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. Author manuscript; available in PMC: 2023 Feb 21.
Published in final edited form as: Int J Gynaecol Obstet. 2015 Oct 18;132(1):11–16. doi: 10.1016/j.ijgo.2015.06.058

A systematic review and meta-analysis of progestogen use for maintenance tocolysis after preterm labor in women with intact membranes

Ahizechukwu C Eke a,*, Tina Chalaan b, Ghadear Shukr b, George U Eleje c, Charles I Okafor c
PMCID: PMC9941008  NIHMSID: NIHMS1871414  PMID: 26489489

Abstract

Background:

The use of progestogens for maintenance tocolysis remains controversial, with randomized controlled trials having conflicting results on their efficacy.

Objectives:

To evaluate the use of progestational agents for maintenance tocolysis after preterm labor in a systematic review of randomized controlled trials.

Search strategy:

Electronic databases were searched for reports published before December 2014. Keywords included “tocolysis,” “progesterone,” “preterm labor,” “17-alpha-hydroxyprogesterone,” and “vaginal progesterone.”

Selection criteria:

Only randomized controlled trials involving progestational agents for maintenance tocolysis were included.

Data collection and analysis:

Outcomes were analyzed on an intent-to-treat basis and meta-analysis was performed where appropriate. Relative risks and mean differences with 95% confidence intervals were calculated.

Main results:

Four studies (362 women) were included. There were no significant differences between progestational agents and placebo/no treatment in terms of delivery before 34 weeks or before 37 weeks of pregnancy, time from randomization to delivery, and respiratory distress syndrome. Progestogens were associated with an increase in the neonatal birth weight (mean difference 203.32 g, 95% confidence interval 110.85-295.80; P = 0.032).

Conclusions:

The current evidence does not support the routine use of progestational agents for maintenance tocolysis after an episode of preterm labor.

Keywords: 17α-hydroxyprogesterone, Preterm labor, Tocolysis, Vaginal progesterone

1. Introduction

Preterm birth remains a significant public health problem and a leading cause of long-term disability [1]. However, the preterm birth rate continues to decrease. According to 2013 data from the Centers for Disease Control and Prevention [2], the preterm birth rate in the USA has dropped to 11.39%, with the vast majority (approximately 75%) of preterm births occurring spontaneously. It has been hypothesized that the decrease in the preterm birth rate could be attributable to lower rates of multiple pregnancies owing to improvements in assisted reproductive technology techniques, decreases in teen births, better use of cervical cerclage, and—most importantly—the use of progesterone for the prevention of preterm birth [3]. The effect of progesterone has been confirmed by studies reported in 2003 and 2011 [4-6]. Interestingly, however, the use of progestogens as uterine tocolytic agents in this context has been studied for several decades with conflicting results [7,8].

The role of progestogens in the maintenance of uterine quiescence was initially reported in 1954, at which time it was suggested that they could be tocolytic agents [9,10]. Several mechanisms of action have since been proposed. Current evidence favors two major mechanisms: an increase in the progesterone concentration in gestational tissues that counteracts the functional progesterone withdrawal associated with preterm birth; and anti-inflammatory effects that counteract the inflammatory process in pregnancies complicated by preterm labor [11]. These anti-inflammatory effects are mediated by: stimulation of the transcription of the genes encoding the Zinc finger E-box-binding homeobox 1 and 2 proteins, which inhibit expression of the genes encoding connexin 43 (an abundant gap junction protein that helps to harmonize contractile activity) and the oxytocin receptor [12]; a reduced synthesis of prostaglandins (infection-mediated cytokine production by fetal membranes/the placenta) [11]; a decreased ratio of progesterone receptor-A to progesterone receptor-B (membrane-bound progesterone receptors within the myometrium that, when activated by progesterone, stimulate gene promotion and prevent the binding of other factors to ultimately reduce uterine contractions); attenuation of the response to inflammation and bleeding in the decidua; and selective nongenomic pathways [13,14].

Randomized clinical trials investigating the use of progesterone for maintenance tocolysis after an episode of preterm labor have produced conflicting data. Some reported a benefit, whereas others did not. Four randomized controlled trials [15-18] have assessed progesterone supplementation in this setting. In three of the four trials [15,17,18], progesterone maintenance therapy after successful parenteral tocolysis did not significantly reduce the rate of preterm birth. However, one trial [16] reported a considerable reduction in the rate of preterm delivery, and another trial [17] described a significantly longer latency period (time from randomization to delivery: 36.1 ± 17.9 vs 24.5 ± 27.2 days). The largest of these progesterone trials [15] was a multicenter randomized controlled trial in which women with a singleton pregnancy between 24 and 31 weeks and preterm labor successfully inhibited by tocolytic treatment were randomly assigned to receive 500 mg of intramuscular 17α-hydroxyprogesterone caproate versus no treatment twice weekly until week 36 of pregnancy. The administration of 17α-hydroxyprogesterone caproate did not significantly increase the time to delivery or reduce the rates of preterm birth before 32 weeks, 34 weeks, or 37 weeks.

A Cochrane systematic review published in 2014 [19] evaluated the use of progestational agents for acute tocolysis of preterm labor. However, a systematic review/meta-analysis on the use of progestogens for maintenance tocolysis does not seem to have been performed previously, despite the availability of randomized trials on this topic. Therefore, a systematic review and meta-analysis were performed to evaluate the efficacy and safety of the use of progestational agents for maintenance tocolysis after an episode of preterm labor.

2. Materials and methods

The present systematic review and meta-analysis was conducted in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for reporting systematic reviews and meta-analyses of randomized controlled trials [20].

2.1. Literature search

Literature searches were performed in the Cochrane Central Register of Controlled Trials, PubMed, African Journals Online, Embase, Medline, Literature in the Health Sciences in Latin America and the Caribbean, Cumulative Index to Nursing and Allied Health Literature, Web of Science, registers of ongoing trials (http://www.ukctg.nihr.ac.uk, https://www.clinicaltrials.gov, http://www.umin.ac.jp/ctr, www.anzctr.org.au, http://www.controlled-trials.com, and www.centerwatch.com), and Google Scholar (all from database inception to December 15, 2014). Keywords including “tocolysis,” “progesterone,” “progestogen,” “preterm labor,” “17-alpha-hydroxyprogesterone,” “vaginal progesterone” were used during the search process. Additional publications were found by reviewing the proceedings of international society meetings in perinatology and international meetings on preterm birth and tocolysis, and by reviewing the bibliographies of identified studies and review articles. For studies with several publications, the data from the most complete report were used and supplemented if additional information—including secondary data analyses—appeared in other publications. No language restrictions were used in the search.

2.2. Study selection

The present review included randomized clinical trials that compared the use of progestational agents with the use of placebo or no treatment for tocolysis in women who remained undelivered after an episode of preterm labor. Trials were excluded if progestational agents were used for the prevention of preterm birth in asymptomatic women rather than specifically for tocolysis, if progestational agents were used for acute tocolysis rather than for maintenance tocolysis, and if the study design was quasi-randomized. Published abstracts were excluded if no additional information on methodological issues and results could be obtained.

All published studies that were deemed suitable were retrieved and reviewed independently by two authors (A.C.E and G.U.E.) to determine whether they should be included. Disagreements were resolved through discussion among the authors. The authors of any selected studies were contacted to complement data on trial methods and/or outcomes as required.

2.3. Outcome measures

The present systematic review examined two primary outcomes resulting from the use of progestational agents and 14 secondary outcomes. The prespecified primary outcome measures were time from randomization to birth (latency period) and delivery before 34 completed weeks of pregnancy. Secondary outcomes included delivery before 37 completed weeks of pregnancy, birth weight of less than 2500 g, need for additional tocolytic therapy for maintenance tocolysis, need for mechanical ventilation, neonatal intensive care unit (NICU) admission, Apgar score less than 7 at 5 minutes, maternal adverse events, cervical length measurements, perinatal death, neonatal morbidity (respiratory distress syndrome, intraventricular or intracerebral bleeding, neonatal sepsis, and necrotizing enterocolitis), recurrent preterm labor, and discontinuation of treatment because of adverse events.

2.4. Assessment of risk of bias

Study quality was appraised as recommended by the Cochrane Collaboration [21], taking into consideration the following seven items: concealment of allocation, random sequence generation, successive masking of participants and personnel to experimental and control medications, blinding of outcome assessment, incomplete outcome data description, selective reporting of data, and bias from other sources. The risk of bias was categorized as low, high, or unclear. Two investigators (A.C.E and G.U.E) independently evaluated the risk of bias in each included trial, and discrepancies were resolved through discussion with other authors of the present paper.

2.5. Data extraction

Using a standardized data abstraction form, two authors (A.C.E. and G.U.E.) independently extracted the following data from each article: study characteristics (method of randomization; concealment of allocation method; masking of providers, patients, and outcome assessors to treatment; and completeness of the data for each outcome), participants (inclusion and exclusion criteria, definition of preterm labor, pregnancy duration at randomization, cervical dilatation and effacement at trial entry, number of women randomly assigned, country and date of recruitment, and baseline characteristics), intervention (route of administration of the study medication, loading and maintenance doses, treatment duration, retreatment, and routine administration of prenatal corticosteroids), and outcomes (number of outcome events and/or mean ± standard deviation for each extracted outcome). Disagreements regarding the extracted data were resolved by discussion among the authors.

2.6. Statistical analysis

The statistical analyses were performed according to the guidelines set by the Cochrane Collaboration [22]. The outcomes were analyzed on an intent-to-treat basis. If no evidence of a substantial difference in the study populations, interventions, or outcome measurements was found, a meta-analysis was performed. For dichotomous data, the summary relative risk (RR) with the 95% confidence interval (CI) was calculated. For continuous data, the mean difference was calculated if an outcome was measured in the same way across trials, and the standardized mean difference (with 95% CI) was calculated if the same outcome was measured in various ways. The results were presented graphically using forest plots. The Mantel-Haenszel statistic was used to fit meta-analytic fixed-effects variables when comparisons were made between progestogens and placebo or no intervention. P < 0.05 was considered statistically significant.

Prespecified subgroup analyses were planned to compare vaginal progesterone/17α-hydroxyprogesterone caproate with placebo or no intervention. However, no trials were identified that addressed these comparisons, so these subgroup analyses were not performed. Additional subgroup analyses were planned to assess the primary outcomes according to several characteristics (definition of preterm labor, dose of progestogens, pregnancy duration at trial entry, cervical dilatation at trial entry, study setting, maintenance therapy, status of fetal membranes, use of alternative tocolytic therapy, and prenatal corticosteroid therapy); however, these were not undertaken because of insufficient data.

Diversity of the results among studies was tested with I2, which delineates the percentage of variation across studies that is ascribable to heterogeneity rather than chance [23]. A value of 0% indicates no heterogeneity, 0%–30% indicates mild heterogeneity, 30%–50% moderate heterogeneity, and 50% or more substantial heterogeneity [23]. A fixed-effects model was used to pool data across studies if no substantial statistical heterogeneity was present. If the I2 value was 50% or more, a random-effects model was used to pool data across studies if the causes of heterogeneity could not be determined and if the average treatment effect was considered clinically meaningful. Publication bias and related biases were assessed visually by examination of the symmetry of funnel plots and statistically by using the Egger test [24]. A probability value of less than 0.1 was considered to indicate significant asymmetry. The analyses were performed using RevMan version 5.3.5 (Cochrane Collaboration, Oxford, UK).

3. Results

In total, the literature search yielded 533 studies, of which 14 full-text articles were examined for eligibility to be included in the present review (Fig. 1). Four studies [15-18] including 362 women met the inclusion criteria. One trial [17] evaluated vaginal progesterone versus placebo or no treatment, another trial [18] evaluated oral micronized progesterone versus placebo or no treatment, and two trials [15,16] evaluated 17α-hydroxyprogesterone caproate versus no treatment (Table 1). Three of the studies [15,16,18] were conducted in France and one study [17] was conducted in Iran. The sample size ranged from 44 [18] to 188 [15] (median 65). Preterm labor was defined as the presence of uterine contractions with evidence of cervical changes in all four trials. All trials included women with a singleton pregnancy and intact membranes, and reported standard maternal and fetal contraindications to tocolysis as exclusion criteria. The pregnancy duration at inclusion ranged from 24 weeks to 35 weeks.

Fig. 1.

Fig. 1.

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Study flow diagram.

Table 1.

Characteristics of the studies included in the systematic review.

Reference Inclusion/exclusion criteria Participants Interventions Selected outcomes
Rozenberg et al. 2012 [15] Inclusion criteria: singleton pregnancy, intact membranes, aged ≥18 years. Exclusion criteria: cervical dilatation ≥3 cm, chorioamnionitis, abnormal FHR, placenta previa, abruptio placentae, PROM, polyhydramnios, intrauterine growth restriction. Women admitted for an episode of preterm labor successfully arrested by tocolytic treatment, pregnancy duration 24 weeks to 31 weeks and 6 days. Recruited 188 women between February 2006 and July 2008. Intervention group (n = 94): 500 mg intramuscular 17P given twice per week until 36 weeks of pregnancy or preterm delivery, whichever occurred first. Control group (n =94): no treatment.

  • Preterm delivery ≤37 weeks, ≤34 weeks, and ≤32 weeks

  • Birth weight

  • NICU admission

  • Bronchopulmonary dysplasia

  • Transient respiratory distress

  • Necrotizing enterocolitis

  • Periventricular leukomalacia
Borna et al. 2008 [17] Inclusion criteria: singleton pregnancy, intact membranes, cervical dilatation ≤2 cm, no cerclage, dating of pregnancy confirmed through first-trimester ultrasonography. Exclusion criteria: complications contraindicating tocolysis, clinical evidence of intra-amniotic infection or pyelonephritis, evidence of fetal growth retardation, sonographic evidence of congenital anomalies inconsistent with life. Women admitted after threatened preterm labor, pregnancy duration 24–34 weeks. Recruited 70 women between March 2004 and December 2005. Intervention group (n = 37): 400 mg/day vaginal progesterone suppository until 34 weeks. Control group (n = 33): no treatment.

  • Time until delivery (latency period)

  • Recurrence of preterm labor within 48 hours after acute tocolysis

  • Low birth weight

  • Perinatal morbidity (respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven sepsis)

  • NICU admission
Facchinetti et al. 2007 [16] Inclusion criteria: singleton pregnancy, intact membranes, cervical dilatation <2 cm, dating of pregnancy confirmed through first-trimester ultrasonography. Exclusion criteria: chorioamnionitis; vascular complications of pregnancy; placenta previa; fetal distress; chronic diseases such as diabetes mellitus, heart disease, and/or autoimmune disorder. Women admitted after threatened preterm labor, pregnancy duration 25 weeks to 33 weeks and 6 days. Recruited 60 women between September 2004 and February 2006. Intervention group (n = 30): 341 mg intramuscular 17P given every 4 days until 36 weeks of pregnancy. Control group (n =30): no treatment.

  • Pregnancy duration at parturition

  • Cervical length throughout pregnancy

  • Birth weight
Noblot et al. 1991 [18] Inclusion criteria: singleton pregnancy, intact membranes, pregnancy duration <34 weeks, cervical dilatation <2 cm. Exclusion criteria: fever, abnormal FHR, intra-amniotic infection. Women undergoing tocolytic treatment for preterm labor, pregnancy duration <34 weeks. Recruited 44 women between February and October 1987. Intervention group (n = 22): four 100-mg capsules of natural micronized progesterone taken orally every 6 h in 1st 24 h, then four 100-mg capsules every 8 h during the following 24 h, then three 100-mg capsules every 8 h from 3rd day onwards. Control group (n = 22): placebo.

  • Duration and amount of intravenous and total ritodrine administered

  • Duration of pregnancy prolongation

  • Duration of hospitalization
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Abbreviations: FHR, fetal heart rate; PROM, premature rupture of membranes; 17P, 17α-hydroxyprogesterone caproate; NICU, neonatal intensive care unit.

Fig. 2 shows the risk of bias for each included study. Two trials [15,17] met four of the seven quality criteria, one trial [16] met two criteria, and the remaining trial [18] met one criterion.

Fig. 2.

Fig. 2.

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Risk of bias of individual studies included in the systematic review.

Two studies [15,16] examined the rate of preterm births before 34 weeks of pregnancy. Neither study reported a significant difference for this outcome measure (Fig. 3). Meta-analysis of the two studies (n = 248) showed that progestational agents had no significant effect on the rate of preterm births before 34 weeks of pregnancy (RR 0.69, 95% CI 0.40–1.20). There was no heterogeneity between the studies (I2 = 0%).

Fig. 3.

Fig. 3.

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Effect of the use of progestational agents versus no treatment or placebo after an episode of preterm labor on the rate of preterm birth before 34 weeks of pregnancy. Abbreviations: M-H, Mantel–Haenszel test; CI, confidence interval; df, degree of freedom.

The time from randomization until birth (latency period) was evaluated in three trials [16-18]. Two trials [16,17] reported a significantly longer time between treatment and birth among women in the experimental group compared with the control group (mean difference 2.42 days, 95% CI −1.48 to 6.31) (Fig. 4). By contrast, Noblot et al. [18] observed no significant difference. The total overall effect in the meta-analysis (n = 174) was not statistically significant. The trials exhibited high heterogeneity (I2 = 75%).

Fig. 4.

Fig. 4.

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Effect of the use of progestational agents versus no treatment or placebo after an episode of preterm labor on the time from randomization until birth (latency period). Abbreviations: SD, standard deviation; IV, independent variable; CI, confidence interval; df, degree of freedom.

Three studies [15,16,18] examined the rate of preterm births before 37 weeks of pregnancy. Facchinetti et al. [16] showed a significant difference between the experimental and control groups (RR 0.29, 95% CI 0.12–0.69). However, Noblot et al. [18] and Rozenberg et al. [15] did not (RR 0.75 [95% CI 0.31–1.80] and RR 1.08 [95% CI 0.74–1.57], respectively). Meta-analysis of these studies (n = 288) showed no significant difference (RR 0.80, 95% CI 0.58–1.10). The heterogeneity between the studies was moderate (I2 = 74%).

The number of days neonates spent in the NICU was examined by Borna et al. [17]. They observed no significant difference between the experimental and control groups for this outcome (mean difference – 0.40 days, 95% CI −4.12 to 3.32).

All four trials examined the birth weight as an outcome measure, with three trials [16-18] showing a significant difference between the study groups. However, Rozenberg et al. [15] did not find a significant difference (mean difference 80.00 g, 95% CI −56.08 to 216.08]). Meta-analysis of the trials (n = 358) showed a significant difference between the birth weights of neonates born to mothers who had received progestational agents and of those born to mothers in the control group (mean difference 203.32 g, 95% CI 110.85–295.80]). However, there was moderate heterogeneity between the four trials (I2 = 61%).

Two trials [15,17] evaluated the development of respiratory distress syndrome in neonates and neither study showed a significant difference between the experimental and control groups. One trial [17] appeared to favor treatment (RR 0.30, 95% CI 0.11–0.83) but this result was not statistically significant. The other trial [15] showed almost no difference (RR 1.13, 95% CI 0.55–2.30). In the overall meta-analysis (n = 318), the frequency of respiratory distress syndrome was not significantly different between the treatment and control groups (RR 0.70, 95% CI 0.40–1.23).

4. Discussion

The present meta-analysis demonstrated no significant effect of progestational agents on the primary and most of the secondary outcomes evaluated in the present systematic review, including delivery before 34 or 37 weeks of pregnancy, time from randomization to delivery, and NICU admission. Birth weight was the only outcome to show a statistically significant difference when maintenance tocolysis with progestogens was compared with the use of placebo or no intervention. Hence, there appears to be a limited role for the use of progestational agents for maintenance tocolysis after an episode of acute tocolysis.

Other studies showed comparable results. Su et al. [19] examined several randomized clinical trials in a Cochrane systematic review/meta-analysis that evaluated the effectiveness of progestational agents when used for acute tocolysis and concluded that there was insufficient evidence to support their use as tocolytic agents. The results of the present review, which focused on maintenance tocolysis, are therefore not surprising. Ngai et al. [25] reached similar conclusions in their comparison of progesterone with no treatment for acute tocolysis. In fact, these authors observed a higher NICU admission rate and a shorter pregnancy duration at delivery in the treatment group. Similar findings were made in the present review, with some of the included trials showing a better result profile in the control group than in the progestogen group. For example, in the study by Rozenberg et al. [15], the rate of NICU admissions was higher in the treatment group than in the control group (24 vs 16).

In the present review, progesterone therapy had meaningful benefits in terms of increasing the neonatal weight and reducing the rate of infants with a low birth weight. These results indicate that progestogens, when used for maintenance tocolysis, might prolong a pregnancy for long enough to achieve a significant increase in fetal growth. Prior studies [19,26,27] showed similar results. Choudhary et al. [26] and Lotfalizadeh et al. [27] both found that the use of progesterone as a tocolytic agent resulted in a reduction in the rate of low birth weight. Similar to the present findings, Choudhary et al. [26] found no significant differences in other perinatal outcomes or in maternal adverse effects.

The present review has several limitations. The high degree of heterogeneity between the trials could limit the validity of the combined results of the meta-analyses, especially given the fact that the findings from larger trials conflicted with those from smaller trials for some of the outcomes. Additionally, there was variation between the trials in terms of dosage, route of administration (vaginal, intramuscular), and population demographics. Most of the studies were not blinded. However, lack of blinding was unlikely to have influenced the present results because the assessment of most outcomes included in the present review was considered to be objective in nature. It is also apparent that most of the studies had low quality.

In conclusion, the current data show conflicting information on the efficacy of progesterone when used as a maintenance tocolytic. Although its use resulted in an increased birth weight, there appears to be a limited role for its use in this context overall. Given the limitations of and inconsistencies between the randomized clinical trials included in the present systematic review, more trials are needed to examine the outcomes arising from the use of progestational agents. If the present results are indeed valid, then clinicians should reevaluate the use of these agents for maintenance tocolysis in preterm labor.

Footnotes

Conflict of interest

The authors have no conflicts of interest.

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