Objective
To determine whether the use of vaginal progesterone in asymptomatic women with a sonographic short cervix (≤25 mm) in the midtrimester reduces the risk of preterm birth and improves neonatal morbidity and mortality.
Study Design
Individual patient data metaanalysis of randomized controlled trials.
Results
Five trials of high quality were included with a total of 775 women and 827 infants. Treatment with vaginal progesterone was associated with a significant reduction in the rate of preterm birth <33 weeks (relative risk [RR], 0.58; 95% confidence interval [CI], 0.42–0.80), <35 weeks (RR, 0.69; 95% CI, 0.55–0.88), and <28 weeks (RR, 0.50; 95% CI, 0.30–0.81); respiratory distress syndrome (RR, 0.48; 95% CI, 0.30–0.76); composite neonatal morbidity and mortality (RR, 0.57; 95% CI, 0.40–0.81); birthweight <1500 g (RR, 0.55; 95% CI, 0.38–0.80); admission to neonatal intensive care unit (RR, 0.75; 95% CI, 0.59–0.94); and requirement for mechanical ventilation (RR, 0.66; 95% CI, 0.44–0.98). There were no significant differences between the vaginal progesterone and placebo groups in the rate of adverse maternal events or congenital anomalies.
Conclusion
Vaginal progesterone administration to asymptomatic women with a sonographic short cervix reduces the risk of preterm birth and neonatal morbidity and mortality.
Preterm birth is the leading cause of perinatal morbidity and mortality worldwide and contributes to 70% of neonatal mortality and approximately half of long-term neurodevelopmental disabilities. A recent systematic review has estimated that 12.9 million births, or 9.6% of all births worldwide, were preterm, of which approximately 11.9 million (92.3%) were in Africa, Asia, Latin America, and the Caribbean. During the last 25 years, the preterm birth rate in the United States increased 36%, from 9.4% in 1981 to 12.8% in 2006. This increase has been attributed to a higher frequency of “indicated” preterm births in singleton gestations and preterm delivery in multiple gestations resulting, in part, from the use of assisted reproductive technologies.
For Editors’ Commentary, see Table of Contents
See related editorial, page 101
Spontaneous preterm labor/delivery is considered to be one of the “great obstetrical syndromes”, a term that emphasizes that obstetrical disorders with a similar phenotype are caused by multiple pathologic processes, have a long subclinical phase, and may result from complex gene-environment interactions.
Progesterone is considered a key hormone for pregnancy maintenance, and a decline of progesterone action is implicated in the onset of parturition. If such a decline occurs in the midtrimester, cervical shortening may occur, and this would predispose to preterm delivery. Therefore, an untimely decline in progesterone action has been proposed as a mechanism of disease in the “preterm parturition syndrome”.
Progesterone actions are mediated by genomic and nongenomic effects which have been studied in the uterine cervix, myometrium, sperm, etc. A blockade of progesterone action can lead to the clinical, biochemical, and morphologic changes associated with cervical ripening. A short cervix detected with transvaginal ultrasound is a powerful predictor of preterm birth in women with singleton and twin gestations. The shorter the sonographic cervical length, the higher the risk of spontaneous preterm birth. Moreover, a short cervix is associated with intraamniotic infection and inflammation, and this may modify the response to interventions.
An interest in the role of progestogens (natural and synthetic) for the prevention of preterm birth has existed for decades. Recently, the administration of vaginal progesterone was proposed for the prevention of preterm birth in women with a sonographic short cervix in the midtrimester based on its biologic effects on the cervix, myometrium, and chorioamniotic membranes. In 2007, Fonseca et al, on behalf of the Fetal Medicine Foundation of the United Kingdom, reported that the administration of vaginal progesterone in women with a cervical length ≤15 mm was associated with a significant 44% reduction in the rate of spontaneous preterm birth <34 weeks of gestation. Similar findings were reported by DeFranco et al in a secondary analysis of a randomized clinical trial of vaginal progesterone in women with a history of preterm birth in which the cervix was measured. Hassan et al reported the largest randomized clinical trial to date, indicating that vaginal progesterone, when administered to women with a cervical length of 10-20 mm, reduces the rate of preterm birth at <33, <28, and <35 weeks, and this was associated with a significant 61% reduction in the rate of respiratory distress syndrome (RDS). Since the publication of the trial of Hassan et al, several trials evaluating vaginal progesterone in women at high risk of spontaneous preterm birth, including a subset of women with a short cervix, have been published.
An individual patient data (IPD) metaanalysis is a specific type of systematic review in which the original research data for each participant in a study are sought directly from the investigators responsible for that trial. Such an approach has been considered the gold standard for summarizing evidence across clinical studies since it offers several advantages, both statistically and clinically, over conventional metaanalyses, which are based on published aggregate data. These advantages include standardizing and updating of data sets, the ability to verify the quality of the data and the appropriateness of the analyses, the improvement of consistency across trials (eg, definition of outcomes), the performance of subgroup analyses that could effectively identify groups of patients who might benefit from an intervention, the investigation of interaction between patient-level covariates and treatment effects, and the performance of time-to-event analyses.
Using IPD from randomized controlled trials, we performed a metaanalysis to evaluate the efficacy and safety of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality in asymptomatic women with a sonographic short cervix in the midtrimester. We also sought to determine whether there were clinical benefits associated with the administration of vaginal progesterone in singleton and twin pregnancies.
Materials and Methods
The study was conducted based on a prospectively prepared protocol, and is reported using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for metaanalyses of randomized controlled trials and suggested guidelines for IPD metaanalyses.
Literature search
We searched MEDLINE, EMBASE, CINAHL, and LILACS (all from inception through December 31, 2011); the Cochrane Central Register of Controlled Trials ( www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.html ) (1960 through December 31, 2011); ISI Web of Science ( www.isiknowledge.com ) (1960 through December 31, 2011); Research Registers of ongoing trials ( www.clinicaltrials.gov , www.controlled-trials.com , www.centerwatch.com , www.anzctr.org.au , www.nihr.ac.uk , and www.umin.ac.jp/ctr ); and Google Scholar using a combination of key words and text words related to progesterone (“progesterone,” “progestins,” “progestogen,” “progestagen,” “progestational agent”) and preterm birth (“preterm,” “premature”). Proceedings of the Society for Maternal-Fetal Medicine and international meetings on preterm birth, reference lists of identified studies, textbooks, previously published systematic reviews, and review articles were also searched. Experts in the field were contacted to identify further studies. No language restriction was used.
Study selection
We included randomized controlled trials in which asymptomatic women with a sonographic short cervix (cervical length of ≤25 mm) in the midtrimester were randomly allocated to receive vaginal progesterone or placebo/no treatment for the prevention of preterm birth. Trials were included if the primary aim of the study was to prevent preterm birth in women with a sonographic short cervix, or if the primary aim was to prevent preterm birth in women with risk factors other than a short cervix, but outcomes were available for patients with a prerandomization cervical length of ≤25 mm. Trials were excluded if they: (1) were quasirandomized; (2) evaluated vaginal progesterone in women with threatened preterm labor, second trimester bleeding, or premature rupture of membranes; (3) evaluated the administration of vaginal progesterone in the first trimester only to prevent miscarriage; or (4) did not report clinical outcomes. Although there is no agreement on what is a sonographic short cervix, we chose 25 mm as the cutoff because this value corresponds approximately to the 10th percentile for cervical length in the midtrimester. In addition, this cervical length is the most commonly used in studies evaluating the predictive accuracy of cervical length for preterm birth.
Two investigators (R.R. and A.C.-A.) independently reviewed all potentially relevant articles for eligibility. Disagreements regarding trial eligibility were resolved by consensus.
Data collection
We contacted the corresponding authors to request access to the data. Authors were asked to supply anonymized data (without identifiers) about patient baseline characteristics, experimental intervention, control intervention, cointerventions, and prespecified outcome measures for every randomly assigned subject and were invited to become part of the collaborative group with joint authorship of the final publication. Data provided by the investigators were merged into a master database specifically constructed for the review. Data were checked for missing information, errors, and inconsistencies by cross-referencing the publications of the original trials. Quality and integrity of the randomization processes were assessed by reviewing the chronological randomization sequence and pattern of assignment, as well as the balance of baseline characteristics across treatment groups. Inconsistencies or missing data were discussed with the authors and corrections were made when deemed necessary.
Outcome measures
The prespecified primary outcome measure was preterm birth <33 weeks of gestation. Secondary outcome measures included preterm birth <37, <36, <35, <34, <30, and <28 weeks of gestation; spontaneous preterm birth <33 and <34 weeks of gestation; RDS; necrotizing enterocolitis; intraventricular hemorrhage (all grades); proven neonatal sepsis; retinopathy of prematurity; bronchopulmonary dysplasia; periventricular leukomalacia; fetal death; neonatal death; perinatal mortality, a composite neonatal morbidity and mortality outcome (defined as the occurrence of any of the following events: RDS, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death); Apgar score <7 at 5 minutes; birthweight <1500 g and <2500 g; admission to the neonatal intensive care unit (NICU); use of mechanical ventilation; congenital anomaly; any maternal adverse event; vaginal discharge; vaginal pruritus; discontinuation of treatment because of adverse events; threatened preterm labor; and neurodevelopmental disability at 18-24 months of age. Neonatal morbidities were defined as in the original study.
Assessment of risk of bias
We assessed the risk of bias using the criteria recently outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Seven domains related to risk of bias were assessed in each included trial since there is evidence that these issues are associated with biased estimates of treatment effect: (1) random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) selective reporting; and (7) other bias. Review authors’ judgments were categorized as “low”, “high”, or “unclear” risk of bias. The assessments considered the risk of material bias rather than any bias. “Material bias” is defined as a bias of sufficient magnitude to have a notable impact on the results or conclusions of the trial. The risk of bias in each trial included was assessed individually by 2 reviewers (R.R. and A.C.-A.). In addition, methods of random sequence generation, allocation concealment, and blinding were confirmed with the authors of the trials. Any differences of opinion regarding assessment of risk of bias were resolved by discussion.
Statistical analysis
Statistical analyses were based on an intent-to-treat basis and included all randomized women and their fetuses/infants. For baseline data, maternal outcomes, and gestational age at birth-related outcomes, the unit of analysis was the pregnancy, whereas for neonatal outcomes, the unit of analysis was the neonate. To assess safety of vaginal progesterone, all patients exposed to progesterone were included. This included all studies and patients, even those in which the cervical length was not measured. IPD were combined in a 2-stage approach in which outcomes were analyzed in the original trial and then summary statistics were generated using standard summary data metaanalysis techniques to give an overall measure of effect (summary relative risk [RR] with 95% confidence interval [CI]). Heterogeneity of the results among studies was tested with the quantity I 2 , which describes the percentage of total variation across studies that can be attributed to heterogeneity rather than chance. A value of 0% indicates no observed heterogeneity, whereas I 2 values of ≥50% indicate a substantial level of heterogeneity. We planned to use a fixed effects model if substantial statistical heterogeneity was not present. Random effects models were also used to test the robustness of results. The number needed to treat (NNT) for benefit or harm with the 95% CI was calculated for outcomes for which there was a statistically significant reduction or increase in risk difference based on control event rates in the trials. Publication and related biases were assessed visually by examining the symmetry of funnel plots and statistically by using the Egger test. A P value < .1 was considered to indicate significant asymmetry.
Access to data from individual patients also allowed the performance of subgroup analyses to examine whether the administration of vaginal progesterone was more effective in some subgroups than in others. Specifically, we assessed the effect of vaginal progesterone in singleton and twin gestations separately. Also, to explore treatment effects according to other patient characteristics, subgroup analyses were prespecified on the basis of sonographic cervical length (<10, 10-20, and 21-25 mm), obstetrical history (no previous spontaneous preterm birth and at least 1 previous spontaneous preterm birth <37 weeks), maternal age (<20, 20-34, and ≥35 years), race/ethnicity (Caucasian, Black, Asian, and other), and body mass index (<18.5, 18.5-24.9, 25.0-29.9, ≥30 kg/m 2 ). To explore effects by trial characteristics, prespecified subgroup analyses were planned according to the daily dose of vaginal progesterone (90-100 vs 200 mg). Definitions and subgroup analyses were specified before any data were obtained or analyzed. Treatment effects in these subgroups were assessed by simple logistic regression models (which included a subgroup-allocated treatment interaction term), with adjustment for between-trial outcome differences. A test for interaction between treatment and subgroup is the standard method to examine whether treatment effects differ between subgroups. This approach tests and estimates the difference between treatment effects across subgroups directly. It involves one statistical test regardless of the number of subgroups. An interaction P value > .05 was considered to indicate that the effect of treatment did not differ significantly between subgroups. Adjustment for predictive baseline characteristics, even when largely balanced, can lead to different estimates of treatment effects. Therefore, multivariable logistic regression models were employed to estimate adjusted treatment effects. In the twin pregnancy subgroup, the lack of independence of twins may have influenced the outcome of the analysis. Thus, for adverse perinatal outcomes in twins, we used analytical methods assuming independence between neonates as well as methods recommended to take into account nonindependence of newborns from twin gestations. We planned sensitivity analyses to test the robustness of the results by excluding trials with any risk of bias and including only studies for which the primary aim was to assess the effects of vaginal progesterone in women with a short cervix. Subgroup and sensitivity analyses were only performed for the primary outcome of preterm birth <33 weeks of gestation and for the secondary outcome of composite neonatal morbidity and mortality. Analyses were performed with the Review Manager (RevMan) version 5.1 (Nordic Cochrane Centre, Copenhagen, Denmark), and SAS version 9.2 (SAS Institute, Cary, NC) software.
Informed consent was provided by the patients upon enrollment in each of the original trials. In this study, the data were not used for any purposes other than those of the original trial, and no new data were collected. Therefore, informed consent specifically for this project was not considered necessary. No patient identifiers were provided by any investigator. This study was exempted for review by the Human Investigations Committee of Wayne State University’s Institutional Review Board, Detroit, MI.
Results
Study selection, details, and quality
The searches yielded 2611 citations, of which 10 were considered for potential inclusion ( Figure 1 ) . Five studies were excluded. Three of these studies evaluated vaginal progesterone in women at high risk for preterm birth (previous preterm birth, uterine malformation, cervical insufficiency, and twins ) but none of them measured or collected data on cervical length. Two of these studies reported that prophylactic administration of vaginal progesterone reduced the risk of preterm birth in women with a previous preterm birth, whereas the study by Norman et al found that vaginal progesterone did not reduce the risk of the composite outcome delivery or fetal death <34 weeks of gestation in women with a twin gestation. The 2 remaining studies evaluated vaginal progesterone as an adjunct to tocolytic therapy after threatened preterm labor. Five studies, which provided data for 775 women (723 [93.3%] with singleton pregnancies and 52 [6.7%] with twin pregnancies) and 827 fetuses/infants (723 [87.4%] from singleton pregnancies and 104 [12.6%] from twin pregnancies), met the inclusion criteria.
The main characteristics of studies included in this IPD metaanalysis are shown in Table 1 . All studies were double-blind, placebo-controlled trials, of which 4 were multicenter, conducted in sites from both developed and developing countries. Two trials were specifically designed to evaluate the administration of vaginal progesterone in women with a sonographic short cervix, one evaluated the use of vaginal progesterone in women with a history of spontaneous preterm birth, another assessed vaginal progesterone in women with a twin gestation, and the remaining trial examined the use of progesterone in women with a prior spontaneous preterm birth, uterine malformations, or twin gestations. Two of these studies reported data of planned secondary analyses for women with a short cervix in additional reports. Data from the trials by O’Brien et al, Cetingoz et al, and Rode et al relevant to women with a cervical length of ≤25 mm before randomization were provided by the authors for inclusion in this review. The 2 trials specifically designed to evaluate the use of vaginal progesterone in women with a short cervix screened a total of 56,711 women, of which 1146 (2.0%) had a sonographic short cervix as defined by the authors for the purposes of each study. Of these women, 715 (62.4%) were randomized; 708 mothers with their 732 infants provided data for the metaanalysis (∼90% of total sample size of the IPD metaanalysis). The other 3 studies provided data for 67 women and 95 infants.
| Study | Participating countries | Primary target population | Inclusion/exclusion criteria | No of women with CL ≤25 mm/fetuses or infants | Intervention | Cointerventions | Primary outcome | |
|---|---|---|---|---|---|---|---|---|
| Vaginal progesterone group | Placebo group | |||||||
| Fonseca et al, 2007 | United Kingdom, Chile, Brazil, Greece | Women with a short cervix | Inclusion: women with a singleton or twin pregnancy and sonographic CL ≤15 mm Exclusion: major fetal abnormalities, painful regular uterine contractions, history of ruptured membranes, and cervical cerclage | 125/136 | 125/138 | Vaginal progesterone capsule (200 mg/d) or placebo from 24-33 6/7 wk of gestation | Cervical cerclage (1 [0.8%] in vaginal progesterone group and 0 [0.0%] in placebo group) | Spontaneous preterm birth <34 wk |
| O’Brien et al, 2007 | United States, South Africa, India, Czech Republic, Chile, El Salvador | Women with a history of spontaneous preterm birth | Inclusion: women with a singleton pregnancy, gestational age between 16 0/7-22 6/7 wk, and a history of spontaneous singleton preterm birth at 20-35 wk of gestation in the immediately preceding pregnancy Exclusion: planned cervical cerclage, history of adverse reaction to progesterone, treatment with progesterone within 4 wk before enrollment, treatment for seizure disorder, psychiatric illness or chronic hypertension at time of enrollment, history of acute or chronic congestive heart failure, renal failure, uncontrolled diabetes mellitus, active liver disorder, HIV infection with CD4 count of <350 cells/mm 3 and requiring multiple antiviral agents, placenta previa, history or suspicion of breast or genital tract malignancy, history or suspicion of thromboembolic disease, müllerian duct anomaly, major fetal anomaly or chromosomal disorder, or multifetal gestation | 12/12 | 19/19 | Vaginal progesterone gel (90 mg/d) or placebo from 18-22 to 37 0/7 wk of gestation, rupture of membranes or preterm delivery, whichever occurred first | None | Preterm birth ≤32 wk |
| Cetingoz et al, 2011 | Turkey | Women at high risk of preterm birth | Inclusion: women with at least 1 previous spontaneous preterm birth, uterine malformation, or twin pregnancy Exclusion: in-place or planned cervical cerclage, serious fetal anomalies | 9/14 | 6/8 | Vaginal progesterone suppository (100 mg/d) or placebo from 24-34 wk of gestation | None | Preterm birth <37 wk |
| Hassan et al, 2011 | United States, Republic of Belarus, Chile, Czech Republic, India, Israel, Italy, Russia, South Africa, Ukraine | Women with a short cervix | Inclusion: women with a singleton pregnancy, gestational age between 19 0/7-23 6/7 wk, transvaginal sonographic CL between 10-20 mm, and without signs or symptoms of preterm labor Exclusion: planned cerclage, acute cervical dilation, allergic reaction to progesterone, current or recent progestogen treatment within previous 4 wk, chronic medical conditions that would interfere with study participation or evaluation of treatment, major fetal anomaly or known chromosomal abnormality, uterine anatomic malformation, vaginal bleeding, known or suspected clinical chorioamnionitis | 235/235 | 223/223 | Vaginal progesterone gel (90 mg/d) or placebo from 20-23 6/7 to 36 6/7 wk of gestation, rupture of membranes or preterm delivery, whichever occurred first | Emergency cervical cerclage (10 [4.3%] in vaginal progesterone group and 6 [2.7%] in placebo group) | Preterm birth <33 wk |
| Rode et al, 2011 | Denmark, Austria | Women with a twin pregnancy | Inclusion: women with a diamniotic twin pregnancy and chorionicity assessed by ultrasound <16 wk of gestation Exclusion: higher order multiple pregnancies, known allergy to progesterone or peanuts as active treatment contained peanut oil, history of hormone-associated thromboembolic disorders, rupture of membranes, pregnancies treated for or with signs of twin-to-twin transfusion syndrome, intentional fetal reduction, known major structural or chromosomal fetal abnormality, known or suspected malignancy in genitals or breasts, known liver disease | 7/14 | 14/28 | Vaginal progesterone pessary (200 mg/d) or placebo from 20-23 6/7 to 33 6/7 wk of gestation | Cervical cerclage (2 [28.6%] in vaginal progesterone group and 2 [14.3%] in placebo group) | Preterm birth <34 wk |
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