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Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data |
Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O'Brien JM, Cetingoz E, Da Fonseca E, Creasy GW, Klein K, Rode L, Soma-Pillay P, Fusey S, Cam C, Alfirevic Z, Hassan SS |
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CRD summary This high quality individual patient data analysis of five studies concluded that vaginal progesterone administration to asymptomatic women with a sonographic short cervix reduced the risk of preterm birth and neonatal morbidity and mortality. The evidence-base is limited by reliance on two studies so the result may not be reliable. Authors' objectives To determine whether the use of vaginal progesterone in asymptomatic women with a sonographic short cervix (25mm or less) in the midtrimester reduced the risk of preterm birth and improved neonatal morbidity and mortality. Searching MEDLINE, EMBASE, CINAHL, LILACS, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Google Scholar and six research registers of ongoing trials were searched without language restriction using specified search terms (all from inception through December 31, 2011). 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. Study selection Randomised controlled trials in which asymptomatic women with a sonographic short cervix in the midtrimester were randomly allocated to receive vaginal progesterone or placebo/no treatment for the prevention of preterm birth were eligible for inclusion. Trials were included if the primary aim of the study was to prevent preterm birth in women with risk factors other than a short cervix, but outcomes were available for patients with a pre-randomisation cervical length of 25mm or smaller. The pre-specified primary outcome measure was preterm birth (33 weeks or fewer of gestation). Multiple secondary outcomes were analysed including risk of adverse events (details reported). Two studies used vaginal progesterone capsules or pessaries 200mg/d, two used vaginal progesterone gel 90mg/d, and the other used vaginal progesterone suppositories 100mg/d. The treatment was initiated at 24 weeks of gestation in two trials, between 20 and 23 weeks of gestation in two trials, and between 18 and 22 weeks of gestation in one trial. Two reviewers independently assessed articles to determine eligibility for inclusion. Discrepancies were resolved by consensus. Assessment of study quality Study quality was assessed using the Cochrane risk of bias tool which considered: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting; and other bias. Additionally the quality and integrity of the randomisation processes were assessed using Individual Patient Data (IPD) to review the chronological randomisation sequence and pattern of assignment and the balance of baseline characteristics. Inconsistencies or missing data were discussed with the trial investigators and corrections were made if necessary. Two reviewers independently assessed quality. Discrepancies were resolved by consensus. Data extraction IPD was obtained from all eligible trial authors. Authors were asked to supply anonymised patient level data about baseline characteristics, experimental intervention, control intervention, co-interventions and pre-specified outcome measures for every randomised patient. Methods of synthesis IPD was analysed using a two-stage method, whereby trial level summary data was generated from IPD and combined using both fixed and random effects models. Heterogeneity was quantified using Ι² and one-stage models were used to assess any differences in effectiveness for pre-specified subgroups (details reported in the paper). Additional analysis was undertaken stratifying neonates according to pregnancy type (singleton versus multiple) with analyses of multiples, accounting for correlation of neonates from the same mother. Funnel plots and Egger tests were used to test for funnel plot asymmetry which may indicate publication or other biases. Results of the review Five trials of high quality were included (775 women, 827 infants). Treatment with vaginal progesterone was associated with a significant reduction in the rate of preterm birth: 33 weeks or fewer (RR 0.58; 95% CI, 0.42 to 0.80), 35 weeks or fewer (RR, 0.69; 95% CI, 0.55 to 0.88), and 28 weeks or fewer (RR, 0.50; 95% CI, 0.30 to 0.81); respiratory distress syndrome (RR, 0.48; 95% CI, 0.30 to 0.76); composite neonatal morbidity and mortality (RR, 0.57; 95% CI, 0.40 to 0.81); birthweight 1500g and below (RR, 0.55; 95% CI, 0.38 to 0.80); admission to neonatal intensive care unit (RR, 0.75; 95% CI, 0.59 to 0.94); and requirement for mechanical ventilation (RR, 0.66; 95% CI, 0.44 to 0.98). There were no significant differences between the vaginal progesterone and placebo groups in the rate of adverse maternal events or congenital anomalies. Ι² was 50% or less in all analyses and there was no indication of differential effectiveness for any of the subgroups investigated. The results were robust to sensitivity analyses (details reported) and the Egger test of funnel plot asymmetry was not significant. Authors' conclusions Vaginal progesterone administration to asymptomatic women with a sonographic short cervix reduced the risk of preterm birth and neonatal morbidity and mortality. CRD commentary This review addressed a clear question and used appropriate methods to search for, acquire and synthesise individual patient data whilst minimising potential for bias. Although the review methodology was robust and trial quality was high, the evidence-base for the findings was limited, with almost all the weight in the analyses derived from only two trials. The limited number of trials has further ramifications as the between trial consistency of results and generalisability could not be accurately assessed. Similarly, the potential for publication biases remain unquantifiable, although the robust search may mitigate this concern. The conclusions reflect the evidence, but the results may not be reliable particularly where outcomes with rare events are concerned Implications of the review for practice and research Practice: The authors recommended that transvaginal sonographic measurement of cervical length be performed at 19 to 24 weeks of gestation. Vaginal progesterone at a dose of 90mg/d should be considered for use in patients with a short cervix, mainly those with a cervical length between 10 and 20mm, from 20 to 36 weeks of gestation. Research: The authors stated that a properly-designed randomised controlled trial of vaginal progesterone in twin gestations was needed. Funding Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; Department of Health and Human Services. Bibliographic details Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O'Brien JM, Cetingoz E, Da Fonseca E, Creasy GW, Klein K, Rode L, Soma-Pillay P, Fusey S, Cam C, Alfirevic Z, Hassan SS. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. American Journal of Obstetrics and Gynecology 2012; 206(2): 124.e1-124.e19 Indexing Status Subject indexing assigned by NLM MeSH Administration, Intravaginal; Female; Humans; Pregnancy; Pregnancy Trimester, Second; Premature Birth /prevention & Progesterone /administration & Progestins /therapeutic use; Risk; Treatment Outcome; control; dosage /therapeutic use AccessionNumber 12012007546 Date bibliographic record published 27/03/2012 Date abstract record published 19/07/2013 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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