang JH, et al: Comparing McRoberts’ and Ru-
bin’s maneuvers for initial management of shoulder dystocia: an objec-
tive evaluation. Am J Obstet Gynecol 192:153-160, 2005
35. Bellew M, Kay SP: Early parental experiences of obstetric brachial
plexus palsy. J Hand Surg 28B:339-346, 2003
36. Queenan JT: Professional liability: some solutions. Obstet Gynecol 98:
3658, 2001
37. Papazian O, Alfonso I, Yaylali I, et al: Neruophysiological evaluation of
children with traumatci radiculopathy, plexopathy, and peripheral
neuropathy. Semin Pediatr Neurol 7:26-35, 2000
38. Metaizeau JP, Gayet C, Plenat F: [Brachial plexus injuries: an experi-
mental study]. Chirug Ped 20:159-163, 1979
39. Sunderland S, Bradley KC: Stress-strain phenomena in human periph-
eral nerve trunks. Brain 84:102-119, 1961
40. Slooff ACJ, Ubachs JMH: Brachial plexus impairment: a birth trauma?
Am J Obstet Gynecol 169:230, 1993
41. Ubachs JMH, Slooff ACJ, Peeters LLH: Obstetric antecedents of surgi-
cally treated obstetric brachial-plexus injuries. Br J Obstet Gynecol
102:813-817, 1995
42. Gurewitsch ED, Johnson E, Hamzehzadeh S, et al: Risk factors for
brachial plexus injury with and without shoulder dystocia. Am J Obstet
Gynecol 194:486-492, 2006
43. Allen RH, Sorab J, Gonik B: Risk factors for shoulder dystocia: an
engineering study of clinician-applied forces. Obstet Gynecol 77:352-
355, 1991
44. Yogev Y, Langer O: Recurrence of gestational diabetes: pregnancy out-
come and birth weight diversity. J Matern Fetal Neonatal Med 15:56-
60, 2004
45. Stamilio DM, Olsen T, Ratcliffe S, et al: False-positive 1-hour glucose
challenge test and adverse perinatal outcomes. Obstet Gynecol 103:
148-156, 2004
46. Raychaudhuri K, Maresh MJ: Glycemic control throughout pregnancy
and fetal growth in insulin-dependent diabetes. Obstet Gynecol 95:
190-194, 2000
47. Schwartz R, Teramo KA: Effects of diabetic pregnancy on the fetus and
newborn. Semin Perinatol 24:120-135, 2000
48. Rouse DJ, Owen J: Sonography, suspected macrosomia, and prophy-
After shoulder dystocia
lactic cesarean: a limited partnership. Clin Obstet Gynecol 43:326-334,
2000
49. Spellacy WN, Miller S, Winegar A, et al: Macrosomia: maternal char-
acteristics and infant complications. Obstet Gynecol 66:158-161, 1985
50. Combs CA, Singh NB, Khoury JC: Elective induction versus spontane-
ous labor after sonographic diagnosis of fetal macrosomia. Obstet Gy-
necol 81:491-496, 1993
51. Gonen O, Rosen DJ, Dolfinn Z, et al: Induction of labor versus expect-
ant management in macrosomia: a randomized study. Obstet Gynecol
89:913-917, 1997
52. Sanchez-Ramos L, Bernstein S, Kaunitz AM: Expectant management
versus labor induction for suspected fetal macrosomia: a systematic
review. Obstet Gynecol 100:997-1002, 2002
53. Conway DL: Choosing route of delivery for the macrosomic infant of a
diabetic mother: cesarean section versus vaginal delivery. J Matern Fetal
Neonatal Med 12:442-448, 2002
54. Conway DL: Delivery of the macrosomic infant: cesarean section versus
vaginal delivery. Semin Perinatol 26:225-231, 2002
55. Allen R, Petersen S, Moore P, et al: Do antepartum and intrapartum risk
factors differ between mild and severe shoulder dystocia? Am J Obstet
Gynecol 189:S208, 2003
56. Dyachenko A, Ciampi A, Fahey J, et al: Prediction of risk for shoulder
dystocia with neonatal injury. Am J Obstet Gynecol 195:1544-1549,
2006
57. Allen RH, Cha SL, Kranker LM, et al: Comparing mechanical fetal
response during descent, crowning and restitution among deliveries
with and without shoulder dystocia. Am J Obstet Gynecol 2007, in
press
58. Allen RH, Bankoski BR, Butzin CA, et al: Comparing clinician-applied
loads for routine, difficult and shoulder dystocia deliveries. Am J Obstet
Gynecol 171:1621-1627, 1994
59. Kim J, Neilipovitz D, Cardinal P, et al: A pilot study using high-fidelity
simulation to formally evaluate performance in the resuscitation of
195
critically ill patients: The University of Ottawa Critical Care Medicine,
High-Fidelity Simulation, and Crisis Resource Management I Study.
Crit Care Med 34:2167-2174, 2006
60. Rosenthal ME, Adachi M, Ribaudo V, et al: Achieving housestaff com-
petence in emergency airway management using scenario based simu-
lation training: comparison of attending vs housestaff trainers. Chest
129:1453-1458, 2006
61. Strom P, Hedman L, Sarna L, et al: Early exposure to haptic feedback
enhances performance in surgical simulator training: a prospective ran-
domized crossover study in surgical residents. Surg Endosc 20:1383-
1388, 2006
62. Jude DC, Gilbert GG, Magrane D: Simulation training in the obstetrics
and gynecology clerkship. Am J Obstet Gynecol 195:1489-1492, 2006
63. Gurewitsch E, Cha S, Johnson T, et al: Traction training for routine and
shoulder dystocia delivers: an experimental study. Am J Obstet Gy-
necol 193:S41, 2005
64. Gonik B, Costello R, Zhang N, et al: Effect of clinician applied maneu-
vers on fetal brachial plexus strain during shoulder dystocia delivery.
Am J Obstet Gynecol 189(6 Suppl 1):S200, 2003
65. Reid DE: Conduct of normal labor and the puerperium, in Reid DE
(ed): Textbook of Obstetrics. Philadelphia, PA, W.B. Saunders Com-
pany, 1962, pp 448-489
66. Freeth D, Ayida G, Berridge EJ, et al: MOSES: Multidisciplinary Ob-
stetric Simulated Emergency Scenarios. J Interprof Care 20:552-554,
2006
67. Gurewitsch E, Stallings S, Tam W, et al: Does maneuver rate affect
shoulder dystocia outcome? Am J Obstet Gynecol 191:S66, 2004
68. Langer O, Berkus MD, Huff RW, et al: Shoulder dystocia: should the
fetus weighing ⱖ4000 grams be delivered by cesarean section? Am J
Obstet Gynecol 165:831-837, 1991
69. Mollberg M, Hagberg H, Bager B, et al: High birthweight and shoulder
dystocia: the strongest risk factors for obstetrical brachial plexus palsy
in a Swedish population-based study. Acta Obstet Gynecol Scand 84:
654-659, 2005
Epidemiologic Approaches for
Studying Recurrent Pregnancy Outcomes:
Challenges and Implications for Research
Cande V. Ananth, PhD, MPH

The study of recurrence of pregnancy-related complications and outcomes can offer

powerful insights to understanding patient-related risks for subsequent pregnancies. Such
studies, when designed, analyzed, and interpreted correctly, can help distinguish genetic
from environmental causes that portend increased recurrence of a particular pregnancy
complication (eg, recurrence of gestational diabetes) or a perinatal outcome (eg, recur-
rence of preterm birth or preeclampsia). Recurrence risk studies can be challenging in
other dimensions, including inherent biases, generalizability of findings, inadequate study
size, and inappropriate use of analytic models to study recurrence. Other common mis-
perceptions in studies of recurrence risk are highlighted, including issues with terminology
and interpretation of recurrence risks. A review of available epidemiologic study designs is
presented and the usefulness and applicability of each design for addressing specific
etiologic questions as they relate to recurrence risks are contrasted.
Semin Perinatol 31:196-201 © 2007 Elsevier Inc. All rights reserved.

KEYWORDS recurrence risk, heterogeneity, epidemiology, clustered data, case-crossover

design, prospective cohort, cohort studies

M ost diseases in medicine do not tend to recur. Preg-

nancy is perhaps the only state that provides the op-
portunity to study recurrence risks. The study of recurrence
of pregnancy-related complications and outcomes can offer
powerful insights to understanding patient-related risks for
subsequent pregnancies. Whereas recurrent outcome re-
search can help guide clinical care for future pregnancies, it
also affords a unique opportunity to explore disease etiolo-
gies through the study of heterogeneity in risk factors or
those that change across successive pregnancies.
This paper provides an overview of some of the fundamen-
tal concepts in studying recurrence, focusing largely on avail-
able epidemiologic and statistical approaches. In addition,
some of the common misperceptions about recurrence re-
search in human reproduction (broadly defined) are ad-
dressed. In particular, several challenges in studying recur-
Division of Epidemiology and Biostatistics, Department of Obstetrics, Gy-
necology, and Reproductive Sciences, UMDNJ-Robert Wood Johnson
Medical School, New Brunswick, NJ.
Address reprint requests to Cande V. Ananth, PhD, MPH, Division of Epidemi-
ology and Biostatistics, Department of Obstetrics, Gynecology, and Repro-
ductive Sciences, UMDNJ-Robert Wood Johnson Medical School, 125
Paterson Street, New Brunswick, NJ 08901-1977. E-mail: cande.
ananth@umdnj.edu
rent events in pregnancy are highlighted with particular
emphasis on: (1) challenges in accurately defining the end-
point being observed; (2) choosing an appropriate epidemi-
ologic design for studying patterns of recurrence risks; (3)
confounding; (4) limitations contributed through various bi-
ases in epidemiologic studies; (5) sample size, statistical
power, and analytic models; (6) a note on terminology; and
(7) interpretation of recurrence risks. Finally, an outline of
some unifying concepts in studies on recurrence is presented.
The fundamental ideas and concepts espoused in this pa-
per regarding epidemiologic approaches to studying recur-
rent pregnancy outcomes stem, in part, from discussions
from the “Second International Symposium on Successive Preg-
nancy Outcomes: A Decade of Progress”, which was held in New
Brunswick, NJ, in August 2005, and the proceedings of this
symposium that are due to be published in a forthcoming
issue of Paediatric and Perinatal Epidemiology.1
Why Study Recurrence?
For epidemiologists as well as clinicians, studying recurrence
provides an opportunity to examine etiologic heterogeneity.
One fundamental, yet much underappreciated, advantage to
studying recurrence is the ability to separate “low-risk”

196 0146-0005/07/$-see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2007.03.008
Studying recurrent events in pregnancy
women from those at “high risk” of recurrence of a particular
pregnancy complication or outcome. This concept was suc-
cinctly illustrated by Wilcox,2 who made a compelling argu-
ment that what separates low risk from high risk of recur-
rence is driven by the etiology of the initial clinical event or
complication. When characteristics of persons in the low-
and high-risk groups differ, then depending on the strength
and magnitude, these differences may provide some clues
about disease causation.
As an illustration, consider a study to examine differences
in risk factors associated with spontaneous and indicated
preterm births. Some studies have shown a few differences
between these two clinical subtypes of preterm birth.3-5 The
ability to separate preterm birth based on the underlying
clinical subtypes addresses issues related to etiologic hetero-
geneity in studying preterm birth.4,6 The similarities in risk
factors between the two subtypes suggest that these two con-
ditions may overlap in terms of similar etiologic profiles.7 Yet,
studying the recurrence of preterm birth provides one oppor-
tunity to examine separately and in greater detail the risk
profiles between low-risk women (women with a previous
term birth) and high-risk women (those with a prior preterm
birth). Whereas the data regarding increased recurrence (of
either spontaneous or indicated preterm birth) suggest a di-
rect biologic influence of the previous preterm birth, other
observed (both fixed and transient) and unobserved factors
that are shared between the two pregnancies also probably
contribute to this increased recurrence.
The heterogeneity in recurrence risks is derived through
variable contributions of genetic effects, environmental influ-
ences, their interaction, and “time.” A genetic contribution to
the recurrence of an adverse reproductive endpoint can be
contributed by the mother such as is seen with inherited
thrombophilias and venous thromboembolism risk. An en-
vironmental effect (eg, smoking during pregnancy) can op-
erate through either, or both, of the pregnancies within
which the recurrence is studied. An interaction between
genes and environment is one when the effect of genotype on
disease risk depends on the type and level of exposure to an
environmental factor, or vice versa. A good example is the
risk of recurrence for neural tube defects in siblings in rela-
tion to a genetic polymorphism (in the folate metabolism
pathway) and the variability in environmental exposure to
folate supplementation. The “time” factor in recurrence stud-
ies, although important to understand heterogeneity in dis-
ease etiologies, is highly complex.8 Exposures or risk factors
inevitably operate through time with varying windows of
opportunity: a short exposure window (eg, exposure to a
teratogen during organogenesis), throughout the pregnancy
(eg, cumulative exposure to smoking throughout preg-
nancy), or a lifetime of exposure (eg, inadequate nutrition
through harsh social conditions9 or across generations).
For example, attempts to separate biologic aging effects
(such as maternal age) from those of aging of the uterine
environment contributed through repeated pregnancies (a
parity effect) on the risk of placental abruption,10 although
straightforward in theory, are challenging to separate in
cross-sectional studies. Consider the task of separating the
197
biologic aging effects from other influences on the recurrence
of a pregnancy complication using the interpregnancy inter-
val as the important “time” factor. Both short and long inter-
vals between pregnancies have been associated with adverse
pregnancy outcomes.11-14 Although short intervals can be as-
sociated with the biologic effect of possible inadequate uter-
ine recovery between pregnancies, there may also be a ten-
dency for couples with an adverse outcome to have another
pregnancy sooner, something known as selective fertility.
Conversely, a long interpregnancy interval may allow ade-
quate replenishment of nutrients to ensure a subsequent suc-
cessful pregnancy, but may be associated with the develop-
ment of a medical disease (such as diabetes or hypertension)
and possibly a change in partner between the two pregnan-
cies. It is extremely difficult to separate the relative effects of
each of these components on the recurrence of a particular
pregnancy complication. Taken together, all these factors in-
evitably contribute to recurrence risks, are highly inter-
twined, and complex to disentangle.
Challenge 1: The Importance
of Accurately Defining
Exposures and End Points
One of the fundamental tenets of any research is to be able to
define both the exposure and the outcome of interest with
high degree of precision. The challenges in defining out-
comes accurately have serious implications both in data an-
alytic approach and in the interpretation of study findings.
Most of the outcomes in perinatal epidemiology and, more
broadly in obstetrics and gynecology, are fairly well defined
and can be measured accurately. Whereas some outcomes,
such as preterm birth, gestational diabetes, and preeclamp-
sia, are easy to define accurately, others are not (eg, preterm
birth clinical subtypes).
Several conditions and reproductive end points present a
challenge regarding an acceptable definition. Intrauterine
growth restriction refers to a fetus that has not been growing
adequately, and is thought to be the result of an underlying
pathological process.15 Because true intrauterine growth re-
striction is very difficult to assess in population-based stud-
ies, a proxy, small-for-gestational age, has instead been used.
The latter refers to infants (at birth) that weigh below a cer-
tain threshold (usually the 10th centile) for a given gesta-
tional age. Although small-for-gestational age is used as a
proxy of “true” in utero fetal growth restriction, not all babies
that are “small” for their gestational age are truly growth
restricted. Thus, inaccuracies in defining an end point can
have serious implications as to how data on recurrence risks
can be interpreted.
Challenge 2: Study Designs
for Studies of Recurrence
Several epidemiologic study designs are available to study
recurrence of a specific disease or outcome. A prospective
cohort study is one that has been a commonly applied design
198
to study recurrence of pregnancy complications. With this
design, women having an index pregnancy are followed lon-
gitudinally over time to record their outcome in subsequent
pregnancies. Existing registry-based data can be used to de-
sign a prospective cohort study assuming an ability to iden-
tify and link women having more than one pregnancy. This is
the most commonly used design in studies of recurrent preg-
nancy outcomes.
For some types of recurrent pregnancy complications,
newer hybrid study designs may offer some advantages.
Most notably, the case-crossover study design is one that
offers great promise for studying the effect of transient
exposures on the risk of outcomes.16 This design helps
answer the question: “Was an outcome triggered by some
specific exposure that occurred immediately preceding the
outcome (ie, an antecedent exposure)?” The distinguish-
ing characteristic of this design is that each case serves as
its own control, and is analogous to a crossover experi-
ment viewed retrospectively. This means that the investi-
gator does not control when a patient starts being exposed
to a potential trigger.17 The case-crossover design has
some similarities to a traditional matched-pair case-con-
trol study.18 In both types of designs, each case has a
“matched” control. However, in a traditional matched
case-control study, the control is a different individual at a
similar time. As in the case in the case-crossover design,
the control is the same person, but observed at a different
time. The case-crossover design applies best when the ex-
posure is intermittent, the effect of risk is immediate and
transient, and the outcome is abrupt. Therefore, it may be
helpful to examine the effects of an abdominal trauma on
the risk of placental abruption among women with a pre-
vious abruption and those with prior normal pregnancy
outcomes.
One of the inherent strengths of the case-crossover de-
sign is the implicit control for confounding bias. Since
every subject in a case-crossover study serves as their own
“control,” confounding is less of an issue relative to studies
that incorporate other designs. This phenomenon was el-
egantly illustrated by Warner and colleagues19 in a con-
dom effectiveness study in preventing infections, where
they demonstrated that epidemiologic studies confounded
by unmeasured differences between condom users and
nonusers underestimate condom effectiveness against cer-
tain infections. For instance, prospective cohort studies
suffer from unmeasured confounding (a term also referred
to as “residual confounding”), often leading to distorted
estimates of the exposure– disease relationship. The case-
crossover method, however, provided a technique for re-
ducing unmeasured confounding in studies of condom
effectiveness.19
Challenge 3: Confounding
A confounder is, by definition, a factor that distorts the
association between an exposure and the outcome unless
adjusted. Three essential criteria for a variable to be clas-
sified as a confounder include: (1) the variable in question
C.V. Ananth
is a risk factor for the outcome being examined among
those unexposed; (2) the factor must be associated with
the exposure in the population from which the subjects
arose; and (3) the variable is not in the causal pathway of
the exposure– outcome relationship.18 Adjustment for po-
tential confounders in any analysis eliminates bias (caused
by those confounders) that could otherwise distort the
exposure– disease association. In a cross-sectional or a
case-control study, adjustment for available confounders
is straightforward; however, the issue of confounder ad-
justment gets more complicated in studies of recurrence.
Consider, as an illustration, if one is interested in quanti-
fying the extent to which preeclampsia recurs between the
first and the second pregnancy. Should one adjust for
potential confounders present in the first pregnancy, sec-
ond pregnancy, or both?
Confounders largely fall into two broad types: time-
independent and time-varying (or time-dependent). In the
former, when the value of a variable for subjects under
study does not change over time (eg, race/ethnicity), the
variable is said to be time-independent. On the contrary,
when the value of the variable changes with time (eg,
parity, maternal smoking or prepregnancy body mass in-
dex across successive pregnancies), the variable is consid-
ered time-dependent. The type of variable being consid-
ered for adjustment during statistical analysis, presumably
to minimize confounding, has implications in studies of
recurrence.
Although sophisticated statistical models have been de-
veloped for correcting time-varying confounders,20,21 sim-
pler approaches can also be undertaken. Consider a sce-
nario where one is interested in estimating the risk of
recurrence of placental abruption, and maternal smoking
(as a binary factor denoting if the women was a smoker or
nonsmoker) is a potential confounder. One efficient ap-
proach to fully adjust for the confounding effects of smok-
ing is to construct a four-level factor as follows: non-
smoker in both pregnancies (coded 0), smoker in the first
but not the second (coded 1), smoker in the second, but
not the first (coded 2), and smoker in both pregnancies
(coded 3). The construction of the new variable is similar
to allowing an interaction effect of smoking status between
the first and second pregnancies. Adjustment for this vari-
able in the regression model will ensure control for con-
founding as opposed to adjusting for smoking effects in
the first or in the second pregnancy alone.
Challenge 4: Biases
in Studies of Recurrence
A couple’s decision to achieve a desired family size introduces
a bias in studies of recurrence. Selective fertility, the tendency
to control fertility on the basis of previous pregnancy out-
comes,22 is one such phenomenon that can affect studies of
recurrence risks.23 Specifically, couples that experience peri-
natal losses in the first pregnancy tend to go on to have
additional pregnancies to achieve a desired family size. This
Studying recurrent events in pregnancy
phenomenon operates across all parity levels, but is particu-
larly a concern in higher-order births, and by analogy, to
older women. Skjaerven and coworkers23 suggest that, al-
though women differ in their inherent risks for perinatal
losses, selective fertility leads to an overrepresentation of
high-risk women at higher birth orders.
Other biases often operate in studies of recurrence, with
bias due to selection being one of the more important of
biases. When a study of recurrence of a reproductive out-
come is restricted to successive singleton live births, for ex-
ample, women with pregnancy losses or stillbirths, either
before the first singleton live birth or between two successive
live births, are inevitably excluded. These inclusion and ex-
clusion criteria have implications to studies on recurrence,
including generalizability or clinical relevance of the find-
ings. Although this is not a critical limitation, careful atten-
tion to such biases must be considered while drawing infer-
ences from such studies.
Challenge 5: Choosing
the Appropriate Study
Size and Analytic Approach
Most published research on recurrent pregnancy outcomes
come from large, population-based data. These studies
mostly come from the Scandinavian countries, notably, Nor-
way, Sweden, and Denmark, and others in Europe such as
Scotland. Data collection from these countries date back sev-
eral decades with perhaps the Norwegian birth registry dat-
ing back to the mid-1960s. Similar data from within the
United States are few, and are largely based on identifying
and linking biologic mothers to their successive pregnancies.
In the United States, these data come primarily from vital
statistics registers that are based on birth and death (fetal and
infant) certificates.
The advantages of using large, population-based registries
to address specific research on recurrent pregnancy out-
comes is the large sample size which, in turn, affords excel-
lent statistical power to discern patterns of recurrence risk. In
addition, such studies offer greater generalizability since they
are population-based. One of the inherent difficulties with
smaller studies on recurrence of a particular pregnancy com-
plication is adequate study size. As an illustration, consider if
one is interested in estimating the risk of recurrence of uter-
ine rupture. Uterine rupture has a reported incidence of 1.6
per 1000 pregnancies in women with a previous cesarean
delivery attempting a subsequent vaginal birth.24 If the goal is
to estimate the recurrence risk of uterine rupture, then the
study should exclude women who have undergone hysterec-
tomy and include only women with a repaired uterine rup-
ture in the first pregnancy who then go on to have a second
pregnancy that again results in a uterine rupture. The rarity of
this sequence of events would require hundreds of thousands
of women to adequately study. To be successful, a study of
this magnitude would need several large registries, perhaps a
collaborative effort of all population-based registries. Smaller
studies will inevitably lead to conclusions being affected by
199
lack of statistical power (type II error). Therefore, picking an
outcome that is observable with an available study popula-
tion is paramount to a successful study.
One of the important assumptions of any statistical test is
the “independence” of observations. Thus, studying a recur-
rent pregnancy-related event entails evaluation of the event
in the same woman twice. Studies dealing with the recur-
rence of an outcome clearly violate this assumption of inde-
pendence. Consider, for example, studies dealing with the
risk of recurrence of fetal growth restriction, a topic reviewed
extensively by Kinzler and Kaminsky in this issue.25 Since a
woman contributes data on two successive pregnancies, with
each pregnancy resulting in a growth-restricted or appropri-
ately grown infant, the responses (fetal growth) tend to be
“correlated.” This tendency of “clustering” gives rise to an
intracluster correlation (the woman, in this instance, is said
to constitute a cluster), which will produce incorrect esti-
mates of variance parameters when left unadjusted.26-28 In
other words, although the odds ratio for the exposure– dis-
ease relationship will remain unaffected due to ignoring the
intracluster correlation, the 95% confidence interval for the
odds ratio will be biased on either direction (depending on
the strength and direction of the intracluster correlation).
This, in turn, will affect significance tests, and eventually
diminish the scientific merit of the intended research. Several
analytic models and methods have been developed to ac-
count for this clustering phenomenon. Although description
of these methods fall well beyond the scope of this paper,
interested readers are referred to papers on this topic with
specific applications to studies on human reproduction.5,29
Challenge 6:
A Note on Terminology
Unfortunately, the terms “multivariable” and “multivariate”
have been used interchangeably in the medical literature.
However, these terms have distinct implications that are im-
portant for recurrence research. Consider, as an illustration,
the setting of a cross-sectional (or case-control) study, where
the goal is to estimate the risk of preeclampsia in relation to
nulliparity (with parous women as the reference). A regres-
sion model to derive an estimate of the relative risk (or odds
ratio) for preeclampsia in relation to nulliparity after adjust-
ing for potential confounders is, by definition, a multivari-
able model. On the other hand, if one is interested in estimat-
ing the effect of change in paternity on the recurrence risk of
preeclampsia, then a study of successive births is required.
Because preeclampsia is repeatedly assessed (ie, in each of the
two pregnancies), a regression model that is adjusted for
potential confounders is a “multivariate” model. Researchers
have used the two terms “multivariable” and “multivariate”
casually, and the medical literature has paid little attention to
its correct usage. Correct use and understanding of terminol-
ogy will facilitate communication among all parties involved
in recurrence research.
200
Challenge 7: Interpretation
of Recurrence Risks
One of the fundamental issues common to studies on recur-
rence of pregnancy outcomes pertains to interpretation. The
biggest challenge is to successfully translate the results of
epidemiologic observations on recurrence risk to clinical de-
cision making for individual patients. Most studies on recur-
rence are population-based, which is a strength in many
ways, but population-based recurrence risks do not readily
lead to customized risks for an individual patient. Aside from
conceptual differences in the regression models for popula-
tion-based versus subject-specific approaches to risk estima-
tion,30,31 the rich set of factors that shape risk in an individual
patient limits the direct translation of population-derived
risks to individuals.
As an illustration, consider the following scenario. The
recurrence risk for stillbirth in a large study is fourfold higher
among women with a previous stillbirth. Let us assume that
one is interested in applying this recurrence risk to an indi-
vidual patient with gestational diabetes that had experienced
a previous stillbirth. But this particular patient may have lost
weight, maintained extremely good glycemic control inter-
conceptionally, or was managed differently in the next preg-
nancy. This is in addition to other contributing factors that
may have been altered, but are difficult to ascertain. That the
recurrence risk for stillbirth for this patient is fourfold higher
is clearly misleading. This illustration highlights the chal-
lenge in applying population-based risk profiles to individual
patient settings. Smulian32 provides a clinical perspective on
many of the issues surrounding interpretation of research in
recurrent pregnancy complications.
Conclusions
No research can be accomplished in isolation, and a study on
recurrence of pregnancy-related conditions is no exception.
Optimizing study design using the best available data, appro-
priately adjusting for confounding and other biases, choosing
appropriate statistical models and, most importantly, careful
interpretation of findings are extremely important. Given the
complexities in all these facets in studies of recurrence, the
challenges are quite daunting. It is clear that as recurrence
research becomes more common and as the methodology
matures, active collaborations will be necessary among epi-
demiologists, biostatisticians, and the clinical community to
get the most out of our efforts.
Observational studies of recurrent pregnancy complica-
tions are difficult to perform well, and cohort studies that
entail a recurrence component are much more complicated.
In addition to the limitations afforded in following prospec-
tive cohorts (including resources, time and personnel ef-
forts), studies of recurrence need to carefully consider the
issues highlighted in this review. Such studies require atten-
tion to inherent biases (eg, selective fertility, selective man-
agement), and failure to recognize and account for such lim-
itations will invariably result in distorted findings of
C.V. Ananth
recurrence risks. More importantly, incorrect models to an-
alyze data arising from correlated responses will likely yield
incorrect statistical and biologic inferences. Finally, correct
interpretation of recurrence risks will greatly enhance our
ongoing pursuits for studying recurrence of adverse out-
comes in pregnancy-related conditions, which is best ap-
proached through a collaborative environment.
Acknowledgments
The author extends special thanks to Russell Kirby, PhD,
Morgan Peltier, PhD, John Smulian, MD, MPH, and Anthony
Vintzileos, MD, for their thoughtful suggestions and valuable
comments that helped improve the paper. Dr. Ananth is par-
tially supported through a grant (HD038902) from the Na-
tional Institutes of Health awarded to him.
References
1. Ananth CV: Second International Symposium on Successive Pregnancy
Outcomes: a decade of progress. Paediatr Perinat Epidemiol 21(Suppl)
2007, in press
2. Wilcox AJ: The analysis of recurrence risks as an epidemiologic tool.
Paediatr Perinat Epidemiol 21(Suppl) 2007, in press
3. Berkowitz GS, Blackmore-Prince C, Lapinski RH, et al: Risk factors for
preterm birth subtypes. Epidemiology 9:279-285, 1998
4. Savitz DA, Blackmore CA, Thorp JM: Epidemiologic characteristics of
preterm delivery: etiologic heterogeneity. Am J Obstet Gynecol 164:
467-471, 1991
5. Ananth CV, Platt RW, Savitz DA: Regression models for clustered bi-
nary responses: implications of ignoring the intracluster correlation in
an analysis of perinatal mortality in twin gestations. Ann Epidemiol
15:293-301, 2005
6. Ananth CV, Vintzileos AM: Maternal-fetal conditions necessitating a
medical intervention resulting in preterm birth. Am J Obstet Gynecol
195:1557-1563, 2006
7. Ananth CV, Getahun D, Peltier MR, et al: Recurrence of spontaneous
versus medically indicated preterm birth. Am J Obstet Gynecol 195:
643-650, 2006
8. Basso O: Options and limitations in studies of successive pregnancy
outcomes: an overview. Paediatr Perinat Epidemiol 21(Suppl) 2007, in
press
9. Wilcox AJ, Skjaerven R, Irgens LM: Harsh social conditions and peri-
natal survival: an age-period-cohort analysis of the World War II occu-
pation of Norway. Am J Public Health 84:1463-1467, 1994
10. Ananth CV, Wilcox AJ, Savitz DA, et al: Effect of maternal age and
parity on the risk of uteroplacental bleeding disorders in pregnancy.
Obstet Gynecol 88:511-516, 1996
11. Basso O, Olsen J, Knudsen LB, et al: Low birth weight and preterm birth
after short interpregnancy intervals. Am J Obstet Gynecol 178:259-
263, 1998
12. Smith GC, Pell JP, Dobbie R: Interpregnancy interval and risk of pre-
term birth and neonatal death: retrospective cohort study. Br Med J
327:313, 2003
13. Zhu BP, Rolfs RT, Nangle BE, et al: Effect of the interval between
pregnancies on perinatal outcomes. N Engl J Med 340:589-594, 1999
14. Conde-Agudelo A, Rosas-Bermudez A, Kafury-Goeta AC: Birth spacing
and risk of adverse perinatal outcomes: a meta-analysis. J Am Med
Assoc 295:1809-1823, 2006
15. Resnik R: Intrauterine growth restriction. Obstet Gynecol 99:490-496,
2002
16. Maclure M: The case-crossover design: a method for studying transient
effects on the risk of acute events. Am J Epidemiol 133:144-153, 1991
17. Maclure M, Mittleman MA: Should we use a case-crossover design?
Annu Rev Public Health 21:193-221, 2000
18. Greenland S, Rothman KJ: Measures of effect and measures of associa-
Studying recurrent events in pregnancy
tion, in Rothman KJ, Greenland S (eds): Modern Epidemiology (ed 2).
Philadelphia, PA, Lippincott Williams & Wilkins, 1998, pp 47-64
19. Warner L, Macaluso M, Austin HD, et al: Application of the case-
crossover design to reduce unmeasured confounding in studies of con-
dom effectiveness. Am J Epidemiol 161:765-773, 2005
20. Bodnar LM, Davidian M, Siega-Riz AM, et al: Marginal structural mod-
els for analyzing causal effects of time-dependent treatments: an appli-
cation in perinatal epidemiology. Am J Epidemiol 159:926-934, 2004
21. Robins JM, Hernan MA, Brumback B: Marginal structural models and
causal inference in epidemiology. Epidemiology 11:550-560, 2000
22. Wilcox AJ, Gladen BC: Spontaneous abortion: the role of heteroge-
neous risk and selective fertility. Early Hum Dev 7:165-178, 1982
23. Skjaerven R, Wilcox AJ, Lie RT, et al: Selective fertility and the distor-
tion of perinatal mortality. Am J Epidemiol 128:1352-1363, 1988
24. Lydon-Rochelle M, Holt VL, Easterling TR, et al: Risk of uterine rupture
during labor among women with a prior cesarean delivery. N Engl
J Med 345:3-8, 2001
201
25. Kinzler WL, Kaminsky L: Fetal growth restriction and subsequent preg-
nancy risks. Semin Perinatol 2007, in press
26. Liang KY, Zeger SL: Regression analysis for correlated data. Annu Rev
Public Health 14:43-68, 1993
27. Zeger SL, Liang KY: Longitudinal data analysis for discrete and contin-
uous outcomes. Biometrics 42:121-130, 1986
28. Liang K-Y, Zeger SL: Longitudinal data analysis using generalized linear
models. Biometrika 73:13-22, 1986
29. Louis GB, Dukic V, Heagerty PJ, et al: Analysis of repeated pregnancy
outcomes. Stat Methods Med Res 15:103-126, 2006
30. Zeger SL, Liang KY: An overview of methods for the analysis of longi-
tudinal data. Stat Med 11:1825-1839, 1992
31. Zeger SL, Liang KY, Albert PS: Models for longitudinal data: a general-
ized estimating equation approach. Biometrics 44:1049-1060, 1988
32. Smulian JC: Research on recurrent pregnancy complications: a clini-
cian’s perspective. Paediatr Perinat Epidemiol Suppl 2007, in press