Progesterone for preterm birthprevention: an evolving
interventionAlan Thevenet N. Tita, MD, PhD; Dwight J. Rouse, MD,
MSPHPreterm birth (PTB) is the number 1cause of neonatal morbidity
andmortality,andaleadingcauseoflong-term disability in the United
States andelsewhere.1,2Overall,PTBaccountsforup to 12.7% of births
in the developedworld; the vast majority of these (75%) occur
spontaneously.1,3Althoughsecondary or tertiary interventions suchas
antenatal corticosteroids, postnatalsurfactant, and improved
neonatal carehave led to reduced morbidity and
mor-talitycausedbyPTB, effectiveprimarypreventive interventions
have remainedelusive. Encouragingly, accumulatingdata suggest that
progesterone may be ef-fective inpreventing PTB, andthe Amer-ican
College of Obstetricians and Gyne-cologists (ACOG) recognizes its
use forthis purpose.4Nevertheless, there is stillconsiderable
uncertainty surroundinghowprogesteroneactuallyworks,indi-cations
for its use, and the optimal pro-gesterone type, mode of
administration,and dose. Both ACOGand the Society ofObstetricians
and Gynecologists of Can-ada(SOGC)acknowledgetheneedforadditional
studies4,5and, asof August2008, there were 20
registeredongoing(orplanned)trialsof progesteroneforthe prevention
of PTB. The purpose ofthis report is to present a concise reviewof
more recent data (since 2000) on
pro-gesteroneusespecicallyforPTBpre-vention focusing on
pharmacologic op-tions, specicclinical indications, andexpected
benets.Materials and methodsWe conducteda searchof the
entirePubMeddatabase(January2000-Octo-ber 2008) using the key words
proges-terone andpreterm. Atotal of 240 ab-stracts were reviewed to
identify allrelevant clinical trials or metaanalyses ofclinical
trials evaluating the effect of an-tenatal maternal use of
progesterone ontheriskofPTB.
Wethenconductedabibliographicreviewoftheselectedre-ports. We also
reviewed national guide-lines for the use of progesterone to
pre-vent PTB. Of a total of 17 reportsidentied, there were 8
clinical trials,6-136 metaanalyses,14-19and 3 reports ofnational
recommendations or guide-lines.4,5,20We abstracted relevant
phar-macologic data on progesterone formu-lation(type, dose, route,
and side effects)andpregnancyoutcomebyriskgroupunder study. We
applied an analytic (asopposed to a synthetic) approach to
thesynthesis of the data from these reports(ie, we analyzed
observed similaritiesand/ordifferences without conductingadditional
metaanalyses). Relative risk(RR) and 95% condence interval (CI)for
pertinent outcomes were obtainedei-ther fromthe reports themselves
or,when not available, calculated from thereported
data.ResultsAmong the 8 clinical trials identied,6-131 was a
subgroup analysis of another in-cludedtrial.10The characteristics
of the 7primary clinical trials and 6
metaanaly-sesaresummarizedinTables1and2,respectively. In addition,
we identied 3relevant national recommendations
ortechnicalreports,2fromACOGand1from SOGC.4,5,20The clinical trials
wereall reportedbetween2003and2008;
2trialswerenotplacebocontrolledand,Fromthe Center for Womens
ReproductiveHealth, Maternal-Fetal Medicine Division,Department of
Obstetrics and Gynecology,University of Alabama at
Birmingham,Birmingham, AL.Received Oct. 7, 2008; accepted Dec.
22,2008.Reprints not available fromthe authors.Dr Tita is funded by
a Womens ReproductiveHealth Research Scholar grant fromtheNational
Institute of Child Health and HumanDevelopment.0002-9378/free 2009
Mosby, Inc. All rights reserved.doi: 10.1016/j.ajog.2008.12.035For
Editors Commentary,see Table of ContentsWe sought to review
emerging data on the use of progesterone to prevent pretermbirth
(PTB). Using the terms preterm or premature and progesterone we
queriedthe PubMed database, restricting our search to January 1,
2000, forward and selectedrandomized clinical trials (RCTs) and
metaanalyses of RCTs that evaluated the useof progesterone for the
prevention of PTB. We reviewed 238 abstracts and supple-mented our
review by a bibliographic search of selected reports. We focused on
thepharmacologic aspects of progesterone and risk factor-specic
outcomes. Weidentied a totalof17 relevantreports:8 individualRCTs,6
metaanalyses,and 3national guidelines. Individual trials and
metaanalyses support that synthetic intra-muscular
17-alpha-hydroxyprogesterone effectively reduces the incidence of
recur-rent PTB in women with a history of spontaneous PTB. One
trial found that vaginallyadministerednatural
progesteronereducedtheriskof earlyPTBinwomenwithaforeshortened
cervix. The data are suggestive but inconclusive about: (1) the
benetsof progesterone in the setting of arrested preterm labor; and
(2) whether progesteronelowers perinatal morbidity or mortality. In
some women, progesterone reduces therisk of PTB. Further study is
required to identify appropriate candidates and
optimalformulations.Key words: preterm birth, prevention,
progesteroneReviews www.AJOG.orgMARCH 2009 American Journal of
Obstetrics &Gynecology 219therefore, not blinded. The
metaanalyseswere all reported between 2005 and 2008but included
clinical trials conducted asearly as the 1950s. The type and dose
ofprogesterone, thecharacteristicsofthestudied subjects, the nature
of the studyoutcomes, and the corresponding resultsvaried
considerably.Pharmacologic aspectsof
progesteroneThekeypharmacologicaspectsofpro-gesterone inthe
reviewedstudies areTABLE 1Individual clinical trials of
progesterone for preventing preterm birth since 2000Study
DesignSampleSizeProgesteroneinterventionPopulation(indication)
Primary outcome(s)Borna and Sahabi6RCT (no placebo) 70 400 mg
vaginalsuppository dailyArrested (threatened)PTL(1) Latency
(days)(2) Recurrence of
PTL................................................................................................................................................................................................................................................................................................................................................................................OBrien
et al9RCT (placebo controlled) 659 90 mg vaginal gel Prior SPTB,
18-22 wk PTB 32
wk................................................................................................................................................................................................................................................................................................................................................................................Fonseca
et al8RCT (placebo controlled) 250 200 mg vaginalcapsule daily
until34 wkShort cervix 15 mmat 20-25 wkSpontaneous PTB 34
wk................................................................................................................................................................................................................................................................................................................................................................................Rouse
et al7RCT (placebo controlled 661 250 mg 17P IM until35 wkTwins at
16-20 wk (1) PTB 35 wk or IUFD 35
wk................................................................................................................................................................................................................................................................................................................................................................................Facchinetti
et al11RCT (no placebo) 60 341 mg 17P IMtwice weeklyArrested PTL
Change in cervical
length................................................................................................................................................................................................................................................................................................................................................................................Meis
et al12RCT (placebo controlled) 463 250 mg 17P IMweeklyPrior SPTB,
16 wk PTB 37
wk................................................................................................................................................................................................................................................................................................................................................................................da
Fonseca et al13RCT (placebo controlled) 142 100 mg daily
vaginalsuppository until 34wkPrior SPTB, 24 wkonwardPTB 37
wk................................................................................................................................................................................................................................................................................................................................................................................IM,
intramuscular; IUFD, intrauterine fetal demise; PTB, preterm birth;
PTL, preterm labor; RCT, randomized clinical trial; SPTB,
spontaneous preterm birth; 17P,
17-alpha-hydroxyprogesterone.................................................................................................................................................................................................................................................................................................................................................................................Tita.
Progesterone for preterm birth prevention: an evolving
intervention. Am J Obstet Gynecol 2009.TABLE 2Metaanalyses of
clinical trials of progesterone for preterm birth prevention since
2000Study No. of trialsNo. of
women(infants)ProgesteroneinterventionPopulation(indication)
Primary outcome(s)Dodd et al1911 2425 (3187) Any antenatal useto
prevent PTB(1) Prior SPTB(2) Multiples (twins)(3) Short cervix(4)
Threatened PTL(1) Perinatal death(2) PTB 34 wk(3)
Neurodevelopmentalhandicap................................................................................................................................................................................................................................................................................................................................................................................Coomarasamy
et al189 (cumulativemetaanalysis) 1062 Any antenatal use (1) Risk
factors for PTBexcluding multiples(1) PTB 37 wk(2) PTB 34 wk(3)
RDS................................................................................................................................................................................................................................................................................................................................................................................Mackenzie
et al173 648 Second-trimesteruse(1) Increased risk forSPTBPTB 37
wk................................................................................................................................................................................................................................................................................................................................................................................Dodd
et al166 988 Any antenatal use Any pregnancy (1) Perinatal death(2)
PTB 34 wk(3)
Neurodevelopmentalhandicap................................................................................................................................................................................................................................................................................................................................................................................Dodd
et al157 1020 Any antenatal use Singletons Multiple adverse infant
andmaternal
outcomes................................................................................................................................................................................................................................................................................................................................................................................Sanchez-Ramos
et al1410 1339 Any antenatal use(placebocontrolled)Women at risk
for PTB (1) PTB 37 wk(2) Perinatal
mortality................................................................................................................................................................................................................................................................................................................................................................................PTB,
preterm birth; PTL, preterm labor; RDS, respiratory distress
syndrome; SPTB, spontaneous preterm
birth.................................................................................................................................................................................................................................................................................................................................................................................Tita.
Progesterone for preterm birth prevention: an evolving
intervention. Am J Obstet Gynecol 2009.Reviews www.AJOG.org220
American Journal of Obstetrics &Gynecology MARCH
2009summarizedinTable3. Twotypes ofprogesterone predominate:
natural andsynthetic.Natural progesteroneAlmost exclusively
administeredvagi-nally, doses of natural
progesteronerangedfrom90-400mgdaily,initiatedvariably at 18-25
weeks (Tables 2 and 3).Only1metaanalysis includedastudywith oral
(micronized) progesterone,and this was among women in
pretermlabor.18Comparedwithoral
administra-tion,vaginalprogesteronebypasseshe-patic rst-pass
effects and, therefore, hasbetterbioavailability. Vaginal
adminis-trationisvirtuallywithout sideeffectssuch as sleepiness,
fatigue, and headachethat can occur with oral use.8,9Endome-trial
bioavailability after vaginal proges-terone use is also reported to
be higherthan with the intramuscular (IM) routedespite lower
serumlevels with theformer.9,21This is attributedtodirecttransport
of progesterone fromvagina tothe uterus: the so-calleduterine
rst-pass effect.22Synthetic
progesterone(17-alpha-hydroxyprogesterone)This
syntheticprogesteronewas
givenexclusivelybytheIMrouteinvariabledoses (25-1000 mg) and
schedules(weekly-thriceweekly). Sideeffectsoc-cur in the majority
of patients ( 50%)but are mild and generally restricted tothe
injection site (injection site reaction,swelling, itching,
bruising).7,12Fol-low-up (to an average age of 4 years) ofchildren
exposed to 17-alpha-hy-droxyprogesterone (17P) as fetuses inthe
Meis trial did not suggest any long-termharmful effects
includinggenitalanomaliesoralterationof gender-spe-cic
roles.23OutcomesIndividual clinical trials have focused onspecic
populations at increased risk forPTBsuchasthosewithahistoryof
aspontaneous PTB (SPTB) or a short cer-vix (Table 1). Althoughother
risk groupssuch as those with presumed cervical in-competence or
uterine malformationswere included in 1 trial,13the over-whelming
majority of women had apriorSPTBandwe, therefore, consid-ered the
trial to be reective of this latterrisk group. Although some
metaanalysesalso stratied results by these risk factors(Tables 4
and 5), others presented sum-mary results without regard to risk
fac-tors (Table 6).History of SPTBThree clinical
trials9,12,13and2meta-analyses17,19evaluated the impact
ofprophylactic progesterone on womenwith a history of SPTB (Table
4). Two of3 trials reported signicant reductions inPTBonthe order
of 30-50%.12,13Vaginalprogesterone (100 mg) was used in 1
ofthesestudies,13whereas250mgofIM17Pwasusedintheother.12Thethirdtrial
did not demonstrate a reduction inPTB with use of 90 mg of vaginal
proges-terone gel.9Both relevant metaanalysesdemonstratedsignicant
reductionsinPTB 37 weeks and/or early PTB 34weeks and approximately
a 30-40% re-ductioninlowbirthweight (LBW) 2500 g.17,19On average,
birthweight was475 g higher inthe progesterone group.17RR for
perinatal or neonatal death andrespiratory distress syndrome (RDS),
al-thoughnotsignicant,were1inallreports, suggesting progesterone
may beassociatedwithreducedrisks of theseoutcomes. Inaddition, the
USmulti-center trial of 17P found signicant re-ductions in
necrotizing enterocolitis(NEC), intraventricular
hemorrhage(IVH)(by75%), andneedforoxygen(by 38%)12; 1 metaanalysis
also reportedtrends suggesting reductions inNECandneed for
ventilator support.17Short cervixTwo trials and 1 metaanalysis
specicallyevaluated the impact of progesterone onwomenwithshort
cervices (Table 5).Bothclinical trialsreportedsignicantreductions
in measures of early PTB.8,10One trial primarily demonstrated a
45-50%reduction in early PTBs 34 weeksamong women with a
foreshortened cer-vix who received 200 mg of vaginal
pro-gesterone.8The cervical length entry cri-terionwas 15mm,
andusingthiscriterion, 1.7% of screened women wereeligible.
Furthermore, progesterone wasassociatedwithanonsignicantreduc-tion
in a composite neonatal morbidityoutcome(comprisingIVH, RDS,
reti-nopathy of prematurity, and NEC: 0.59RR(95%CI, 0.26-1.25).8The
meta-analysis included only this 1 study
eval-uatingwomenwithashortcervixand,therefore, presents identical
results.19The other trial,10was not really an inde-pendent trial,
but rather a subgroupanalysis involving only 49 women withcervical
length 28 mm from anotherTABLE 3Progesterone: pharmacologic types
and protocolsType Route Dose (mg) Timing ReferencesSynthetic17PIM
250 Weekly from 16-20
wk7,12,15,19.............................................................................................................................................................................................IM
341 Twice
weekly11,19.............................................................................................................................................................................................IM
250 Thrice
weekly19.............................................................................................................................................................................................IM
500
Weekly15.............................................................................................................................................................................................IM
250 Every 3 days from 28
wk15.............................................................................................................................................................................................IM
1000 Weekly from 16
wk15.............................................................................................................................................................................................IM
25 Every 5
days14..............................................................................................................................................................................................................................................NaturalprogesteroneVaginal
200 Nightly, 24-33
wk8,19.............................................................................................................................................................................................Vaginal
400 Daily, 18 wk to
delivery6,19.............................................................................................................................................................................................Vaginal
100 Daily capsules to 34
wk13.............................................................................................................................................................................................Vaginal
90 Daily, 18 wk to
delivery9.............................................................................................................................................................................................Oral
900-1600 Daily, from onset of
PTL18..............................................................................................................................................................................................................................................IM,
intramuscular; PTL, preterm labor; 17P,
17-alpha-hydroxyprogesterone...............................................................................................................................................................................................................................................Tita.
Progesterone for preterm birth prevention: an evolving
intervention. Am J Obstet Gynecol 2009.www.AJOG.org ReviewsMARCH
2009 American Journal of Obstetrics &Gynecology 221reviewed
trail.9It suggested a reductionin PTB at 32 weeks but not in
overallPTB 37 weeks among those receiving90 mg of vaginal
progesterone comparedwith those on placebo. Because this cer-vical
length criterion was generated posthoc, the results of this
subgroup analysisshould be viewed cautiously.Multiple
pregnanciesOne clinical trial7and 2 metaanaly-ses16,19reported the
impact on twinpregnancy (Table 5). The relatively largeclinical
trial using250mgof IM17Pfound no impact on the composite pri-mary
outcome of early PTB 35 weeksor stillbirth, early PTB alone, or any
ofseveral morbidities including RDS.7The2 metaanalyses together
included only 2trials (including the above) of progester-one for
the prevention of PTB in
multi-plegestation,andfoundnoimpactoneither PTBor perinatal
morbidity ormortality.16,19Both these studies
in-volvedIMprogesterone inunselectedTABLE 4Selected perinatal
outcomes among women with a historyof spontaneous preterm birth:
progesterone vs placeboStudyPTBawk: RR (95% CI)Perinatal deathRR
(95% CI)Neonatal deathwk: RR (95% CI) Mean GA (wk)bRDSwk: RR (95%
CI)Dodd et al19 34: 0.15 (0.04-0.64)c 37: 0.68 (0.45-1.02)0.65
(0.38-1.11) 0.44 (0.16-1.18) n/a 0.79
(0.57-1.10)................................................................................................................................................................................................................................................................................................................................................................................OBrien
et al9 32: 0.9 (0.52-1.56) 37: 1.08 (0.76-1.52)n/a 0.87 (0.29-2.60)
36.6 vs 36.6 0.91
(0.56-1.50)................................................................................................................................................................................................................................................................................................................................................................................Mackenzie
et al17 37: 0.57 (0.36-0.90)c0.39 (0.07-2.24) n/a 1.92
(0.37-4.21)c0.64
(0.39-1.07)................................................................................................................................................................................................................................................................................................................................................................................Meis
et al12 37: 0.66 (0.54-0.81)c 32: 0.58 (0.37-0.94)c0.64 (0.30-1.37)
0.44 (0.17-1.13) n/a 0.63
(0.38-1.05)................................................................................................................................................................................................................................................................................................................................................................................da
Fonseca et al13 37: 0.49 (0.25-0.96)cn/a n/a n/a
n/a................................................................................................................................................................................................................................................................................................................................................................................CI,
condence interval; GA, gestational age; n/a, not available; PTB,
preterm birth; RDS, respiratory distress syndrome.Except where
indicated, all data represent relative risks (95% CI) that, when 1,
favor progesterone.aGA cut-off given; bActual mean GA or difference
in mean GA (95% condence interval [CI]) for progesterone use
compared with placebo or no treatment; cResults indicate
statistical
signicance.................................................................................................................................................................................................................................................................................................................................................................................Tita.
Progesterone for preterm birth prevention: an evolving
intervention. Am J Obstet Gynecol 2009.TABLE 5Outcomes for
progesterone vs placebo among other groups at risk for preterm
birthStudy/indicationPTBawk: RR (95% CI) Mean GA (wk)bPerinatal
deathwk: RR (95% CI)Neonatal deathwk: RR (95% CI)RDSwk: RR (95%
CI)SHORT CERVIXFonseca et al8 34: 0.56 (0.36-0.86)c0.38 (0.10-1.38)
0.29 (0.06-1.42) 0.59
(0.26-1.29)................................................................................................................................................................................................................................................................................................................................................................................DeFranco
et al10( 28 mm) 32: 0 vs 29.6%c1.7 (36.3 vs 34.6) n/a 0 vs 3.7%
0.18
(0.02-1.31)................................................................................................................................................................................................................................................................................................................................................................................Dodd
et al19 34: 0.58 (0.38-0.87)cn/a 0.38 (0.10-1.40) 0.29 (0.06-1.37)
0.59
(0.29-1.19)................................................................................................................................................................................................................................................................................................................................................................................MULTIPLERouse
et al7 35: 1.1 (0.9-1.4) -0.3 (34.6 vs 34.9) n/a n/a 1.2
(0.8-1.6)................................................................................................................................................................................................................................................................................................................................................................................Dodd
et al16 37: 1.62 (0.81-3.25) n/a 1.95 (0.37-10.33) n/a
n/a................................................................................................................................................................................................................................................................................................................................................................................Dodd
et al19 37: 1.01 (0.92-1.12) 1.95 (0.37-10.33) n/a 1.13
(0.86-1.47)................................................................................................................................................................................................................................................................................................................................................................................THREATENED
PTBBorna and Sahabi6n/a 2 (36.7 vs 34.5)cn/a n/a 0.30
(0.11-0.83)c................................................................................................................................................................................................................................................................................................................................................................................Facchinetti
et al11 37: 0.29 (0.12-0.69)cn/a n/a n/a
n/a................................................................................................................................................................................................................................................................................................................................................................................Dodd
et al19 37: 0.29 (0.12-0.69cn/a n/a n/a 0.30
(0.11-0.83)c................................................................................................................................................................................................................................................................................................................................................................................CI,
condence interval; GA, gestational age; n/a, not available; PTB,
preterm birth; RDS, respiratory distress syndrome; RR, relative
risk.Except where indicated, all data represent relative risks (95%
condence interval) that, when 1, favor progesterone.aGA cut-off
given;bDifference in mean GA (respective mean GA) for progesterone
use compared with placebo or no treatment;cResults indicate
statistical
signicance.................................................................................................................................................................................................................................................................................................................................................................................Tita.
Progesterone for preterm birth prevention: an evolving
intervention. Am J Obstet Gynecol 2009.Reviews www.AJOG.org222
American Journal of Obstetrics &Gynecology MARCH 2009multiple
pregnancies. A subgroup anal-ysis of the positive trial of vaginal
proges-terone (200 mg) among women with aforeshortened cervix by
the plurality oftheir pregnancy yielded a signicant re-duction in
PTB 34 weeks among sin-gletons but anonsignicant
reductionamongtwins.Thislackofasignicantreduction in twins could be
either a re-sult of a true lack of effectiveness in thisgroup,
oralternatively, inadequatesta-tistical power.Arrested preterm
laborAs shown in Table 5, only 2 clinical tri-als6,11and 1
metaanalysis19reported onthe use of progesterone for arrested
pre-term labor. One clinical trial involved 70women with arrested
preterm labor whoreceivedvaginal
progesterone(400mgdaily).6Theprimaryoutcomeofmeanlatency to
delivery was signicantlylonger in the progesterone group by
ap-proximately 12 days (36 vs 24 days),
cor-respondingtohighermeangestationalage and birthweight at
delivery of morethan2weeks and500g,
respectively.Progesteronealsosignicantlyreducedthe risk of LBW (RR,
0.52; 95% CI, 0.28-0.98) and RDS (RR, 0.30; 95% CI,
0.11-0.83).6Inaddition, recurrent pretermla-bor occurred less often
in theprogesteronegroup(35%vs 58%), asdid neonatal intensive care
departmentadmission(24%vs39%)andneonatalsepsis (5% vs 18%). The
second trial in-volvedtwice-weekly administrationof341 mg of 17P
(vs no treatment) to 60womenwithsingletonpregnancy andar-rested
preterm labor.11PTB was signi-cantly lower (Table 5), time to
deliverynearly 10 days longer (35 vs 25 days),
andmeanbirthweightapproximately300ghigher (3103 vs 2809 g) in the
progester-one group. The difference in PTB 35weeks (10% vs 23%) was
not statisticallysignicant (RR, 0.43; 95% CI, 0.12-1.5)but cervical
shortening was signicantlyattenuatedamong womenreceiving
pro-gesterone. Together with their smallsample sizes the major
limitationof thesetrialswasthelackofblinding. There-viewed
metaanalysis included only these2 trials and, therefore,
reectedtheirndings.19Combined outcomes (withoutstratication by risk
factors)Atotal of 4 metaanalyses presented over-all results without
stratifying by specicrisk population (Table 6).14-16,18Thendings
revealed a consistent signicantreduction in PTB and early PTB
corre-sponding to a 40-50%reduction inLBW. Perinatal or neonatal
mortalityand RDS were also consistently reduced,albeit
nonsignicantly. Based on theMeis trial alone, 2 metaanalyses also
re-portedasignicant
75%reductioninIVH15,16and1reportedareductioninNEC.16Evaluationbycommencementof
treatment before or after 20 weeks andby cumulative weekly dose of
progester-one500mgor500mg(withoutregard to route) did not reveal
any dif-ferential impact.16Cumulative meta-analysis by
progressively adding trialsfromthe earliest to the more
recentshowed signicant reductions in birth
37weeksasearlyas1975.18Thislattermetaanalysiswaslimitedbytheinclu-sionof
dataonwomenwhoreceivedprogesterone for habitual abortion.18National
recommendation/guidelinesWe reviewed 3 reports providing
recom-mendations or guidelines
frombothACOGandSOGC.4,5,20ACOGrecom-mendsthatprogesteronesupplementa-tionbeofferedtowomenwithapriorSPTB
to prevent recurrent PTB.4ACOGhas just reafrmed this position
speci-cally for women with a current singletonpregnancy, and
further recommendsthat progesterone may be considered forwomen with
an incidentally discoveredshortened cervix (15 mm) but recom-mends
against routine
ultrasonographicscreeningtoidentifyashortenedcer-vix.20TheSOGCrecommendsfurtherclinical
trials of progesterone for allwomen at risk for PTB.5However,
theyalso recommend that women with aprior SPTB or with a short
cervix ( 15mm)becounseledandofferedproges-terone supplementation if
desired. Bothorganizations recognize the need for fur-ther studies
todeterminetheoptimaldose and route of progesterone, and theimpact
of progesterone on perinatalmorbidity and
mortality.ConclusionsTaken together, the reviewed datastrongly
suggest that prophylactic use ofprogesterone leads to signicant
reduc-tions in measures of PTB and LBW. TheTABLE 6Outcomes for
progesterone vs placebo for metaanalyses without stratication by
risk factors for preterm birthStudy/indicationPTBawk: RR (95%
CI)Perinatal deathRR (95% CI)Neonatal deathwk: RR (95% CI) Mean GA
(wk)RDSwk: RR (95% CI)Coomarasamy et al18 37: 0.42 (0.31-0.57)b 34:
0.51 (0.34-0.77)bn/a n/a n/a 0.55
(0.31-0.96)b................................................................................................................................................................................................................................................................................................................................................................................Dodd
et al16 37: 0.65 (0.54-0.79)b 34: 0.15 (0.04-0.64)b0.66 (0.37-1.19)
0.59 (0.27-1.30) n/a 0.63
(0.38-1.05)................................................................................................................................................................................................................................................................................................................................................................................Dodd
et al15 37: 0.59 (0.49-0.72)b0.60 (0.32-1.12) 0.44 (0.14-1.13) n/a
0.63
(0.38-1.05)................................................................................................................................................................................................................................................................................................................................................................................Sanchez-Ramos
et al14 37: 0.45 (0.25-0.80)b0.69 (0.38-1.26) n/a n/a 0.83
(0.25-2.76)................................................................................................................................................................................................................................................................................................................................................................................CI,
condence interval; GA, gestational age; n/a, not available; PTB,
preterm birth; RDS, respiratory distress syndrome; RR, relative
risk.Except where indicated, all data represent relative risks (95%
condence interval) that, when 1, favor progesterone.aGA cut-off
given for progesterone use compared with placebo or no
treatment;bResults indicate statistical
signicance.................................................................................................................................................................................................................................................................................................................................................................................Tita.
Progesterone for preterm birth prevention: an evolving
intervention. Am J Obstet Gynecol 2009.www.AJOG.org ReviewsMARCH
2009 American Journal of Obstetrics &Gynecology
223dataalsosuggest,butlessconclusively,thatprogesteronemayconferneonatalmorbidityandmortalitybenet.How-ever,
the benet of progesterone mayvary by risk group, route of
administra-tion, and dose. Therefore, additional
re-searchisneededtoclarifytheseissues.For now, when progesterone is
used forPTB prevention, the following approachwould appear rational
based on theavailable data: (1) for womenwithaprior SPTB, weekly
IM17P(250 mg) ini-tiatedat 16-20weeks, ordailyvaginalprogesterone
(at least 100 mg) beginningbefore week 24 should be given; (2)
forwomen with a short cervix ( 15 mm),200 mg of vaginal
progesterone suppos-itories may be reasonable, although only1
properly conducted and analyzed trialsupports such an approach; (3)
forwomen with a twin pregnancy, proges-terone is not routinely
indicated, al-thoughits use may be prudent inthe spe-cic scenarios
of a prior SPTB (250 mg17PIM) or signicantly (15 mm)
fore-shortenedcervix(200mgsuppositoryvaginally);and(4)forwomenwithar-rested
preterm labor, progesterone (400mg daily vaginal suppository or 341
mg17P IMtwice weekly) may be consideredbut the available data are
seriously lim-ited by lack of blinding. It is encouragingthat there
are multiple ongoing trials thatshould further clarify the role of
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