To perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) that investigated the clinical benefits of 17-alpha hydroxyprogesterone caproate (17OHPC) in the prevention of recurrent preterm birth (PTB) among singleton pregnant women with a previous history of PTB. We searched four major databases up till April 2021 and assessed the risk of bias in the included studies. We meta-analyzed various maternal-neonatal endpoints (n=18) and pooled them as mean difference or risk ratio (RR) with 95% confidence interval (CI) using the random-effects model. Six RCTs met the inclusion criteria, comprising 2,573 patients (17OHPC=1,617, control=956). RCTs revealed an overall low risk of bias. The rates of PTB <35 weeks (n=5 RCTs; RR, 0.77; 95% CI, 0.63–0.93;
Preterm birth (PTB) is defined as labor starting before 37 completed weeks of gestation since the last menstrual period [
The exact cause of preterm labor remains undetermined. However, some predisposing factors may lead to it. Examples of some maternal factors include congenital anomalies in the genital system, hormonal imbalances, and chronic medical conditions [
In women with a prior history of spontaneous PTB, all efforts are directed toward preventing the occurrence of recurrent PTB. Unfortunately, this risk seems to be unavoidable. Moreover, the available medical options have their own side effects, in addition to their doubtful efficacy [
Besides, the synthetic progesterone 17-alpha hydroxyprogesterone caproate (17OHPC) has been used for circumventing the recurrence of PTB in high-risk groups. Some studies have shown that 17OHPC is beneficial for decreasing the incidence of PTB [
Overall, the available literature reveals conflicting results about the efficacy of 17OHPC in preventing recurrent PTB. Fernandez-Macias et al. [
Therefore, we conducted a systematic review and meta-analysis of RCTs to holistically assess the efficacy of 17OHPC in the prevention of recurrent PTB among singleton pregnant women with a previous history of PTB, with an aim to provide comprehensive evidence to inform better clinical practice.
This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [
Only RCTs were considered, and they were included if they met the following evidence-based PICO inclusion criteria: (i) population: pregnant women (singleton pregnancy) with a prior history of PTB; (ii) intervention: 17OHPC; (iii) comparator: any control intervention including placebo or no treatment; and (iv) outcomes: reliable extraction of any of the primary endpoints (PTB <37 weeks, PTB <35 weeks, PTB <32 weeks, neonates with low birth weight <2.5 kg at delivery, and neonatal death) or secondary endpoints (gestational age at delivery in weeks, birth weight in kg, neonatal intensive care unit [NICU] admission, bronchopulmonary dysplasia, respiratory distress syndrome, necrotizing enterocolitis, sepsis, retinopathy, intraventricular hemorrhage grade III–IV, patent ductus arteriosus, maternal corticosteroid administration, cesarean delivery, and tocolytic therapy. We excluded all secondary studies (such as meta-analyses, reviews, and conference abstracts), animal studies, pharmacokinetic studies, and studies with incomplete reported data. Moreover, we excluded patients with other risk factors of PTB such as placenta previa or a prior history of miscarriage.
We searched PubMed, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases until April 2021 for RCTs that met our inclusion criteria. We used the following search strategy: ((preterm labor) OR (preterm birth) OR (premature delivery) OR (pre-mature labor) OR (early delivery) OR (early labor)) AND ((17-OHPC) OR (17-α-hydroxyprogesterone caproate) OR (17P) OR (hydroxyprogesterone hexanoate)).
We screened the retrieved articles in three steps. The first step involved importing the results from the electronic databases to a Microsoft Excel sheet software (Microsoft, Redmond, WA, USA) using EndNote software (Clarivate, Philadelphia, PA, USA). The second step included the title and abstract screening of the imported citations. The third step included a full-text screening of the included citations from the second step. Additionally, we manually searched the references of the included papers for possible missed RCTs. Two investigators independently completed the database search and study selection, and conflicts were resolved by consultation with a third investigator.
We collected three categories of data from each included study. The first category included the baseline characteristics of the included studies and participants (such as the first author, year of publication, country, recruitment period of study participants, study groups, sample size, mean participant age, type of control treatment, and 17OHPC dose). The second category included the primary and secondary endpoints of the meta-analysis. The third category included data on the risk of bias assessment. Six investigators (in groups of two investigators per group) collected the data, and conflicts were resolved by consultation with the first investigator.
We evaluated the risk of bias of the included studies in accordance with the Cochrane risk of bias assessment instrument [
We performed a meta-analysis of this study using the Review Manager software (Cochrane, London, UK). Our study included continuous and dichotomous outcomes. Continuous outcomes were analyzed using mean difference (MD) and 95% confidence interval (CI), whereas dichotomous outcomes were analyzed using risk ratio (RR) and 95% CI. In this meta-analysis, the different studies estimated different yet related intervention effects with assumed heterogeneity at the clinical and methodological levels. Therefore, the random-effects model was used because it is more conservative than the fixed-effects model [
The included RCTs yielded an overall low risk of bias.
The pooled analysis showed no significant difference between groups regarding the rate of PTB <37 weeks (n=6 RCTs; RR, 0.79; 95% CI, 0.62–1.01;
The pooled analysis showed that the rate of neonates with a low birth weight (<2.5 kg) at delivery did not differ between both the groups (n=4 RCTs; RR, 0.79; 95% CI, 0.45–1.37;
The pooled analysis showed that the rate of neonatal death was significantly lower in the 17OHPC group compared with the control group (n=4 RCTs; RR, 0.41; 95% CI, 0.20–0.84;
The pooled analysis showed that the mean gestational age at delivery did not differ between both the groups (n=2 RCTs; MD, 1.63 weeks; 95% CI, −0.49 to 3.76;
The pooled analysis showed that the mean birth weight at delivery was significantly increased in the 17OHPC group compared with the control group (n=3 RCTs; MD, 0.12 kg; 95% CI, −0.06 to 0.30;
The pooled analysis showed that the rate of retinopathy (n=2 RCTs; RR, 0.42; 95% CI, 0.18–0.97;
The pooled analysis showed that the rates of cesarean delivery (n=2 RCTs; RR, 1.04; 95% CI, 0.89–1.21;
In this meta-analysis, we evaluated the efficacy of 17OHPC at preventing PTB by pooling data from six RCTs, comprising a total of 2,573 patients (1,617 and 956 patients in the 17OHPC and control groups, respectively). Overall, compared with the control group, the rates of PTB (<35 and <32 weeks), neonates with a low birth weight (<2.5 kg), neonatal death, neonatal necrotizing enterocolitis, and neonatal retinopathy were beneficially reduced in the 17OHPC group. Moreover, in contrast to the control group, 17OHPC treatment was correlated with a higher mean birth weight. Nevertheless, there were no significant difference between both the groups with respect to the rates of neonatal (NICU admission, bronchopulmonary dysplasia, respiratory distress, and intraventricular hemorrhage grade III/IV) and maternal (cesarean delivery, corticosteroid therapy, and tocolytic therapy) outcomes.
PTB represents a syndrome rather than a disease that is associated with different etiologies and pathological pathways [
Comparing 17OHPC treatment with vaginal progesterone suppositories, Pirjani et al. [
In the study by Fernandez-Macias et al. [
Cervical length is a key determinant of PTB [
All the included studies in this meta-analysis started 17OHPC as early as 14/16 weeks of gestation until 36/37 weeks of gestation to prevent the risk of PTB. However, the rates of complaints have not been consistently reported. Carter et al. [
According to the U.S. Food and Drug Administration [
Fernandez-Macias et al. [
Among singleton pregnant women with a prior history of PTB, this systematic review and meta-analysis suggests that 17OHPC may favorably decrease the risk of recurrent PTB (<35 and <32 weeks). Moreover, 17OHPC may advantageously decrease the rates of neonatal death and retinopathy. Considering the efficacy of 17OHPC versus control, future research should include multi-centric trials examining the therapeutic efficacy and safety of 17OHPC versus active comparators or the combination of 17OHPC and an active progestogen.
No potential conflict of interest relevant to this article was reported.
This study does not require approval of the Institutional Review Board because no patient data is contained in this article.
Not applicable.
None.
Supplementary Table 1, Supplementary Fig. 1-6 associated with this article can be found online at
Detailed authors’ judgment of the risk of bias of the included randomized controlled trials
Meta-analysis of the rates of preterm birth <37 weeks (A) and <35 weeks based on the cervical length at enrollment. 17OHPC, 17-alpha hydroxyprogesterone caproate; M-H, Mantel-Haenszel; CI, confidence interval.
Meta-analysis of the mean gestational age at delivery. 17OHPC, 17-alpha hydroxyprogesterone caproate; SD, standard deviation; CI, confidence interval.
Meta-analysis of the mean birth weights at delivery before (A) and after (B) sensitivity analysis using the leaveone- out method. 17OHPC, 17-alpha hydroxyprogesterone caproate; SD, standard deviation; CI, confidence interval.
Meta-analysis of neonatal complications: neonatal intensive care unit admission (A), bronchopulmonary dysplasia (B), respiratory distress syndrome (C), necrotizing enterocolitis (D), sepsis (E), retinopathy (F), intraventricular hemorrhage grade III-IV (G), and patent ductus arteriosus (H). 17OHPC, 17-alpha hydroxyprogesterone caproate; M-H, Mantel-Haenszel; CI, confidence interval.
Meta-analysis of maternal outcomes: cesarean delivery (A), corticosteroid therapy (B), and tocolytic therapy (C). 17OHPC, 17-alpha hydroxyprogesterone caproate; M-H, Mantel-Haenszel; CI, confidence interval.
Funnel plots of the rate of preterm labor <37 weeks (A), rate of preterm labor <35 weeks (B), rate of preterm labor <32 weeks (C), rate of low birth weight (<2.5 kg) (D), rate of neonatal death (E), and mean birth weight at delivery (F). RR, risk ratio; SE, standard error; MD, mean difference.
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the literature search.
The risk of bias summary (A) and graph (B) of the included studies.
Meta-analysis of the rates of preterm birth <37 weeks (A), <35 weeks (B), and <32 weeks (C). 17OHPC, 17-alpha hydroxyprogesterone caproate; M-H, Mantel-Haenszel; CI, confidence interval.
Meta-analysis of the rates of a low birth weight (<2.5 kg) at delivery before (A) and after (B) sensitivity analysis using the leave-one-out method. 17OHPC, 17-alpha hydroxyprogesterone caproate; M-H, FULL NAME; CI, confidence interval.
Meta-analysis of the rate of neonatal death. 17OHPC, 17-alpha hydroxyprogesterone caproate; M-H, Mantel-Haenszel; CI, confidence interval.
The baseline characteristics of patients in the included studies
Study | Country | Recruitment period (weeks) | Group | N | Age (yr) | 17OHPC dose | Type of treatment in control group | Period of 17OHPC use (weeks) | Cervical length at enrollment (mm) |
---|---|---|---|---|---|---|---|---|---|
Blackwell et al. [ |
USA | 160/7 to 206/7 weeks | 17OHPC | 1,130 | 30.0±5.2 | 250 mg IM weekly | Placebo | 16 to 36 | Non-selected |
Control | 578 | 29.2±5.2 | |||||||
| |||||||||
Ibrahim et al. [ |
Egypt | Second trimester (weeks not specified) | 17OHPC | 25 | 25.3±4.15 | 250 mg IM weekly | Placebo | 14 to 36 | Non-selected |
Control | 25 | 25.6±3.85 | |||||||
| |||||||||
Jafarpour et al. [ |
Iran | 160/7 | 17OHPC | 50 | 25.4±2.6 | 250 mg IM weekly | No placebo | 16 to 37 | >30 |
Control | 50 | 25.0±2.38 | |||||||
| |||||||||
Meis et al. [ |
USA | 16+0 to 20+6 weeks | 17OHPC | 310 | 26.0±5.6 | 250 mg IM weekly | Placebo | 16 to 36 | Non-selected |
Control | 153 | 26.5±5.4 | |||||||
| |||||||||
Berghella et al. [ |
USA | 16+0 to 22+6 weeks | 17OHPC | 52 | 26.3±4.5 | 250 mg IM weekly | No placebo | 16 to 36 | <25 |
Control | 100 | 26.8±5.3 | |||||||
| |||||||||
Saghafi et al. [ |
Iran | 16 weeks | 17OHPC | 50 | 28.98±5.36 | 250 mg IM weekly | No placebo | 16 to 37 | Non-selected |
Control | 50 | 29.32±5.69 |
Values are presented as mean±standard deviation unless otherwise indicated.
17OHPC, 17-alpha hydroxyprogesterone caproate; IM, intramuscularly.