PRETERM BIRTH: AN OVERVIEW OF

RISK FACTORS AND OBSTETRICAL

MANAGEMENT

Amanda Stewart* and Ernest GrahamDepartment of Gynecology & Obstetrics, Division of Maternal Fetal Medicine, Johns Hopkins Hospital, Baltimore, Maryland›

Preterm birth is the leading cause of neonatal mortality and amajor public health concern. Risk factors for preterm birth include a his-tory of preterm birth, short cervix, infection, short interpregnancy inter-val, smoking, and African-American race. The use of progesterone ther-apy to treat mothers at risk for preterm delivery is becoming more wide-spread. Tocolytics may not prevent preterm birth but have a role inprolonging pregnancy for administration of medications to benefit thepreterm infant. These include antenatal steroids and, if indicated, magne-sium sulfate for neuroprotection and intravenous antibiotics for Group BStreptococcus prophylaxis. '2011 Wiley Periodicals, Inc.Dev Disabil Res Rev 2010;16:285–288.

Key Words: preterm labor; premature birth; neonatal morbidity and

mortality

Prematurity is currently a major public health concernand is the leading cause of neonatal mortality. The rateof preterm birth was on a continual rise in the United

States from 1981 until 2006 reaching a rate of 12.8% with thegreatest increase occurring in infants born between 34 and 36weeks of gestational age; however, in 2008 the rate of pretermbirth declined to 12.3% [Martin et al., 2010]. Centers forDisease Control (CDC) data from 2008 estimates that 36.1%of all infant deaths are preterm related, and the mortality ratedue to prematurity is as high as 45% in African-Americaninfants [Matthews et al., 2010].

PATHOPHYSIOLOGY OF PRETERM BIRTHThe process that results in labor and birth involves a cas-

cade of events that is incompletely understood. Many possibletheories and pathways have been proposed, some of which aresupported by clinical evidence. Myometrial and amnioticmembrane overdistention, decidual hemorrhage, premature fe-tal endocrine activation (through the hypothalamic-pituitary-adrenal axis), and intrauterine infection/inflammation have allbeen implicated in the pathophysiology of preterm labor[Simhan et al., 2007]. Progesterone withdrawal and estrogenactivation have also been thought to play a role in parturition.As gestation progresses to term, the myometrial sensitivity toprogesterone changes. There is an increased expression of pro-gesterone receptors in the myometrium, leading to decreasedprogesterone availability to suppress the expression of estrogen

receptors. The myometrium becomes more sensitive to estro-gen, and myometrial contractility increases [Kamel, 2010].This pathway accounts for the role of progesterone administra-tion in the prevention of preterm birth.

RISK FACTORSRisk factors for preterm birth include a history of pre-

term birth, short cervix, infection, short interpregnancy inter-val, smoking, and African-American race. A prior pretermbirth is a major risk factor for subsequent preterm birth. Inpatients who experience a preterm birth, the recurrence riskis twofold higher. In addition, the gestational age of the initialpreterm birth is predictive of the gestational age of the subse-quent preterm birth. Of all women with a prior preterm birthwho deliver preterm in a subsequent pregnancy, 50% of deliv-eries occur within 1 week and 70% of deliveries occur within2 weeks of the gestational age of the prior preterm delivery[Spong, 2007]. In an observational study performed by theNational Institute of Child Health and Human Development(NICHD) Maternal Fetal Medicine Units (MFMU) networkamong women with a history of at least one previous pretermbirth at <32 weeks, women underwent endovaginal ultra-sounds once between 16 and 18 weeks and then every 2weeks until 24 completed weeks gestation. Closed cervicallength measurements as well as the presence or absence ofdynamic changes of the cervix were assessed. The primaryendpoint was spontaneous preterm birth at <35 weeks gesta-tion. The results showed that cervical length between 16 and18 weeks was most predictive of recurrent preterm birth.Cervical length measurements <25 mm had a positive predic-tive value of 75%, and cervical length measurements <15 mmhad a positive predictive value of recurrent preterm birth at<35 weeks gestation of 100% [Owen, 2001].

Evidence of intrauterine infection is present in manycases of preterm birth and occurs more commonly in births at

*Correspondence to: Amanda Stewart, The Johns Hopkins Hospital, Houck 228,600 N. Wolfe Street, Baltimore, MD 21287.E-mail: astewa30@jhmi.eduReceived 20 May 2011; Accepted 16 June 2011Published online in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/ddrr.124

DEVELOPMENTAL DISABILITIESRESEARCH REVIEWS 16: 285 – 288 (2010)

' 2011Wiley Periodicals, Inc.

less than 30 weeks gestation. Bacterialinvasion results in a release of endotox-ins and exotoxins. This activates thedecidua and membranes to producecytokines which then activates prosta-glandin synthesis and stimulates uterinecontractions [Goldenberg et al., 2000].

An interpregnancy interval of lessthan 6 months is an independent riskfactor for preterm delivery. In an obser-vational cohort study in 2003 of 89,413women, an interpregnancy interval ofless than 6 months conferred an oddsratio of 2.2, 1.6, and 3.6 for extremelypreterm birth, moderately pretermbirth, and neonatal death, respectively[Smith et al., 2003].

MANAGEMENT ANDPREVENTION OFSPONTANEOUS PRETERMBIRTH

Fetal fibronectin testing has gainedpopularity in use as a tool to help triagepatients presenting with preterm contrac-tions. Fetal fibronectin is an extracellularglycoprotein that acts as an adhesivebetween the fetal membranes and theuterine wall. Fetal fibronectin is foundnormally in vaginal secretions in the firstand late third trimesters. Fetal fibronectinshould be virtually undetectable between22 and 35 weeks gestation, and its pres-ence during this period is believed to bepathologic. In a multicenter trial per-formed by Peaceman et al. [1997], 763women who presented with symptoms ofpreterm labor had fetal fibronectin testingand pregnancy outcome data analysis.Compared with women who had nega-tive results, women with positive resultswere more likely to deliver preterm.Also, the negative predictive value fordelivery within 7 days, 14 days, and lessthan 37 weeks were 99.5%, 99.2%, and84.5% respectively.

Numerous studies have been con-ducted to evaluate the role of progester-one in the prevention of spontaneouspreterm birth. Progesterone inhibits theformation of gap junctions and inhibitsmyometrial contractions. Its use has alsobeen shown to prevent spontaneousabortion in women in whom the cor-pus luteum has been excised [Mack-enzie et al., 2006]. A double-masked,placebo-controlled, randomized trialwas performed to evaluate the use of17-OH progesterone supplementationin women with a history of pretermbirth [Meis et al., 2003]. Meis et al. inthe NICHD MFMU network studied463 women with singleton pregnanciesand a history of preterm birth. Womenwere enrolled between 16 and 20 weeks

gestation and were randomized toreceive either weekly intramuscularinjections of 17-OH progesterone orplacebo. The study showed a statisticallysignificant reduction in preterm deliveryat less than 37 weeks, less than 35weeks, and less than 32 weeks. Therewere also reductions in neonatal mor-bidity and mortality. In that same year,DaFonseca et al. published a study eval-uating the use of vaginal progesteronesupplementation in women at high riskof preterm delivery.

‘‘The American Collegeof Obstetricians andGynecologists (ACOG)published a committeeopinion recommendingthe use of progesteronesupplementation to

prevent preterm birth inwomen with a history ofspontaneous preterm

birth.’’

A double-blind, randomized controltrial of 142 women to receive eitherprogesterone 100 mg vaginal supposi-tory or placebo was performed, and theresults showed a statistically significantreduction in preterm birth at less than37 weeks and less than 34 weeks in theprogesterone group [Da Fonseca et al.,2003]. DaFonseca et al. later studied theutility of progesterone supplementationin patients with a short cervix. Usingtransvaginal ultrasound, cervical lengthmeasurements were obtained between20 and 25 weeks gestation in patientsreceiving routine prenatal care. Womenwith cervical length measurements lessthan 15 mm were randomized toreceive either 200 mg progesterone viavaginal suppository or placebo. Theresults showed a statistically significantdecrease in the rate of preterm birth atless than 34 weeks. There was also a non-significant decrease in neonatal morbidity[Fonseca et al., 2007]. The AmericanCollege of Obstetricians and Gynecolo-gists (ACOG) published a committeeopinion recommending the use of pro-gesterone supplementation to preventpreterm birth in women with a historyof spontaneous preterm birth [ACOGCommittee Opinion, 2003].

ANTENATALCORTICOSTEROIDADMINISTRATION

Respiratory distress syndrome(RDS) is the leading cause of early neo-natal death and morbidity and primarilyaffects infants born prematurely. Corti-costeroid administration prior topreterm birth accelerates fetal lung de-velopment and also decreases neonatalmorbidity from necrotizing enterocolitisand intraventricular hemorrhage. ACochrane review of 21 studies supportsthe use of a single course of antenatalsteroid administration to accelerate fetallung maturity [Roberts and Dalziel,2006]. The Betacode trial by Elimianet al. was a double-blind, placebo-controlled, randomized trial of antenatalbetamethasone compared with dexa-methasone. In the study, 299 women athigh risk for preterm delivery wererandomized to receive either two dosesof betamethasone, 12 mg 24 hr apart,or four doses of dexamethasone, 6 mggiven 12 hr apart. The results showedthat there was no statistically significantdifference between the two groups inthe rates of RDS, need for vasopressortherapy, necrotizing enterocolitis, reti-nopathy of prematurity, neonatal sepsis,patent ductus arteriosus, or neonataldeath [Elimian et al., 2007]. Treatmentwith betamethasone and dexamethasoneare equivalent in preventing neonatalmorbidity and mortality; however, asbetamethasone requires two rather thanfour injections, it is more commonlyused in clinical practice.

ANTIBIOTICS FOR GROUP BSTREPTOCOCCUSPROPHYLAXIS

Group B Streptococcal (GBS)infection is the primary infectious causeof neonatal morbidity and mortality inthe United States. Neonatal Infectionoccurring within the first week of life isdescribed as early onset disease, andpreterm birth is an important risk factorfor early onset disease. The incidence ofGBS disease has decreased dramaticallyover the years from 1.7 per 1,000 livebirths in the 1990s to approximately0.34–0.37 per 1,000 live births in 2008[CDC, 2010]. Current strategies toreduce the incidence of GBS diseasehave been effective against early onsetdisease but do not prevent late onsetdisease. Approximately 10–30% ofwomen are colonized with GBS, andthis is the primary risk factor for earlyonset neonatal disease. Current clinicalpractice is to perform vaginal and rectalGBS screening at 35–37 weeks gestation

286 Dev Disabil Res Rev � PRETERM BIRTH � STEWART AND GRAHAM

for all pregnant women, and treat thosewho are positive at the time of delivery;however, if they have had a urine cul-ture positive for GBS during the cur-rent pregnancy or a previous infant withinvasive GBS disease they are not cul-tured but automatically given antibioticprophylaxis at the time of delivery.Beta-lactam antibiotics (i.e., penicillin Gand ampicillin) given intravenously formore than 4 hr prior to delivery havebeen shown to be effective in prevent-ing vertical transmission of GBS.

TOCOLYSISInhibition of myometrial contrac-

tions is termed tocolysis. Tocolytic ther-apy in women presenting with signs ofpreterm labor may possibly prolongpregnancy for 24–48 hr. This acutetocolysis of preterm labor allows for theadministration of antenatal corticoste-roids. Tocolytics currently in use bymany obstetricians include magnesiumsulfate, indomethacin, nifedipine, andterbutaline. In a multicenter random-ized controlled trial, magnesium sulfatewas compared with nifedipine for acutetocolysis in patients presenting in pre-term labor [Lyell et al., 2007]. The pri-mary outcome of interest was preven-tion of preterm delivery for 48 hr.There was no difference between thegroups in delay of delivery, gestationalage at delivery, or neonatal outcomes.Nifedipine, however, was shown tohave fewer maternal side effects. Arecent Cochrane review reviewed theeffectiveness of cyclooxygenase inhibi-tors, that is, indomethacin, as tocolyticsfor preterm birth [King et al., 2005].They reviewed 13 trials that included atotal of 713 women. The data showedthat there was a reduction in birth lessthan 37 weeks gestation, an increase ingestational age at birth by an average of3.5 weeks, and an increase in birthweight; however, the authors concludedthat because the trials had small num-bers that there was insufficient evidenceon which to base recommendations forthe use of indomethacin in the preven-tion of preterm birth. Currently, thereis controversy as to whether tocolyticscan prevent preterm delivery for longerthan 48 hr or improve neonatal out-come [Berkman et al., 2003].

NEONATAL OUTCOMESThe complications that are seen

with prematurity represent the imma-turity of the developing fetal organsystems, and the risk of these complica-tions decrease with increasing gesta-tional age. In the newborn period,

infants born prematurely are atincreased risk for intraventricular hem-orrhage, white matter damage, respira-tory distress, and sepsis. Following thenewborn period, they are at increasedrisk for intellectual and learning disabil-ities, cerebral palsy, vision loss, chronicrespiratory impairment, hearing loss,and feeding difficulty. Late pretermbirth, defined as preterm birth between34 and 36 weeks gestation, hasincreased by 20% in women aged 25years and over from 1990 to 2006[Martin et al., 2009].

‘‘Tocolytic therapy inwomen presenting withsigns of preterm labormay possibly prolongpregnancy for 24–48 hr.This acute tocolysis ofpreterm labor allows forthe administration of

antenatal corticosteroids.’’

These infants, although at lowerrisk of mortality and morbidity thaninfants born at earlier gestational ages,are still at significant risk of long-termmedical, cognitive, and behavioral mor-bidities. Talge et al. evaluated the asso-ciation between late preterm birth andcognitive and socioemotional outcomesat 6 years of age. Late preterm infantswere associated with higher rates of be-havioral problems and lower IQ at age6 [Talge et al., 2010].

MAGNESIUM SULFATE FORNEONATALNEUROPROTECTION

Cerebral palsy is among the mostcommon chronic disabilities of child-hood, affecting approximately one in500 school-aged children. The rates ofcerebral palsy are 6–9% for infants bornat less than 32 weeks gestation andincreases to 16–28% for infants born atless than 26 weeks gestation [Milligan,2010]. There has been a recent surge ofinterest surrounding the use of magne-sium sulfate, not as a tocolytic, but as aneuroprotective therapy. A randomized,controlled trial was conducted byRouse and colleagues in the NICHDMFMU network. Women at high riskfor imminent preterm delivery between24 and 31 weeks gestation were

randomized to receive magnesium sul-fate or placebo. The primary outcomeof interest was a composite of stillbirthor infant death or cerebral palsy at 2years corrected age or older. Of the1,096 patients in the study group, 87%had preterm premature ruptured mem-branes, and almost 20% had previouslyreceived magnesium sulfate for tocoly-sis. Two year follow-up was available for97% of the children. The results showedthat moderate or severe cerebral palsy,corresponding to a Gross Motor Func-tion Classification System score of twoor higher, occurred less frequently inthe magnesium sulfate group. The com-posite primary outcome was not differ-ent between groups [Rouse et al.,2008]. Some interpreted this data asshowing that magnesium sulfate pre-vents cerebral palsy regardless of thegestational age at which it is given, butothers interpreted the same data asshowing that magnesium sulfate onlyprevents cerebral palsy before 28 weeksgestation. In a response to this growingarea of research, ACOG published acommittee opinion stating that theavailable research suggests that ‘‘magne-sium sulfate given before anticipatedearly preterm birth reduces the risk ofcerebral palsy in surviving infants’’[ACOG Committee Opinion, 2010].Although the same dose of magnesiumsulfate is generally used, a 6 g loadingdose followed by infusion at 2 g/hr forat least 12 hr, varying institutions havereported treatment at different gesta-tional ages. University of Alabama atBirmingham uses magnesium sulfate forneuroprotection between 24 and 28weeks gestational age and at ParklandHospital in Dallas, between 23 and 32weeks gestational age [Cunninghamet al., 2010].

CONCLUSIONSMore than 10% of all pregnancies

in the United States end in pretermbirth, and although advances in neona-tal care have improved outcome forpreterm infants, prematurity remainsthe most common underlying cause ofneonatal morbidity and mortality. Pre-term contractions are common in allpregnancies, and no effective diagnostictests have been developed to identifypatients destined for preterm delivery.There is controversy as to how well, ifat all, tocolytics are effective in prevent-ing preterm delivery. Although individ-ual studies have shown benefit fromtocolytics, the preterm delivery rate inthe United States remains unchangedeven with the widespread use of these

Dev Disabil Res Rev � PRETERM BIRTH � STEWART AND GRAHAM 287

agents. Progesterone therapy has beenshown to reduce the incidence of pre-term delivery, and its use is becomingmore widespread. Some therapies havebeen shown to benefit the preterm neo-nate such as antenatal steroids and mag-nesium sulfate to prevent neurologicinjury. Preterm birth remains the majorunsolved problem of modern obstetricsand continues to be the focus of a greatdeal of research. n

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