Professional Documents
Culture Documents
Fetal Growth
Restriction: The
Etiology
DEV MAULIK, MD, PhD
Department of Obstetrics and Gynecology, Winthrop University
Hospital, 259 First Street, Mineola, New York
Abstract: Fetal growth restriction (FGR) is etiologi- cases and, even when present, may not
cally associated with various maternal, fetal and necessarily imply a causal link with fetal
placental factors, although such an association may
not be present in many cases. Maternal factors growth compromise. The nature, the
include hypertensive diseases, autoimmune disorders, timing, and the severity of these dis-
certain medications, severe malnutrition, and mater- orders exert a profound influence over
nal lifestyle including smoking, alcohol and cocaine the type and severity of growth restric-
use. Fetal etiologies include aneuploidy, malforma- tion and perinatal prognosis. This review
tions, syndromes related to abnormal genomic
imprinting, perinatal viral or protozoan infections, aims to provide a current and concise
preterm birth, and multiple gestation. Placental review of the clinical and pathologic
factors may involve many conditions including conditions whose presence make FGR
anatomical, vascular, chromosomal and morpholo- more probable. A list of risk factors for
gical abnormalities. Better understanding of these FGR is presented in Table 1 and selected
etiologic conditions may lead to improved predic-
tion, prevention and management of FGR. etiologic conditions are discussed below.
Key words: fetal growth restriction, etiology, mater-
nal factors, fetal factors, placental factors
Maternal Etiology
MATERNAL HYPERTENSIVE
Introduction CONDITIONS
Numerous maternal, fetal, and placental Hypertensive disorders are present in
disorders may interfere with the normal 30% to 40% of pregnancies complicated
mechanisms that regulate fetal growth with FGR. Any maternal vasculopathic
culminating in fetal growth restriction disorders may lead to fetal growth
(FGR). A demonstrable association, deficiency. These conditions include pre-
however, may not be apparent in many eclampsia, chronic hypertension with or
without superimposed preeclampsia,
Correspondence: Dev Maulik, MD, PhD, Department autoimmune disorders, chronic severe
of Obstetrics and Gynecology, Winthrop University
Hospital, 259 First Street, Mineola, NY 11501. nephropathy, and pregestational dia-
E-mail: wirving@winthrop.org betes complicated with vasculopathy.
228
Etiology of FGR 229
TABLE 1. Etiologic Risk Factors for Fetal CI: 3, 6) with mild preeclampsia, 12%
Growth Restriction (95% CI: 9, 15) with severe disease, and
Maternal Factors 23% (95% CI: 18, 29) with early onset
Maternal hypertension disease.2 Defective maternal placental
Preeclampsia vascular adaptation underlies both pre-
Chronic hypertension eclampsia and FGR and is further
Secondary hypertension
Renal disease discussed elsewhere in this review. The
Diabetes with vasculopathy presence of previous hypertensive disease
Autoimmune syndromes—antiphospholipid in preeclamptic mothers significantly
syndrome, lupus increases the risk of FGR.3
Thrombophilia There is evidence that even in the
Cyanotic heart disease
Asthma absence of proteinuria, elevated diastolic
Hemoglobinopathy blood pressure in pregnancy is associated
Phenylketonuria with small for gestational age (SGA)
Uterine anomalies–large submucous myomas, infants even when adjustments are made
septate uterus, synechia for potential confounders such as ma-
Life style
Smoking ternal age, maternal weight, smoking,
Substance abuse–Alcohol, heroin, ethnicity, and gestational age at deli-
methadone, cocaine, others very.4 However, the risk is less than that
Therapeutic agents seen with proteinuric hypertension. Mild
Malnutrition chronic hypertension in pregnancy is
Environmental pollution
Fetal Factors associated with variable increases in the
Aneuploidy birth of SGA infants (8.0% to 15.5%).5
Trisomy 13, 18, and 21 With chronic hypertension noted in the
Triploidy first trimester, the rate of SGA rises
Genomic imprinting and uniparental disomy (30% to 40%). Similarly, proteinuria
Malformations
Gastroschisis, omphalocele, diaphragmatic noted in early pregnancy independently
hernia, congenital heart defect elevates the risk of fetal growth compro-
Preterm birth mise (odds ratio (OR) 2.8; 95% CI: 1.6,
Multiple gestation 5.0). Interestingly, maternal antihyper-
Infection—malaria, rubella, cytomegalovirus, tensive therapy not only fails to improve
herpes, toxoplasmosis
Unexplained elevated a-fetoprotein fetal growth, but some b blockers such as
Placental Factors atenolol may increase the risk of growth
Confined placental mosaic restriction.
Placenta previa
Abruptio placentae
Infarction MATERNAL AUTOIMMUNE
Circumvallate placenta DISORDERS
Placenta accreta Maternal autoimmune diseases in preg-
Hemangioma nancy, especially with vascular involve-
ment, are associated with adverse
perinatal outcome. Mothers with antipho-
Preeclampsia is associated with a 4- spholipid antibody syndrome demonstrate
fold increase in the risk of having a small significant increase in stillbirths. Systema-
for gestational age infant [relative tic lupus erythematosus in pregnancy is
risk = 4.2; 95% confidence interval (CI) associated with an almost 3–fold rise in
2.2–8.0].1 The worse the severity and the fetal deaths when antiphospholipid anti-
earlier the onset of preeclampsia, the bodies (APA) are positive than when
lower the birth weight. In one report, the they are negative.6 There is significant
decline in the birth weight was 5% (95% evidence that antiphospholipid antibody
230 Maulik
syndrome adversely affects fetal growth. prospective cohort study, Cliver et al11
In a prospective study, 24% of fetuses noted an average birth weight reduction
with birth weight below the 10th centile of 6% when smoking continued through-
had positive APA.7 In another prospective out gestation compared with only 1.7%
study, the relative risk of growth restric- when smoking was stopped after the first
tion with positive APA was 6.22 (95% trimester. The effect is dose-dependent
CI: 2.43–16.0).8 and is significantly enhanced by comor-
bidities such as hypertension. Thus the
THROMBOPHILIA risk of having an SGA infant from
Controversy surrounds the association smoking is higher in mothers who are
between fetal growth restriction and hypertensive than in those who are not
maternal thrombophilia gene poly- (40% vs. 5%, respectively).12 In the
morphism related to factor V Leiden United States, smoking during preg-
G1691A, prothrombin G20210A, and nancy continues to decline although
methylenetetrahydrofolate reductase approximately 11% of mothers were still
C677 T A1298C. There is a dearth of smokers in 2003.13 This represents a
large prospective studies of sufficient decline of 44% since 1989.
power in this field. Whereas several Alcohol consumption in pregnancy
studies demonstrated that the risk of may result in fetal alcohol syndrome or
thrombophilia was significantly in- fetal alcohol spectrum disorders.14 Along
creased in FGR, others could not corro- with dysmorphic features and mental
borate this. However, a recent meta- retardation, restriction of fetal growth
analysis of 10 case-control studies remains a cardinal feature of these
showed a significant association between conditions. A surveillance conducted in
FGR and the presence of factor V 2002 by the Center for Disease Control
Leiden (OR, 2.7; 95% CI, 1.3–5.5) and and Prevention (CDC) noted that ap-
prothrombin gene variant (OR, 2.5; 95% proximately 10% of pregnant women
CI, 1.3–5.0).9 The relationship between consumed alcohol, and 2% indulged in
methylenetetrahydrofolate reductase binge drinking (Z5 drinks on 1 occa-
mutation and FGR remains unsubstan- sion) or frequent drinking (Z7 drinks in
tiated. a week or binge drinking).15 Increased
prevalence was noted among women
MATERNAL LIFESTYLE who are younger, unmarried, non-
Maternal use of various recreational Hispanic whites, or present smokers.
agents and addictive substances is asso- It is not prudent to recommend a safe
ciated with FGR. A causal relationship, threshold for pregnancy as no more than
however, is often difficult to establish 1 drink per day has been shown to
because of associated confounders such be associated with FGR and lower
as malnutrition, the simultaneous use of Apgar scores.16
multiple substances, stress and other life- Cocaine use in pregnancy is associated
style variables. Only a selection is dis- with significant maternal and fetal risks
cussed here as the list of substances that including maternal stroke, cardiac ar-
can affect fetal growth is extensive. rhythmia, and hypertension, placental
Maternal cigarette smoking leads to abruption, fetal brain injury and still
decreased fetal weight.10 The effect is birth. There has been some uncertainty
primarily mediated by carbon monoxide about its effect on fetal growth. How-
generation, which interferes with fetal ever, the recent multicenter study
oxygenation. The vasoactive property of conducted by the National Institute of
nicotine may also play a part. In a Child Health and Human Development
Etiology of FGR 231
Neonatal Research Network has shown insight. During the harsh Dutch famine
that in utero cocaine exposure was of 1944-1945, daily average caloric in-
associated with slowing of fetal growth take below 1500 during the third trime-
after controlling for confounders.17 ster was associated with significant
The growth parameters included birth reductions in birth weight and size.19
weight, length, and head circumference. Moreover, subsequent within-family
The more advanced the gestation, the analysis suggested possible intergenera-
worse the growth compromise. tional effect as the expected increase in
offspring birth weights with increasing
THERAPEUTIC AGENTS birth order was not seen after maternal
Many therapeutic agents have been intrauterine exposure to severe under-
implicated in causing FGR. These nutrition (average daily calories <1000)
include antineoplastic medications, anti- in the first trimester of pregnancy.20 In
convulsants such as phenytoin, b block- comparison with the firstborn siblings,
ers, especially atenolol, and steroids. The the average birth weight of the second
causal relationship with FGR is clear for born infants was 252 g less (95% CI,
some of these agents such as those for – 419 to – 85), and of the third born
cancer chemotherapy, but uncertain infants was 419 g less (95% CI – 926 to
for others. In practice, use of these 87), after correcting for confounding
medications is guided by the appropri- variables.
ateness of the indications, the risk/bene-
fit considerations, and the availability of ENVIRONMENTAL POLLUTION
alternative therapies. A current contro- Epidemiological investigations on the
versy involves the use of antenatal impact of environmental pollution on
glucocorticoids for inducing fetal lung pregnancy outcome show significant but
maturity in preterm labor. Although slight increase in the frequency of
there is overwhelming evidence of sig- FGR.21 This effect was discernible even
nificant benefits of a single course of with relatively low concentrations of
steroid in labor before 34 weeks gaseous pollutants such as sulfur diox-
of gestation, the safety and efficacy of ide, nitrogen dioxide, carbon monoxide,
repeated courses remain unsubstan- and ozone.22 The consequence of ex-
tiated.18 The available animal and treme exposure to airborne toxic agents
human data suggest substantial potential was unfortunately provided by the
perinatal risks from multiple courses World Trade Center (WTC) disaster.23,24
including suppression of fetal somatic WTC dust mostly contained coarse
growth and neurodevelopmental pro- particles consisting of pulverized cement,
blems and such practice has been clearly glass fibers, asbestos, lead, polycyclic
discouraged by the National Institutes of aromatic hydrocarbons, polychlorinated
Health Consensus Development Panel.18 biphenyls, and polychlorinated furans
and dioxins. Airborne particulate levels
MALNUTRITION were highest at the site immediately after
The effect of maternal undernutrition on the attack, and declined over time and
fetal development depends upon the with increasing distance. Follow-up of
severity of deprivation and the trimester 182 pregnant mothers who were within
of exposure. The effect spans genera- 1 mile of the WTC within 1 month of
tions. Animal experimentations, studies September 11, 2001 demonstrated a
on mothers exposed to famine, and the 2- fold increase in SGA infants. Mothers
nutritional intervention trials in the third exposed to environmental tobacco
world populations continue to provide smoke were more vulnerable to fetal
232 Maulik
growth decline when exposed to poly- FGR. Genomic imprinting and fetal
cyclic aromatic hydrocarbons-related growth have been discussed in a separate
materials. review in this issue. Abnormal imprint-
ing results in abnormal phenotypes
including fetal growth restriction and
Fetal Etiology dysmorphic features. The classic exam-
ples of such disorders include Prader
ANEUPLOIDY Willi syndrome, and Silver-Russell syn-
Fetal chromosomal abnormalities are drome (SRS). Loss of function of im-
strongly associated with fetal growth printed genes on the paternal allele in the
restriction. Traditionally, approximately 15q11–13 imprinted region results in
7% of FGR is attributable to aneu- Prader Willi syndrome, which is char-
ploidy. However, a higher frequency acterized by growth deficit in utero and
has been reported from high-risk referral other developmental problems. SRS is
centers. For example, in 1 center chro- clinically characterized by prenatal and
mosomal defects were identified in al- postnatal growth deficits and dys-
most 20% of growth-restricted fetuses morphic features. About 10% of SRS
referred for further assessment between cases demonstrate maternal UPD invol-
17 and 39 weeks gestation.25 Approxi- ving imprinted regions in chromosome 7.
mately 90% of the fetuses with trisomy
18 will demonstrate FGR compared with FETAL MALFORMATIONS
30% of those with trisomy 21. Fetuses A population-based study conducted by
with aneuploidy are at a markedly the CDC demonstrated that over 22% of
increased risk of multiple malformations infants with congenital malformations
and demonstrate a higher frequency of are growth-restricted with a relative risk
somatic asymmetry, normal or increased of 2.6.27 Multiple malformations in-
amniotic fluid volume, and normal creased the risk of FGR, the frequency
uterine and/or umbilical artery Doppler of which increased from 20% in infants
indices. However, most fetuses with with 2 defects to 60% in infants with 9 or
asymmetric growth restriction, no struc- more defects. There is a preponderance
tural anomalies, and over 23 weeks of heart defects, anencephaly, and ab-
gestation are chromosomally normal. dominal wall defects. The cardiac defects
Early growth restriction has been asso- most often associated with SGA include
ciated with increased odds of trisomy 18 tetralogy of Fallot, endocardial cushion
and 13.26 Whether this was related to an defect, hypoplastic left heart, pulmonary
overestimation of the gestational age in stenosis, and ventricular septal defect.
these cases needs to be resolved. A single umbilical artery even in the
absence of any other malformations or
GENOMIC IMPRINTING AND aneuploidy may be associated with
UNIPARENTAL DISOMY growth restriction.
Uniparental disomy (UPD) is the inheri-
tance of both homologs of a chromo- PERINATAL INFECTION
some from a single parent. Although About 5% to 10% of the cases with
rare, uniparental disomy has been asso- FGR are attributable to viral or proto-
ciated with FGR, several autosomal zoan infections in utero. The viral agents
chromosomes and the X chromosome that are most often implicated include
have been implicated. Maternal UPD of rubella, cytomegalovirus, human immu-
chromosome 16 is the most frequently nodeficiency virus, and varicella-zoster.
encountered example in relation with A decline in the cell population is
Etiology of FGR 233
believed to be the most frequent mecha- individual growth potential. This was
nism for decline in growth. Protozoan observed in a case control study invol-
infections that can cause FGR include ving spontaneous preterm births. It was
malaria and toxoplasmosis. More re- observed that almost 30% of the fetuses
cently, there is a greater realization of born before 35 weeks were under the 10th
the magnitude of the profound negative centile compared with only 4.5% of the
impact of malaria on maternal and fetal fetuses born at 37 weeks or later.32
health.28 The adverse effects include Obviously the growth restriction preceded
maternal anemia, prematurity, and premature onset of parturition, raising
FGR. The outcome is worse with primi- the speculation that the latter may be
gravidity, presence of maternal anemia, causally related to the former and may
and concomitant human immunodefi- represent fetal adaptive response to stress
ciency virus infection. In sub-Saharan in utero.33 If proven, such a possibility
Africa, about 40% of FGR cases are may have implications for the optimal
attributable to gestational malaria. management of these pregnancies.
Worldwide, 45 million pregnant mothers
are at risk of growth restriction because MULTIPLE GESTATION
of malaria. Multifetal gestation significantly chal-
Although bacterial infections have not lenges the maternal system to provide
usually been implicated in causing an optimal environment for sustaining
growth restriction, there is emerging fetal growth. Individual fetuses in multi-
evidence that subclinical infection and ple pregnancy demonstrate a growth
inflammation as evidenced by histologic trajectory different from that observed
chorioamnionitis may lead to fetal in singleton fetuses. Growth curves of
growth restriction. Furthermore, extra- twin and singleton fetuses are similar
genital infection may also be associated until approximately 30 to 32 weeks after
with fetal growth deficit. Recent findings which the growth of twins lags behind
that maternal periodontal disease may that of singletons.34 The higher the fetal
lead to preterm and small for gestational number, the earlier the onset of the
age births provide a modifiable etiology growth deceleration. This phenomenon
that could potentially reduce the fre- reflects fetal adaptation to shared re-
quency of FGR.29 In a prospective sources and does not necessarily imply
longitudinal study involving mostly growth compromise. Others however
African-American mothers, it was shown have refuted the notion of a twin growth
that those with higher levels of Porphy- curve divergent from that of the single-
romonas gingivalis-specific IgG at mid- tons. Despite this controversy, the risk of
trimester had higher odds of giving birth FGR is increased in multiple gestation
to low birth weight infants (OR: 4.1; and depends on chorionicity and also on
95% CI: 1.3–12.8) even after controlling factors that affect growth in the single-
for smoking, age, IgG levels against tons. Thus SGA at birth is noted in
other selected periodontal pathogens, approximately 20% of the dichorionic
and race.30 fetuses and 30% of the monochorionic
fetuses. Etiologic factors are similar to
PRETERM BIRTH those noted in the singletons and include
An association between fetal growth hypertensive disorders, malformations,
restriction and prematurity has long smoking, poor weight gain, and low
been recognized.31 The association is prepregnancy body mass index. An
even stronger when the diagnosis of additional consideration is the discor-
growth restriction is based on the fetus’ dancy of the growth between the twins
234 Maulik