“Carol Davila” University of Medicine & Pharmacy

Bucharest, ROMANIA

Preterm birth
Manuela Russu, MD, PhD
Habilitated Professor
Head of “Dr. I. Cantacuzino”
Discipline of Obstetrics & Gynecology

MCR, 2018
 Definitions
 1935: American Academy of Pediatrics: prematurity as a live-born infant
weighting ≤ 2500 g. These criteria were used widely until it became apparent that
there were discrepancies between GA and birthweight because of IUFGR
1961: WHO: added gestational age as a criterion for premature infants, defined as
those born at ≤ 37 wks . A distinction was made between low birthweight (≤
2500 g) & prematurity ( ≤ 37 wks )
 1995: American College of Obstetricians & Gynecologists:
suggested: “preterm birth be defined as those infants
delivered prior to the completion of 37wks”
 With continued improved care of the preterm infant, other definitions have been
developed: for example, the Collaborative Group on Antenatal Steroid Therapy
(1981) reported that:
the great preponderance of mortality and serious morbidity from preterm birth is
prior to 34 weeks
 Moreover, low birthweight, defined as less than 2500 g, has been modified now to
describe very-low birthweight, infants weighting ≤ 1500 g; and
extremely-low birthweight, those who weight ≤ 1000 g
 Fetal development
 With respect to GA: fetus/ infant: preterm, term, or postterm
 With respect to size: fetus/ infant: normally grown or
appropriate-for-gestational age, small in size or small-
for-gestational age, overgrown or large-for-gestational
age
• In recent years, the term small for gestational age has been
widely used to categorize an infant whose birthweight is usually
below the 10th percentile for its GA
• Other often-used terms have included fetal growth retardation or
intrauterine growth retardation
• Within the past 10 years: term “restriction” has largely replaced
the term “retardation”, because the latter may erroneously convey
mental delay rather than only the intended suboptimal fetal
growth
 Fetal development
 The infant whose birthweight is above the
90th percentile has been categorized as large-
for-gestational age, and the infant whose weight
is between the 10th and 90th percentiles is
designated appropriate-for-gestational age
 Thus, an infant born before term can be small or large
for GA and still be premature according to chronological
GA
 Moreover, some premature infants have also suffered
growth restriction in utero. It is important to recognize that
prematurity may not only encompass those births occurring
before term, but also frequently includes infants who have
suffered subnormal in utero growth
WHITE PAPER OF PRETERM BIRTH, 2012
 Romanian Demographic Data

• In common with many Eastern European countries, Romania

has experienced a decline in population in recent years.
• The population growth rate is - 0.127% :
Romanian National Statistic Institute, 2007
• The highest rate of perinatal mortality in Europe:
early neonatal mortality is 6.09 in Romania vs 3.75/ 1000
life births in Europe (2005)
• Infant mortality rate: 9.2 deaths/1,000 live births (May 2010)
down from 17.3 deaths/1,000 live births in 2002
Romanian National Statistic Institute, 2010
 Questions

1. Which is the inferior limit of GA

for fetal survive without
disabilities ?
2. Which are the predictive tools
for pregnant women at risk of
preterm birth ?
3. What is the management to
prevent preterm birth ?
4. What is the proper management
when preterm birth is in evolution ?
 Lower Limit of Survival
Although it is impossible to precisely set the
earliest limit for neonatal survival, certain factors
inevitably have an impact on the clinical decision-
making process:
23 weeks gestation- the lowest limit for survival -
the 6th range branch of bronchial development
What can we do to protect “very” preterm fetus?
• fetal heart monitoring
• cesarean section
• Delivery management prior to 26 wks, or for fetuses
smaller than 750 g, was variable and individualized
 Chances for survival increase appreciably at or
above 1000 g birthweight
 Lower Limit of Survival
The frontier for infant survival has been progressively pushed
earlier into gestation primarily as a result of continued
innovations in neonatal intensive care.
1993: Copper et al -USA : compiled gestational age-specific
neonatal mortality rates for 3386 live-born infants
prospectively enrolled between 1982 and 1986 :
• neonatal mortality decreased from 100% at 23 wks to ~
10% at 29 wks, with little additional improvement through
34 wks
1995: Rutter- England: identical mortality rates for 2678
live-born infants delivered in between 1990 and 1993
The period of gestation from 23 to 25 wks poses
the greatest dilemma for both the obstetrician and pediatrician.
The probability of neonatal death before 26 wks exceeds 75%
 Long-Term Outcomes
 Whereas few infants with birthweights < 750 g were actively treated
during the 1970s, beginning in the 1980s, treatment is now often
practiced for infants with birthweights of at least 500 g and those born
at 24 wks or > Hack et al, 1994
 The high rate of significant neonatal morbidity in these infants, &
the likelihood of a normal life, must be weighed against the apparent
triumph of survival
 Several investigators: measured long-term outcomes in infants
delivered at the very frontier of survival during the 80’: when
birthweights < 750 g & survived, they are at “serious disadvantage in
every skill required for adequate performance.” Specifically, 45% of
the survivors needed special education facilities, 21% IQ (less < 70), &
many had subnormal growth and visual ability
 Rutter, 1995: reviewed: outcomes in extremely premature infants
that full resuscitation and intensive care should definitely be given at
26 wks, probably be given at 25 wks, possibly be given at 24 wks, but
not at 23 wks or earlier
 Outcome of live-born infants delivered
between 22 and 25 wks and given intensive
care -Allen MC, 1993
GA Live Birth Alive at 6 months Infants without
(weeks) (no/%) severe brain
abnormalities*
(no /%)
22 29 0 -
23 40 6 (15) 1 (3)
24 34 19 (56) 7 (21)
25 39 31 (79) 28 (72)
* Grade III or IV intraventricular hemorrhage or periventricular leukomalacia
 Upper Limit of Significant Prematurity
 Not only has the frontier for neonatal survival been pushed earlier
into pregnancy, but survival of larger preterm infants has become as
good as that for term infants
 Most thresholds—defined as the gestational wk at which the
incidence of complications attributable to preterm delivery became
indistinguishable from term infants  were between 32 and 34
wks
• Respiratory distress syndrome, although decreasing
precipitously between 33 and 34 wks (31 to 13%, respectively) still
developed in ~ 6% of births between 35 and 38 wks
 DePalma et al, 1992: birthweight threshold for neonatal
mortality was 1600 g, and the threshold for neonatal
morbidity due to complications of prematurity was
approximately 1900 g
Pathophysiology
 Causes of Preterm Birth
Medical Conditions Lifestyle
 Placenta previa or abruption • cigarette smoking
 Amnionic fluid infection: intact/ • poor nutrition
ruptured membranes • poor weight gain
 Immunological: antiphospholipid during pregnancy
antibody Syndr • low maternal prenatal
 Cervical incompetence weight gain
 Uterine anomaly, hydramnios, • use of drugs: cocaine
fibromyomas or alcohol
 Maternal—preeclampsia
low maternal age,
 Drug intoxication poverty, short stature,
 Trauma or surgery occupational factors,
 Fetal anomalies psychological stress
 No cause (“idiopathic”)
 Smith R - Parturition. N Engl J Med, 2007; 356: 271-283
5 pathways which can develop in cascade or separately, sometimes
much long time previous to preterm labor onset/ premature membrane
rupture
• Compromise of the structure of uterine cervical support (cervix
incontinence/incompetence, former surgery : cone/cervical excision, LLETZ)

• Myometrial & Membrane overdistension (multiple pregnancy,

polygydramnios, macrosomic fetus from DM, műllerian tract compartimentation
abnormalities, uterine myoma), which drive to myometrial activation, - a key
event in preterm labor

• Decidual hemorrhage (placental separation),

• Intrauterine infection/ inflammation (bacterial vaginosis, trichomoniasis,

urinary tract infection- which frequent are previous to chorio- amnionic infection
& preterm membrane rupture);

• Early endocrine fetal activation, by maternal or fetal stress

 The Mechanisms of PB are similar to those of term birth,
centered by:

 membrane activity: membrane receptors as β adrenergic receptors-

are modulated in order to acute stimulate/block the contraction of
myometrial contractile proteins (actine, myosine)

 E & P4 intracellular receptors - are modulated in order to

chronic stimulate/block myometrial contraction, with multiple enzymes
involvement

 Ca +2 : central element of myometrial contractile proteins :

a) binding the excitation to contraction,
b) intracellular presence of Ca +2 ions is controlled by calmoduline,
the regulatory protein of Calcium binding, which itself is binding to
myosine
 Intracellular cytosolic Ca+2 quantity
modulates uterine relaxation/contraction,
as the intracellular cytosolic Ca+2 quantity is low/high.
 Pathophysiology
Csapo A,1969: term labor is initiated by “progesterone
withdrawal”
 Schwarz et al, 1976: activation of phospholipaze A2–
enzyme from many germs from the genital tract , clives arahidonic acid from
fetal membranes, thereby making free arachidonic acid available for
prostaglandin synthesis .
 Bennett, Elder, 1992: common genital tract bacteria do not
themselves produce prostaglandins
 Cox et al , 1989: bacterial endotoxin (lipopolysaccharide) introduced
into the amnionic fluid stimulates decidual cells to produce cytokines &
prostaglandins that may initiate labor
 Romero et al (1987, 1988); Cox et al (1988): endotoxin in the
amnionic fluid

Csapo A - The luteo-placental shift, the guardian of pre-natal life.

Postgrad Med J; 1969; 45: 57-64.
 Pathophysiology
It is proposed a cascade in human birth initiation:
“functional progesterone withdrawal”- first elaborated by
Csapo A, 1969 and sustained recently by Schmitz T, et al,
2006, with the switch of the PR- B isoform of 116 kDa in
favor of PR- A isoform of 94 kDa, abundant in
reproductive tissues - Honest H, 2002
Romero R, et al, 2010 (USA): maternal- fetal genetic
interaction which predisposes at PB:
o ILR6 connected to fetal inflammation control
increases the PB with 50%,
o high risk when the mother has genes with DNA
variants codefing proteins involved in extracellular
matrix biology - COL4A3
 Amniotic fluid infection. Pathogenesis
 Endogenous host products secreted in response to infection are
responsible for many of the effects of infection
• In endotoxin shock: bacterial endotoxins exert their deleterious effect
through the release of endogenous cell mediators (cytokines) of the
inflammatory response
• Similarly, preterm parturition due to infection is thought to be initiated
by secretory products resulting from monocyte (macrophage)
activation
o Cytokines: IL-1, IL-6, TNF are such secretory products implicated in
preterm labor
o Narahara, Johnston , 1993: platelet-activating factor
(produced in the fetal lungs & kidneys): found in the amnionic fluid, is
synergistically involved in activating the cytokine network
o Thus, the fetus appears to play a synergistic role in the initiation of
preterm birth due to bacterial infection. Teleologically, this could be
advantageous to the fetus interested in extricating itself from an
infected environment
 Amniotic fluid infection. Pathogenesis
 The route of access with intact
membranes is unclear
Gyr, et al, 1994: E. coli can permeate living
chorioamnionic membranes and intact membranes
at the cervix are not necessarily a barrier to
ascending bacterial invasion of the AF
 Alternatively, the pathway for bacterial initiation
of preterm labor may not require colonization of
the AF
 Cox, et al, 1993: cytokine network of cell-mediated
immunity can be activated locally in decidual tissue that
lines the forebag membranes
 Amniotic fluid infection:
Amniocentesis for diagnosis

Romero R, et al,1993: evaluated the diagnostic value of AF in

120 women with preterm labor & intact fetal membranes:
• white blood cell count
• low glucose
• high Il-6, and
• Gram stains positive for bacteria.Women with positive AF
cultures were considered infected: a negative Gram stain
was the most reliable test to exclude AF bacteria (specificity
99%) and
• a high Il-6 was the most sensitive test (sensitivity 82%) in
detecting AF containing bacteria
 Amniotic fluid infection:
Amniocentesis for diagnosis

 Oligohydramnios identified by ultrasound is linked to

antepartum clinical chorioamnionitis
Gonik et al,1985; Vintzileos et al, 1986
 Vintzileos et al, 1985: reported that fetal infection
could be predicted reliably using daily biophysical
profiles, but this observation was not confirmed by
others
Carroll et al, 1995; DeVoe et al, 1994;
Gauthier et al, 1992; Miller et al, 1990
Bacterial Vaginosis
Diagnosis:
the normal,
(1) vaginal pH greater than 4.5
lactobacillus-
(2) an amine odor when vaginal secretions are mixed
predominant with potassium hydroxide
vaginal flora is (3) vaginal epithelial cells heavily coated with bacilli
replaced with (“clue cells”)
anaerobic (4) few white cells with a mixed flora (as compared
bacteria, with the normal predominance of lactobacilli) on Gram
Gardnerella staining of vaginal secretions
vaginalis, &
Hillier et al, 1995: BV is associated with :
Mycoplasma
preterm birth, preterm ruptured membranes, infection
hominis of the chorion and amnion, and AF infection
Hillier et al, 1995 Platz-Christensen et al, 1993: BV may precipitate
preterm labor by a mechanism similar to the cytokine
network pathway proposed for AF bacteria

Thorsen et al, 1996: a prospective study of 3600 Danish women: BV diagnosed before 24 wks
was not related to ruptured membranes before 37 wks or to low birthweight
 Neonatal Complications of Preterm Birth
 Neonatal Morbidity (compozite) & mortality are strongly influenced by GA,
specially in pregnancies before 28 wks
- RDS; - Bronchopulmony Dysplasia
- intraventricular Hemorrhage;→ leukomalacia, hydrocephalus
- Necroziting Enterocolitis; Neonatal Sepsis
- Death: Prematurity is the second cause of mortality in the first 5 yrs of
life, worldwide - Chang HH, et al, 2011
 The premature survivors have serious future health problems:
- visual (post-hyperoxygenation retinopathy), hear, neurological
development : neonatal encephalopathy, cerebral palsy,
- mood and/or learning problems during childhood, and adolescence

It is wished a birth at ≥ 39 weeks:

Committee Opinion No. 560. Medically indicated late-preterm and
early-term deliveries. American College of Obstetricians and
Gynecologists. Obstet Gynecol 2013;121:908–10.
 Identification of Women at Risk for
Preterm Birth
 Obstetrical approaches to preterm birth have
traditionally been focused primarily on treatment
interventions rather than earlier identification of
women at risk & prevention of preterm labor
 Papiernik , Kaminski (1974); Creasy, et al
(1980): have emphasized the potential importance of
early identification of women at risk for preterm
birth
 Identification of Women at Risk for
Preterm Birth Risk-scoring Systems
 Papiernik’s score (1974) modified by Creasy et al (1980)
has been tested in several regions of the USA
• In this system, scores of 1 through 10 are given to a
variety of pregnancy factors: socio-economic status,
reproductive history, daily habits, current
pregnancy complications
• Women with scores of ≥ 10 are considered to be at high
risk for preterm delivery
 NIH-sponsored Maternal–Fetal Medicine Network Units
(Mercer et al, 1996): risk assessment failed to identify
most women who have preterm delivery
 Identification of Women at Risk for Preterm Birth

Short Cervix/Cervical Dilatation

 Asymptomatic cervical dilatation after midpregnancy has
gained attention as a risk factor for preterm delivery
• Some have considered such dilatation to be a normal
anatomical variant, particularly in parous women
• Recent studies have suggested that parity alone is not
sufficient to explain cervical dilatation discovered early in
the third trimester
• Cook, Ellwood, 1996: longitudinally studied the cervix
between 18 and 30 wks using transvaginal ultrasound in
both nulliparous and parous women
• Cervical length & diameter were identical in both groups of
women throughout these critical weeks
 Identification of Women at Risk for Preterm Birth:
Cervical Dilatation
Papiernik et al, 1986; Stubbs et al, 1986; Copper et al, 1995;
Iams et al, 1996:
Using trans-vaginal sonography:
• those women with dilatation of 1 cm or more,
or effacement of more than 30%, were at
increased risk for preterm delivery
• mean cervical length at 24 wks was ~ 35 mm,
& those women with progressively shorter
cervices experienced increased rates of preterm
birth
Other methods used for predicting
preterm birth
 Home uterine activity monitoring (HUAM), not
currently recommended for use.
 Assessments of salivary estriol, based on the belief
that the adrenal gland production of
dehydroepiandrosterone increases before the
onset of labor, which results in an increase of
maternal estriol
 Bacterial vaginosis detection: prospective
treatment trials eradicating asymptomatic BV failed to
reduce the risk of preterm delivery
 Fetal fibronectin (FFN)
 Other methods used for predicting
preterm birth
• FFN: a basement membrane protein that helps bind
placental membranes to the decidua.
 While a negative FFN is helpful in predicting women
who are not destined to deliver preterm,
 a positive FFN has limited value in predicting women
who will deliver preterm.
 Nevertheless, FFN has a predictive value in identifying
patients who will or will not deliver within the
subsequent 1-2 weeks.
 Signs and Symptoms

• It have been empirically associated with impending preterm

birth:
 painful or painless uterine contractions (PUC), menstrual-like
cramps,
 pelvic pressure
 watery or bloody vaginal discharge
 pain in the low back
• Such symptoms are common in normal pregnancy, and
• are therefore often dismissed by patients, physicians, & nurses
• these are a late warning sign of preterm birth: only
appeared within 24 hours of preterm labor
 Diagnosis of Preterm Labor
 Early differentiation between
true & false labor is difficult
before there is demonstrable
cervical effacement & dilatation
 PUC alone can be misleading,
because of Braxton Hicks
contractions, which are irregular,
nonrhythmical, and either painful or
painless, can cause confusion in the
diagnosis of preterm labor
 Not infrequently, women who
deliver before term have uterine
activity that is attributed to
Braxton Hicks contractions,
prompting an incorrect diagnosis of
false labor
Herron, et al (1982): require
the following criteria to
document preterm labor:
- regular uterine contractions
after 20 wks or before 37
weeks, which are 5 to 8
minutes apart or less, and one
or more of the following:
- (1) progressive change in
the cervix,
- (2) cervical dilatation of
≥2 cm, or
- (3) cervical effacement of
80% or more
 Diagnosis of Preterm Labor:
Cervical dilatation assessment → not digital
Sonographic measurement of
cervical dilatation &
effacement:
 Iams, et al, 1994:measure cervical
length in women with preterm labor
between 24 and 34 wks compared
with digital examinations to predict
preterm birth before 36 weeks
 When the cervix was less than
3 cm in length as measured with
sonography, then 100% of the
women delivered preterm. In
contrast, cervical dilatation of 2
cm or more, or effacement of
50% or more, were predictive of
preterm birth in 62% & 83%,
respectively
Transperineal cervical sonography
vs transvaginal: advantage of avoiding
vaginal instrumentation with preterm
ruptured membranes or placenta previa
Richey, et al (1995): significant
correlation between the 2 methods
Speculum examinations to
diagnose ruptured membranes
Brown, et al (1993):
 If the fetus or membranes were
visible, the cervix was usually 3 cm or
more dilated
 Similarly, visual estimates of 4 cm or
more cervical dilatation were
significantly correlated with actual
cervical dilatation of 4 cm or more
 Cervical trauma for abortion
increases the risk of cervical
incontinence ( > 2 demand
abortions without laminaria
or misoprostol;
The use of laminaria and
misoprostol generate a lower
risk of late miscarriage &
PB). In cases with a cervix ≤
“Funneling” 25 mm at 24 wks RR for PB =
transvaginal ultrasonic examination 6. 2, and at 28wks RR= 9.6,
sensibility : 49% for birth at
+ cervical stress test: 35wks, Value of more
“funneling” after transducer importance than that of
suprasymphizis pressure
cervical “funneling”
 Antepartum Management
 Women with pregnancies identified to be at risk for
preterm birth, and those who present with signs &
symptoms of impending preterm delivery, have become
candidates for a large number of interventions intended to
improve infant outcomes
 In the absence of maternal or fetal indications that
warrant intentional delivery, most interventions are
expected to forestall preterm birth or enhance the infants’
ability to cope with the extrauterine environment

 In many instances, the interventions described in the

following section should be considered investigational and
not necessarily recommended for clinical practice
Preterm Labor with Intact Membranes

When to avoid preterm labor ?

o Prior to 37 wks
o There is no maternal pathology which
risks to fail
How to avoid preterm labor?
 Management (1)

Therapeutical Strategies. On discuss some

assessments:
a) Correct Diagnosis of PB: different terms are defining
clinical situations:
 PB risk: presence of any risk factor induces this Dg
 Threatening for PB: 24- 37wks pregancy with PUC,
without cervical changes
 PB iminent : the above signs & symptoms+ vaginal
blood loss
 PB in active evolution : all above+ cervical changes
 Premature membrane rupture
 Management (2) Therapeutical Strategies
b) Correct Assessment of GA: according to first day LMP and GA
confirmation by one/more of the next:
- IPT + before the day of the future second waited menstruation
- uterine sizes at bi- manual uterine gynecological examination done before 12th week
- fetal heart depiction at ultrasound done before 12th week
- GA ultrasound estimaton (limits of 1 week in the first trimester, 2 weeks in the
IInd trimester, & de 3 wks in the al IIIrd trimester)
c) Assessment of fetal wellbeing: normal fetal morphology, for not treating a
fetus with life threatening abnormalities, or an oligohidramnios, or a negative non-
stress test, positive stress test, repeated severe decelerations, dyastolic reverse-
flow on UA, vaginal blood loos sugestive for premature separation of normal
inserted placenta.
d) Assessment of maternal health appreciation if pregnancy prolongation is not
deletorious for mother’s health, & if specific medication may be recommended.
Heart, renal, respiratory failures, malignant hypertension, blood malignancy, other
severe disorders impose pregnancy termination immediatly as the fetus has gained
viability by pulmonary maturation- spontaneous or medically induced.
e) Establishment of PB score risk
 Management (3) Therapeutical Strategies
. f) PB Prevention : Strategical Recommendations : Australia
(2014) , USA (2015)
1) avoidance of late preterm birth induction for non- medical reasons: between
34 & 37 wkst (advanced maternal age 40- 49 yrs, pregnancy prevoius obesity)
2) low dose aspirin (81 mg/zi) from 12 wks. in pregancies with high risk of PE,
IFGR, which increase the risk of iatrogenic PB - LeFevre ML, 2014
3) reduction/ stop of smoking during pregnancy
4) reduction to one of the number of transfered embryos in ART, strategy that
does not substantial reduce the number of life fetuses
5) increased interval between deliveries to minimun 18 months– this
prolongation will reduce the risks of inflammation and nutritional deficiencies
6) progesterone supplementation in pregnancies with history of PB - from 16
to 36 + 6 dysi
7) universal screening for ultrasonic cervical lenght measurement, and
progesterone and prophilactic cerclage
 Low dose Aspirin (81 mg/day) from the 12th wk. in
pregnancies with high risk of PE, IUFGR, which increase the
risk of iatrogenic PB
USPSTF Recommendations for the risk of PE
LeFevre ML, 2014
1. Patients with high risk of PE, with one or more characteristics :
- History of PE, multiple gestation, chronic HT, DM type 1 and 2,
kidney disorders, autoimmune disorders (LES, anti-phospholipid
antibodies)
2. Patients with moderate risk of PE :
- nuliparity, BMI >30, relative of degree I with history of PE,
socio-economic precarity, age ≥35 yrs, history of IUFGR or other
data of fetal/neonatal poor prognosis, and > 10 years interval in
between gestations
 High dose Aspirin (150mg/day)

 Trudinger BJ, et al, 1988- performed a double-

blinded, randomized clinical trial using 150 mg of
aspirin in pregnant women with abnormal UA
Doppler findings.
 The result was an increase in birth weight of 516 g
and an increase in placental weight.

Trudinger BJ, Cook CM, Thompson RS, et al (1988)- Low-dose aspirin therapy
improves fetal weight in umbilical placental insufficiency. Am J Obstet Gynecol. 159(3):681-
5.

These recommendations are reconsidered again

 Management (4)

Prevention: - bed rest (↓ uterine contractility),

- correct hyidration – minimum 2 l/day
- antispastic drugs (drotaverine, scopolamine),
- sedation (benzodiazepines, pasiflora)
- antibiotics for all associated infections *

- in utero transfer

* Many studies of the last 10-15 yrs did not revealed notable
benefits when propfilactic antibiotics were used, special when
intact membranes -Hutzal CE, et al, 2008, or from the
prognosis of preterm neonates -Cochrane Database Syst Rev,
2013
 * Preterm Labor with Intact Fetal
Membranes
The cornerstone of treatment of women with signs & symptoms of
preterm labor and intact membranes is to avoid delivery prior to 37
wks if possible
Antimicrobials, for the purpose of delaying delivery in
women with preterm labor, have been studied specifically in
women with intact membranes
• Results with a variety of antimicrobial agents have been
disappointing
Romero, 1993; Gordon, 1995; Klebanoff, 1995; Cox, 1996
• It is likely that administration of antimicrobials after
preterm labor has begun is too late to interfere with
propagation of the cytokine cascade that modulates uterine
activity
 Management (6)

Medication: b) Antibiotics
 Cases with sexually transmited diseases, vaginitis, UTI, severe
respiratory infections must be adequate treated
In USA ( last 30 yrs): eritromycine, ampiciclyne, clindamycine
Kenyon S, et al, 2010; McGregor JA, et al,1986;
Miller JM, et al,2000
 Cases with intact membranes, with vaginal positive cultures
with groupe B streptococus: were treated long time with
intravenous Peniciline, for prevention of vertical perinatal
prevention, even it was proved that it does not substantially
reduce the rate of PB
 Cases with premature ruptured membranes will benefit from
antibiotics during the duration of waiting corticoids’ effects and
the moment of birth with the lowest risks of morbidity /mortality
of the preterm baby Kenyon S, et al, 2010
 Preterm Labor with Intact Membranes
3. Glucocorticoid Therapy
 Liggins, Howie, 1974: randomized study to evaluate the effects
of maternally administered betamethasone (12 mg i.m. in 2
doses 24 hs apart) to prevent respiratory distress in subsequently
delivered preterm infant. Infants born before 34 wks had a significantly
lowered incidence of respiratory distress & neonatal mortality from
hyaline membrane disease if birth was delayed for at least 24 h after
completion of 24 h of betamethasone given to the mother and for up to
7 days after completion of steroid therapy (best efficacy = in 3 to 7
days, after completed regimen)
 The mechanism by which betamethasone or other corticosteroids are
currently thought to reduce the frequency of respiratory distress involves
induction of proteins that regulate biochemical systems within type II
cells in the fetal lung that produce surfactant (Ballard PL, Ballard
RA, 1995). The physiological effects of glucocorticoids on
the developing lungs include increased alveolar surfactant,
compliance, & maximal lung volume
 Management of Preterm Labor
c) Glucocorticoid Therapy
Meta-analysis for randomized trial of cortico-steroids for
fetal maturation:
 reduces respiratory distress by 50%
 reduces neonatal mortality by 50%
NIH Consensus Development Panel,1995:
 data are insufficient to assess effectiveness of
corticosteroids in pregnancies complicated by:
• hypertension
• diabetes mellitus
• multiple gestation
• fetal growth restriction
• fetal hydrops
 On debates:
- the use of corticoids in multiple pregnancy
Batista L, et al, 2008; Choi SJ, et al, 2009
- extra extreme prematurity (< 24 wks)
Hayes EJ, et al, 2008; Mori R, et al, 2011
- intrauterine fetal growth restriction
Torrance HL, et al, 2009; Vidaeff AC, et al, 2011.

Latest data agree the administration of betametazone

in:
- high risk pregnancies for late PB (between 34 -36 wks
+ 6 dys) with single/multiple fetuses -ACOG, 2016,
because up to the age of 31 yrs there were not found
congnition problems, in such cases - ACOG, 2016
 Quality of evidence to support use of
corticosteroids to promote fetal maturation
NIH Consensus Development Panel on the Effect of
Corticosteroids for Fetal Maturation on Perinatal Outcome,1995
Evidence Treatment-to- Evidence
Neonatal mortality delivery interval
Good
< 24 hr fair
Respiratory distress
Good
syndrome 24 hr to 7 days good
Intraventricular > 7 days Inadequate
Good
hemorrhage
for or against
Preterm ruptured
Fair
membrane
Delivery at 24–28 wks Good Chapman et al, 1996:
Delivery at > 34 wks Inadequate corticosteroid treatment for women
for or with preterm ruptured membranes
against who delivered infants
weighing < 1000 g is not beneficial
 Methods Used to Inhibit Preterm Labor
Bed Rest: either in the hospital or at home. No conclusive investigations on the
benefits of bed rest to prevent preterm birth
Hydration & Sedation: 500 mL of lactated Ringer solution i.v. over 30 min. and
8 - 12 mg of i.m. morphine sulfate. Not found to be more beneficial than bed rest
Beta-adrenergic Receptor Agonists: hexoprenline ® + progesterone
Magnesium Sulfate ??? (Cohrane Data Base- excluded)
Prostaglandin Inhibitors: aspirin & other salicylates, indomethacin, naproxen,
sulindac; closure of the ductus arteriosus, necrotizing enterocolitis, and
intracranial hemorrhage
Calcium Channel-blocking Drugs : Nifedipine®
Atosiban: A nonapeptide oxytocin analog; Tractocile®
Nitric Oxide Donor Drugs: smooth-muscle relaxant in vasculature, gut, uterus.
Nitroglycerin: patches/i.v.
Combined therapy: long-term tocolysis: i.v. terbutaline + magnesium sulfate; mean
duration of 61 days in cases with intact membranes and 1 case received therapy for 123
days. Kosasa et al (1994)
 Places of action of tocolytics at the level of myimetrial cells
Legendă: COX cyclooxigenaze, PIP3: Phosphatidylinositol tryphosfat,
IP3: inositol triphosfat, cAMP: AMP cyclic, cGMP guanosine
monophosfat cyclic
 d) Beta adrenergic Receptor Agonists
 The adrenergic receptors are located on the outer surface of the
smooth muscle cell membrane, where specific agonists can couple with
them
 Adenyl cyclase in the cell membrane is activated by the receptor
stimulation
 Adenyl cyclase enhances the conversion of ATP to cyclic AMP,
which in turn initiates a number of reactions that reduce the intracellular
concentration of ionized calcium and thereby prevent activation of
contractile proteins
Flier & Underhill, 1996: have comprehensively reviewed
adrenergic receptors
There are 2 classes of β-adrenergic receptors:
• β 1-receptors: dominant in the heart & intestines
• β 2-receptors: dominant in the myometrium, blood vessels, and
bronchioles
 Beta 2-adrenergic Receptor Agonists
Ritodrine: lower mortality rate, developed respiratory distress less
often, and achieved a gestational age of 36 wks or a birthweight of 2500
g more often than did infants whose mothers were not so treated
Merkatz et al, 1980.
Terbutaline (Fenoterol )- not used since 1995 - ACOG
Isosuprine (Duvadilan )

Hexoprenaline (Gynipral ): vials, tb

Overview of Beta-Adrenergic Drugs to Inhibit Preterm Labor:
 delay delivery for no more than 48 hs
 β-adrenergic receptor desensitization - Hausdorff et al, 1990
 useful to facilitate maternal transport to tertiary care centers,
 delay delivery sufficiently to effect fetal maturation with
glucocorticoids
 Management of Preterm Labor
e) Progesterone - P4
Crucial for pregnancy evolution, from preconception to term,
making hormone modulation of gestation.
• P4 increases local production of Th2 and/or Leukemia
Inhibiting Factor (LIF), cytokines that maintain gestation.
• P4 restores β-adrenergic receptors when desensitization
apears

The Latest Recommendations:

- Treatment initiation during weeks 16- 26
How HY, et al, 2007; Romero R, et al, 2012
- Continuation to weeks 34- 36
Russu M, et al, 2014; Norman JE, et al, 2016
 Progesterone for preterm birth
Progesterone supplementation was advocated for
preterm prevention
Dodd JM, Flenady V, Cincotta R et al, for
Cochrane Database Syst Rev. 2006
Progestins/Progesterone derivates are suppressing
Thrombin- and Il-1{beta}-Induced Il -11, which
are related to preterm delivery, abruption
placentae, and chorioamnionitis.
Cakmak H, Schatz F, Huang S-TJ, et al, 2005
IL-1βInduced Il-11: a cytokine with pleiotropic biological
effects, including induction of Th-2 type, and inhibition of
Th-1 type cytokine responses, paradoxically, it enhances the
synthesis of prostaglandins, which induce labor.
 Progesterone for preterm birth
Only three formulations are considered safe:
 natural progesterone administered vaginally (as either a pessary or a cream):
200- 300mg/day
 a semi-synthetic drug: dydrogesterone: up to 6 tbs/day
 a synthetic caproate ester of naturally occurring
17 α-hydroxyprogesterone *, given as a long-acting intramuscular injection.

 Vaginal route of administration: better bioavailability of Progesterone in the uterus

(10 fold higher to that of i.m. administration) & minimal systemic undesirable effects
Cicinelli E, de Ziegler D, 1999
Tavaniotou A, Smitz J, Bourgain C, Devroey P, 2000
*17 alpha-hydroxyprogesterone is produced by the placenta itself

Utrogestan®, Crinone®, Duphaston®, Lutinus®

 Progesterone for preterm birth
Progesterone/ 17 alpha-hydroxyprogesterone are
administered for miscarriage and preterm birth prevention at
different pregnancy’s ages:
 16-20 wks: Meis PJ, Klebanoff M, Thom E, et al (2003)
for National Institute for Child Health and Human
Development: reduced the rate of delivery before 32 wks
from 18.6% to 11.4% - P: 0.0180, and before 35 wks from
30.6 to 20.6 % - P: 0.0165
 24-34 wks: da Fonseca EB, Bittar RE, Carvalho MH,
Zugaib M, 2003: reduced the rate of delivery before 34 wks
from 34% to 19%
Russu M, et al,2008: Preconception to 36 wks: the rate of
delivery after 35 wks increased from 56% to 96.5%
 Magnesium Sulfate
 It has been recognized for some time that ionic
magnesium in a sufficiently high concentration can alter
myometrial contractility in vivo as well as in vitro. Its role is
presumably that of a calcium antagonist
 Steere & Petrie, 1977: concluded that i.v. administered
magnesium sulfate, 4 g given as a loading dose followed by
a continuous infusion of 2 g/hr, will usually arrest labor
 No benefits for such therapy were found, and this method of
tocolysis was abandoned at Parkland Hospital, because of high toxic
doses necessary to inhibit contractions
 Calcium Channel-blocking Drugs
 Smooth muscle activity, including myometrium, is directly
related to free calcium within the cytoplasm, and a reduction in
calcium concentration inhibits contraction. Calcium ions reach the
cytoplasm through specific membrane portals or channels, and
calcium-channel blockers act to inhibit, by a variety of different
mechanisms, the entry of calcium through the cell membrane
channels. Calcium-entry blockers, because of their smooth muscle
arteriolar relaxation effects, are currently being used for the treatment
of coronary artery disease & hypertension
 Nifedipine treatment postponed delivery at least 3 days in
women with preterm labor at 33 wks or less. No serious maternal or
fetal side effects were noted - Ulmsten et al, 1980, - Denmark)
 nifedipine is superior to ritodrine in efficacy and has fewer side
effects (Papatsonis et al, 1996)
 Tocolytic agents:
potential complications
Beta-adrenergic Agents ACOG: Preterm Labor.
Hyperglycemia
Technical Bulletin no. 206, June 1995
Hypokalemia
Hypotension Magnesium Sulfate
Pulmonary edema Pulmonary edema
Heart failure Respiratory depression
Arrhythmias Cardiac arrest
Myocardial ischemia
Maternal tetany
Maternal death
Profound muscular paralysis
Emesis, headaches, tremulousness,
Fever, hallucinations Profound hypotension

Indomethacin
Hepatitis Nifedipine
Renal failure Transient hypotension
Gastrointestinal bleeding
 Intrapartum Management of preterm birth
 Whether labor is induced or spontaneous, continuous electronic
monitoring for abnormalities of fetal heart & uterine contractions
 Fetal tachycardia, specially in the presence of ruptured membranes,
is suggestive of sepsis
 Intrapartum acidemia (umbilical artery blood pH < than 7.0) may
intensify some neonatal complications usually attributed solely to
prematurity
 Prevention of infection with streptoccocus group B: ampicillin 2
g i.v. every 6 hs until delivery for women in labor prior to 37 wks
 Magnesium sulfate: reduces incidence of cerebral palsy
when surviving infants with birthweights < 1500 g. Magnesium
given to fetus via the mother perhaps playes a role in regulation of
vasculature supplying the germinal matrix of fetal brain that is
especially vulnerable to hemorrhage in preterm infant (Nelson &
Grether, 1995)
 a liberal episiotomy once the fetal head reaches the perineum
 Management for active preterm birth
Many debates regarding the route of delivery in preterm birth
Cesarean Section– increased up to 35%
 < 32 weeks – cesarean section
 32-34 weeks – discussed

 >34 weeks – connected to obstetrical pathology

Reddy UM, Zhang J, Sun L, et al. Neonatal mortality by attempted route of delivery
in early preterm birth. Am J Obstet Gynecol 2012
Fetal outcome is directly influenced by the degree of
prematuriry and not by the route of delivery
Rules imposed to be respected for all deliveries with preterm babies:
- conduction of labort under CTG monitoring
- integrity of membranes up to expulsion,

- myorelaxant drugs, a petidine derivate for analgesia, without a prolonged

labor, or epidural analgesia, if it is possible;
- oral/ endovenous hydratation and fetal metabolic resuscitation, plus oxygen

- prophilactic epiziotomy/perineotomy and expulsion assisted in the presence

of neonatologist