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REVIEW ARTICLE

Progesterone for the prevention of preterm birthamong women at increased risk: A systematic reviewand meta-analysis of randomized controlled trials

Roberta Mackenzie, MD,a Mark Walker, MD,b Anthony Armson, MD,c

Mary E. Hannah, MDCMa

Department of Obstetrics and Gynaecology, Sunnybrook and Womens College Health Sciences Centre,

University of Toronto,a Toronto, Ontario; Department of Obstetrics and Gynaecology, Ottawa General Hospital,

University of Ottawa,b Ottawa, Ontario; Department of Obstetrics and Gynaecology, IWK Health Centre,

Dalhousie University, Halifax, Nova Scotia, Canadac

Received for publication January 31, 2005; revised May 17, 2005; accepted June 7, 2005

KEY WORDSPreterm birth

Randomized

controlled trial

Progestational agentSystematic review

Objective: This study was undertaken to determine whether progestational agents, initiated in thesecond trimester of pregnancy, reduce the risk of delivery less than 37 weeks, among women at

increased risk of spontaneous preterm birth.

Study design: Medline, pre-Medline, EMBASE, and Cochrane Central Register of Controlled

Trials were searched. Randomized controlled trials with less than 20% lost to follow-up wereincluded.

Results: Three trials were eligible for inclusion. There was a significant reduction in risk of

delivery less than 37 weeks with progestational agents (relative risk [95% CI] = 0.57 [0.36-0.90]).

There was no significant effect on perinatal mortality or serious neonatal morbidity.

Conclusion: Progestational agents, initiated in the second trimester of pregnancy, may reduce therisk of delivery less than 37 weeks gestation, among women at increased risk of spontaneous

preterm birth, but the effect on neonatal outcome is uncertain. Larger randomized controlled

trials are required to determine whether this treatment reduces perinatal mortality or serious

neonatal morbidity.

2006 Mosby, Inc. All rights reserved.

Preterm birth is a leading cause of perinatal andneonatal mortality, neonatal morbidity, and long-term

neurodevelopmental problems.1-3 The risk of mortality

and morbidity is strongly influenced by the gestational

ageat delivery, the birth weight, and whetherthere is more

than 1 fetus (twins or a higher order multifetal preg-

nancy).3-6 Also, the cost of neonatal intensive care and

long-term care for infants born preterm, is enormous.7,8

The incidence of preterm birth has been increasing inmany industrialized countries since the early 1980s.9,10

The preterm birth rate in Canada rose from 6.3% of live

births in 1981 through 1983, to 6.6% in 1991 to 7.6% in

2000.9,10 In New Zealand, singleton preterm birth rates

rose from 4.3% in 1980 to 5.9% in 1999.11

Spontaneous preterm birth, that is preterm birth

after labor or rupture of the membranes, represents

approximately 75% of all preterm births.12 Of all

treatments evaluated for the prevention of spontaneousReprints not available from the authors.

0002-9378/$ - see front matter 2006 Mosby, Inc. All rights reserved.

doi:10.1016/j.ajog.2005.06.049

American Journal of Obstetrics and Gynecology (2006) 194, 123442

www.ajog.org


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preterm birth to date, progestational agents have dem-

onstrated the greatest promise. The exact mechanism of

progesterone in the prevention of preterm birth is not

known, although progesterone has been shown to pre-

vent the formation of gap junctions, to have an inhib-

itory effect on myometrial contractions, and to prevent

spontaneous abortion in women in early pregnancy after

excision of the corpus luteum.

13-15

Progesterone has alsobeen shown to delay parturition in animals.16

The first randomized controlled trial of progestational

agents for the prevention of preterm birth in women at

increased risk was published in 1970 by Papiernik.17 This

trial demonstrated efficacy in a group of 99 women who

received 17 alpha-hydroxyprogesterone caproate (17P)

or placebo in the third trimester. Johnson et al18 subse-

quently reported a significant reduction in the preterm

birth rate among a small sample of high-risk women

when 17P treatment was initiated in the second trimester.

Other trials followed, of which the largest and most

promising was the study conducted by Meis et al19

through the Maternal Fetal Medicine Units Network ofthe National Institute of Child Health and Human

Development in the United States.

We undertook this systematic review and meta-anal-

ysis to determine whether treatment with a progesta-

tional agent, initiated in the second trimester of

pregnancy, decreases the risk of delivery before 37

weeks gestation and other adverse perinatal outcomes

in women at increased risk of spontaneous preterm birth.

Material and methods

Pre-Medline, Medline (1996-2003), EMBASE (1980-

2003), and the Cochrane Library were systematically

searched using the following keywords: progesterone

AND pregnancy outcome, pregnancy AND pro-

gesterone AND labour, premature, pregnancy

AND progesterone combined (AND) with each of

the following terms: infant, premature, labour, pre-

mature, and prematurity as well as pregnancy

AND 17 alpha-OH progesterone caproate. All

searches were limited to humans and to women. Refer-

ences from articles and systematic reviews of random-

ized controlled trials of treatment with progestational

agents in pregnancy were also reviewed. No attempt wasmade to search for unpublished studies.

Studies were considered eligible for inclusion in the

review if the study design was a randomized controlled

trial, comparing a progestational agent with either a

placebo or no treatment, with treatment initiated during

the second trimester of pregnancy among women at

increased risk of spontaneous preterm birth. Women

were considered to be at increased risk for preterm birth

if they had a risk factor that has been associated with a

spontaneous preterm birth.20 We restricted our review

to studies with treatment initiated in the second trimes-

ter to evaluate the efficacy of progesterone therapy after

the potentially teratogenic period of the first trimester

but before the initiation of the parturition process in the

third trimester.

Studies were excluded if data were not presented

according to intention to treat, if more than 20% of

women or infants in either group were lost to follow-up,if there was no information presented on any of the

outcomes of interest, or if women had signs or symptoms

of threatened abortion, preterm labor, or had ruptured

membranes at enrollment or initiation of treatment.

If the title or abstract described a study that did not

meet the eligibility criteria, the study was not reviewed in

furtherdetail. Papers for all other titles and abstracts were

reviewed. The selection of abstracts for further review and

assessment of eligibility was determined independently by

2 principal reviewers (R.M. and M.W.), and disagree-

ments were resolved by consensus after discussion with

the other 2 reviewers (A.A. and M.H.). Data were

abstracted from the included studies independently bythe 2 principal reviewers (R.M. and M.W.).

The primary outcome was delivery less than 37 weeks

gestation. Secondary outcomes included delivery before

35, 34, and 32 weeks gestation, birth weight less than

2500 g, birth weight less than 1500 g, spontaneous

abortion or perinatal death, measures of serious neona-

tal morbidity, and congenital anomalies.

Baseline data were analyzed descriptively. Statistical

analyses were conducted by using the program Review

Manager 4.1 (Cochrane Collaboration, Oxford, UK).

We calculated a summary relative risk (RR) and 95% CI

for dichotomous variables and a weighted mean differ-ence (WMD) and 95% CI for continuous variables, with

the use of the DerSimonian and Laird random-effects

model.21 A random-effects model incorporates between-

study variation and gives wider CI than a fixed-effects

model, which ignores between-study variation in esti-

mating the CI. This gives a more conservative estimate

of the summary pooled result. Results were considered

to be statistically significant if the 95% CI did not

encompass 1.0 for RR or 0 for WMD or if the P value

was less than .05. Tests of heterogeneity among pooled

results were conducted by using simplec2 analysis.

Subgroup analyses were planned for studies that used

different progestational agents, for women with single-ton versus multiple pregnancies and for women with a

history of previous preterm birth versus other risk

factors for spontaneous preterm birth.

Results

The search yielded 735 titles/abstracts, of which 682

were excluded without further review. The remaining

53 papers were reviewed in more detail. Of the 53

Mackenzie et al 1235


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papers, 50 were excluded for the following reasons: the

study design was not a randomized controlled trial(n = 26)22-47; the women enrolled were not at increased

risk for spontaneous preterm birth (n = 4)48-51; the

women enrolled had signs or symptoms of threatened

abortion, preterm labor, or had ruptured membranes

(n = 10)52-61; and treatment was not initiated in the

second trimester of pregnancy (n = 10).17,62-70 The re-

maining 3 studies were included in the analysis.18,19,71

Description of studies and quality

The Meis et al trial19 recruited the largest number of

participants (463), whereas the sample sizes of trials by

Johnson et al

18

and da Fonseca et al

71

were relativelysmall (50 and 157, respectively). For the 3 studies, data

were included for a total of 648 women and 643 infants;

399 subjects received progestational agents and 249

received placebo.

The characteristics of the studies and populations

studied are detailed in Table I. All the studies were

randomized controlled studies. The Meis et al study19

used a computer-generated randomization sequence us-

ing the Urn method of randomization, with stratification

according to clinical center and allocation in a 2:1 ratio,

after a prerandomization run-in period. Study treat-

ments were packaged centrally and distributed to cen-

ters. In the da Fonseca et al study,71 a random numbertable was used to generate the randomization sequence

and allocations to drug A or B were placed in consec-

utively numbered sealed envelopes. The Johnson et al

study18 did not describe the method of randomization

but indicated that caregivers and patients were masked

to allocation group. All studies were double masked,

with women in the control group receiving a placebo that

was identical in appearance.

For 2 studies,18,19 the progesterone treatment was 17

alpha-hydroxyprogesterone caproate. In both of these

studies, 250 mg was injected intramuscularly on a

weekly basis. Treatment began at 16 to 20 weeks

gestation in the Meis et al study and at less than 24

weeks gestation in the Johnson et al study. The drug

was discontinued in all women when they reached 36 to37 weeks gestation or at delivery if this was earlier. In

the Meis et al study, the placebo was castor oil and in

the Johnson et al study the placebo was castor oil plus

46% benzyl benzoate. For the third study, the proges-

terone treatment was natural progesterone given daily as

a 100 mg vaginal suppository, beginning at 24 weeks,

and was discontinued at 34 weeks gestation.71 The

placebo was identical in appearance.

Baseline characteristics were similar in the progester-

one and placebo groups in all 3 studies (Table II). The

Table I Characteristics of included studies

Author and

year of

publication

Risk factor(s) for

preterm birth Country

Progestational agent

group N = No women

randomized/no women

(infants) followed

Control group

N = No of women

randomized/no women

(infants) followed

Johnson et al, 197518 R2 preterm births, R2

spontaneous abortions,

or combination of both

USA 17P 250 mg IM weekly from

!24 wks to 37 wks;

N = 23/19 (18)

Placebo consisting of castor oil

and 46% benzyl benzoate IM

weekly from !24 wks to 37 wks;N = 27/25 (26)

Meis et al, 200319 Previous spontaneous

preterm delivery

USA 17P 250 mg IM weekly from

16-20 wks to 36 wks;

N = 310/306 (301)

Placebo (castor oil) IM weekly

from 16-20 wks to 36 wks;

N = 153/153 (153)

Da Fonseca et al, 200371 Previous spontaneous

preterm birth,

prophylactic cerclage,

or uterine malformation

Brazil Natural progesterone 100 mg

daily by vaginal suppository

from 24 wks to 34 wks;

N = 81/74 (74)

Placebo of identical appearance

daily by vaginal suppository

from 24 wks to 34 wks;

N = 76/71 (71)

IM, Intramuscular.

Table II Baseline characteristics of women in includedstudies

Baseline characteristic

Progestational

agent group

Placebo

group

Mean maternal age (y)

Johnson et al, 197518 24.7 24.3

Meis et al, 200319 26.0 26.5

Da Fonseca et al, 200371 27.6 26.8

Previous preterm delivery (%)

Meis et al, 200319 100% 100%

Da Fonseca et al, 200371 90.3% 97.2%

Mean gestational age at

randomization or initiation

of treatment (wks)

Johnson et al, 197518 16.7 14.0

Meis et al, 200319 18.4 18.4

Da Fonseca et al, 200371 26.5 25.2

Multiple pregnancy (%)

Johnson et al, 197518 0 4

Meis et al, 200319 0 0

Da Fonseca et al, 200371 0 0

1236 Mackenzie et al


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mean gestational age at enrollment varied between 14.0

and 26.2 weeks gestation. One study enrolled 1 woman

withtwins; otherwiseall women had singleton pregnancies.

Women in all 3 studies received tocolytics for preterm

labor and in the da Fonseca et al trial, tocolytic use

occurred substantially more frequently in the placebo

group (Table III). In the Johnson et al trial, womenthought to have cervical incompetence received a cervi-

cal cerclage and these women also received 100 mg of

progesterone in oil, intramuscularly, every 4 to 6 hours,

for 24 to 36 hours after the procedure.

Primary and secondary outcomes

The risk of delivery less than 37 weeks gestation was

significantly lower with treatment with a progestational

agent versus placebo (summary RR [95% CI]: 0.57 [0.36-

0.90]) (FigureandTable IV). The risks of delivery before

35 weeks, 34 weeks, and 32 weeks gestation were also

significantly lower in the progestational agent versusplacebo groups (Table IV). The risk of birth weight less

than 2500 g was lower (summary RR [95% CI]: 0.66

[0.51-0.87]) and mean birth weight was higher (WMD

[95% CI]: 475.0 [16.56-933.44]) with treatment with a

progestational agent versus placebo (Table IV).

Progestational agents had no effect on the risk of

congenital anomalies (summary RR [95% CI]: 1.33

[0.41-4.34]) or on the risk of spontaneous abortion, or

perinatal death or on measures of serious neonatal

morbidity (Table V).

There was no statistical heterogeneity for the pooled

results for any of the outcomes. Subgroup analyses were

not performed given the small number of eligible trialsin the review.

Comment

Given the impressive results of the 1975 article by

Johnson et al,18 it is difficult to understand why prenatal

progesterone therapy for women at increased risk of

preterm birth was not investigated more thoroughly until

recently.19,71 The small sample size and virtual elimina-

tion of preterm birth less than 37 weeks with progester-

one therapy may have been met with skepticism despite

the absence of other significant differences or co-inter-

ventions between groups to explain the findings. In

addition, the attempt by Johnson et al30 to increase the

original sample size yielded disappointing results. How-

ever, the follow-up study had insufficient funding to

continue the double blind, randomized study design. Inthe same year, Goldstein et al29 published the results of a

meta-analysis that showed no beneficial effect of proges-

terone treatment on rates of miscarriage, stillbirth,

neonatal death, or preterm birth. Soon after, Hartikai-

nen-Sorri et al64 reported the absence of benefit of

progesterone treatment in twin pregnancies. Despite

the general agreement that further well-controlled re-

search was necessary, very few investigators or funding

agencies seemed interested in pursuing the question for

over a decade.

Before 2003, when da Fonseca et al published their

findings,71 indications for progesterone therapy were

limited to infertility and reproductive endocrine settings.Their study suggested that the risk of preterm birth less

than 37 weeks in high-risk women could be reduced by

more than 50%. The reduction in risk of preterm

delivery less than 34 weeks was even more impressive

(2.8% in treatment group compared with 18.6% in the

placebo group). Mean uterine contraction frequency

from 28 to 34 weeks in progesterone recipients was also

significantly less than in the placebo group. Although

there were concerns about the postrandomization ex-

clusion of women with premature rupture of membranes

and therapeutic preterm delivery, excluded subjects were

equally distributed between groups. Also, in our meta-analysis, we were able to include data for those women

with therapeutic preterm delivery and the findings were

similar. It is therefore unlikely that inclusion of these

subjects would have significantly altered the findings.

Despite these methodologic concerns, the potential for

preterm birth prevention with vaginal progesterone was

established.

The Meis et al trial19 provided convincing evidence

that treatment with 17 alpha-hydroxyprogesterone cap-

roate, initiated during the second trimester of preg-

nancy, reduced the risk of preterm birth for women at

increased risk of spontaneous preterm birth. However, it

was not clear if this evidence was adequate to recom-mend treatment with a progestational agent for women

at increased risk of spontaneous preterm birth, gener-

ally. Specifically, there was uncertainty as to whether

treatment with progestational agents would also reduce

the risk of more important clinical outcomes, such as,

perinatal and neonatal mortality and/or measures of

serious neonatal morbidity. This evidence is essential,

before recommending treatment with progestational

agents generally, for women at increased risk of spon-

taneous preterm birth, as there is always the potential

Table III Cointerventions

Cointervention

Progestational

agent group

Placebo

group

Tocolytic use (%)

Johnson et al, 197518 11.1% 8.0%

Meis et al, 200319 17.6% 15.9%

Da Fonseca et al, 200371 19.4% 31.4%

Antenatal corticosteroids (%)Meis et al, 200319 17.8% 19.7%

Cervical cerclage (%)

Johnson et al, 197518 22.2% 12.0%



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of perinatal death was lower with progesterone treat-

ment and there were trends toward reductions in risk for

respiratory distress syndrome, ventilatory support, and

necrotizing enterocolitis. These measures of neonatal

morbidity, however, were reported only in the Meis et al

trial, thus limiting our ability to assess these outcomes

beyond that study. The lack of demonstrable benefit on

mortality or measures of neonatal morbidity may be

because of inadequate power. We calculate that a trialwould need at least 1450 women or 725 per group to find

a reduction in risk from 15% to 10%, for respiratory

distress syndrome, with 80% power and a 2-tailed alpha

error of .05.75 The trials in this review were too few and

too small to find such a clinically important reduction in

risk.

Our review differs substantially from the previous

reviews of trials of treatment with a progestational agent.

The review by Kierse,31 which was published in 1990, was

restricted to trials that evaluated a specific progestational

agent, 17 alpha-hydroxyprogesterone caproate. The re-

view included 7 trials, 6 of which we excluded, because the

study did not enroll women at increased risk for sponta-

neous preterm birth49 or because treatment was not

initiated in the second trimester of pregnancy.17,64,67-69

In particular, treatment was initiated in the third trimes-

ter (28-32 weeks) in Papierniks study,17 whereas Yemini

et al68 began treatment in the first (12G 3.6 weeks). The

Daya review,25 published in 1989, only included trialswhich enrolled women with a history of recurrent mis-

carriage. The review included 3 trials, all of which we

excluded, because treatment was not initiated in the

second trimester of pregnancy.62,65,69 The Goldstein re-

view, also published in 1989, included 15 trials involving

the use of a progestational agent for the maintenance of

pregnancy.19 We excluded 14 of these, because the study

did not enroll women at increased risk of spontaneous

preterm birth (n = 3),49-51 women enrolled had signs or

symptoms of threatened abortion, preterm labor, or had

Table V Effect of progestational agents on spontaneous abortion, perinatal death, and neonatal morbidity

Outcome

Progestational agent

group N/N (%)

Placebo group

N/N (%) RR* 95% CI

Spontaneous abortion or perinatal deathy

Johnson et al, 197518 1/19 (5.3) 7/26 (26.9) 0.20 0.03-1.46

Meis et al, 200319 19/306 (6.2) 11/153 (7.2) 0.86 0.42-1.77

TOTAL/SUMMARY RR 20/325 (6.2) 18/179 (10.1) 0.55 0.14-2.15

Perinatal deathyz

Johnson et al, 197518 0/18 (0) 7/26 (26.9) 0.09 0.01-1.56

Meis et al, 200319 14/301 (4.7) 11/153 (7.2) 0.65 0.30-1.39

TOTAL/SUMMARY RR 14/319 (4.4) 18/179 (10.1) 0.39 0.07-2.24

Respiratory distress syndrome or

respiratory problemszx

Meis et al, 200319 29/294 (9.9) 23/150 (15.3) 0.64 0.39-1.07

Ventilatory supportzx

Meis et al, 200319 26/292 (8.9) 22/149 (14.8) 0.60 0.35-1.03

Grade 3/4 intraventricular hemorrhagezx

Meis et al, 200319 2/294 (0.7) 0/151 (0) 2.58 0.12-53.33

Bronchopulmonary dysplasiazx

Meis et al, 200319 4/294 (1.4) 5/150 (3.3) 0.41 0.11-1.50

Necrotizing enterocolitiszx

Meis et al, 200319 0/294 (0) 4/150 (2.7) 0.06 0.00-1.05

Patent ductus arteriosuszx

Meis et al, 200319 7/294 (2.4) 8/149 (5.4) 0.44 0.16-1.20

Retinopathy of prematurityzx

Meis et al, 200319 5/294 (1.7) 5/150 (3.3) 0.51 0.15-1.73

Sepsiszx

Meis et al, 200319 9/294 (3.1) 4/150 (2.7) 1.15 0.36-3.67

Fetal congenital anomaliesz

Johnson et al, 197518 2/18 (11.1) 1/26 (3.8) 2.89 0.28-29.52

Meis et al, 200319 6/301 (2.0) 3/153 (2.0) 1.02 0.26-4.01

TOTAL/SUMMARY 8/319 (2.5) 4/179 (2.2) 1.33 0.41-4.34

Perinatal death, Stillbirth or neonatal death.

* A summary relative risk was calculated for dichotomous variables.

y In the Johnson study, there was 1 set of twins in the placebo group that accounted for 2 of the 7 deaths.z Spontaneous abortions were excluded from these calculations.x All fetal deaths are excluded from these calculations.



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ruptured membranes (n = 4),54,57,59-61 or because treat-

ment was not initiated in the second trimester of preg-

nancy (n = 7).17,62,64-66,68,69 The review included the only

randomized controlled trial in twins but, because treat-

ment was initiated at 28 to 33 weeks, it did not meet our

criteria for inclusion.64 None of the previous reviews

included the Meis et al and da Fonseca et al studies.19,71 A

recent meta-analysis by Sanchez-Ramos et al

76

included10 randomized controlled trials of progesterone com-

pared with placebo. There was considerable heterogene-

ity among the selected studies in terms of the indication

for and timing of treatment. We excluded 7 of these

studies in our review because treatment was not initiated

in the second trimester,17,64,65,68,69 subjects were not at

risk for preterm birth,49 or participants had symptoms of

threatened abortion.61 The remaining 3 studies are the

focus of this review.18,19,71

The Keirse review found a reduction in risk of preterm

birth but no effect on risk of pregnancy loss less than 20

weeks gestation, with 17 alpha-hydroxyprogesterone

caproate; the Daya review found a decreased risk ofpregnancy loss at less than 20 weeks gestation with

progestational agents; the Goldstein review found no

benefit to treatment with progestational agents. Sanchez-

Ramos meta-analysis confirmed that the use of proges-

tational agents reduced the incidence of pretermbirth and

low birth weight infants but did not demonstrate any

reduction in hospital admissions for preterm labor or

perinatal mortality. All reviews called for more random-

ized controlled trials.

In summary, our review has found that progesta-

tional agents, initiated in the second trimester of preg-

nancy, reduce the risk of delivery less than 37 weeksgestation for women at increased risk of spontaneous

preterm birth, but their effect on spontaneous abortion

or perinatal mortality, or measures of neonatal morbid-

ity is uncertain. Treatment of women with progesta-

tional agents to reduce the complications of preterm

birth should continue to be confined to women enrolled

in well-designed randomized controlled trials.

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