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Progesterone treatment may not prevent early preterm birth in twin pregnancy, according to the results of a randomized, double-blind, placebo-controlled study and meta-analysis reported in the June 11 Online First issue of The Lancet.

"Women with twin pregnancy are at high risk for spontaneous preterm delivery," write Jane E. Norman, MD, from the University of Edinburgh, United Kingdom, and colleagues from STudy Of Progesterone for the Prevention of Preterm birth In Twins (STOPPIT). "Progesterone seems to be effective in reducing preterm birth in selected high-risk singleton pregnancies, albeit with no significant reduction in perinatal mortality and little evidence of neonatal benefit. We investigated the use of progesterone for prevention of preterm birth in twin pregnancy."

Between 2004 and 2008 at 9 UK National Health Service clinics specializing in the management of twin pregnancy, 500 women were recruited and randomly assigned to receive daily vaginal progesterone gel 90 mg (n = 250) or placebo gel (n = 250) for 10 weeks beginning at 24 weeks' gestation. Assignment was by permuted blocks of randomly mixed sizes. Analysis was by intent-to-treat, and the main endpoint of the study was delivery or intrauterine death before 34 weeks' gestation.

To assess the efficacy of progesterone in preventing early (<>

In each group of the randomized trial, 3 women were lost to follow-up. The combined proportion of intrauterine death or delivery before 34 weeks of pregnancy was 24.7% (61/247) in women receiving progesterone vs 19.4% (48/247) in women receiving placebo (odds ratio [OR], 1.36; 95% confidence interval [CI], 0.89 - 2.09; P = .16). Both groups had similar rates of adverse events.

Similarly, progesterone did not appear to prevent early preterm birth in women with twin pregnancy, based on results of the meta-analysis (pooled OR, 1.16; 95% CI, 0.89 - 1.51).

"Progesterone, administered vaginally, does not prevent preterm birth in women with twin pregnancy," the study authors write. "The biological mechanism by which preterm delivery occurs might be different in twin and singleton pregnancy, and this hypothesis merits further study. Perhaps stretching of uterine muscle has a substantial role in preterm labour in twin pregnancy, and infection and inflammation a role in singletons."

Limitations of this study include participation rate of only 40% of eligible women and performance of the study mostly in tertiary referral centers.

In an accompanying comment, Lex W. Doyle, from the University of Melbourne in Melbourne, Australia, notes that progesterone might be beneficial in multiple pregnancies even if delivery is not delayed.

"Magnesium sulphate, which is not successful as a tocolytic despite being widely used for that purpose, improves neurological outcome for the preterm infant," Dr. Doyle writes. "Other trials in progress should continue to completion, survivors of all trials should be followed up into childhood, and data pooled to establish the balance between long-term benefits and risks of progesterone to prevent preterm delivery, of both singletons and multiple births."

The Chief Scientist Office of the Scottish Government Health Directorate supported this study. Some of the study authors have disclosed various financial relationships with government and charitable organizations for research into understanding the mechanism of term and preterm labor and investigating treatments, a small drug company that was considering developing treatments of preterm labor, and/or the pharmaceutical industry. One study author has been named as an inventor on patent applications for 2 compounds potentially useful in preterm labor prevention, and another was chair of the Data Safety and Monitoring Board.

Dr. Doyle has disclosed no relevant financial relationships.

Lancet. Published online June 11, 2009.

Clinical Context

Study Highlights

• Women with ongoing twin pregnancies were recruited from 9 UK National Health Service hospitals, with gestation and chorionicity established by scan before 20 weeks' gestation.
• Excluded were women with pregnancies complicated by structural or chromosomal abnormalities, planned cervical suture, planned elective delivery before 34 weeks, and planned intervention for twin-twin transfusion before 22 weeks.
• Women were recruited at booking and at 22 weeks and were randomly assigned to either progesterone gel 90 mg or identical-appearing placebo gel for intravaginal insertion from 24 weeks.
• The progesterone was delivered via an applicator with a twist-off top for single use by self-insertion.
• The applicator contained 1.45 g and delivered 1.125 g of gel with 8% progesterone or excipients.
• The primary outcome was delivery or intrauterine death before 34 weeks and 0 days.
• Delivery of the first twin was used to define time of delivery.
• The gestational age was calculated from the ultrasound scan done before 20 weeks.
• Maternal secondary outcomes were gestation at delivery, method of delivery, and duration of stages of labor.
• Neonatal secondary outcomes were admission to the neonatal unit and duration of neonatal care.
• A meta-analysis was performed of similar studies, with outcome of delivery before 34 weeks' gestation using search of PubMed and the Cochrane Controlled Trials register and the Jadad criteria for quality of studies.
• In the randomized trial, mean age of women was 33 years, 12% to 18% were current smokers, 71% to 72% currently used alcohol, and 48% to 49% were multiparous.
• 3 patients from each randomized group were lost to follow-up.
• The proportion of women delivering or with an intrauterine death before 34 weeks was 24.7% in the progesterone group vs 19.4% in the placebo group (OR, 1.36; P = .16).
• Progesterone did not reduce the incidence of preterm delivery or death before 34 weeks.
• Subgroup analysis suggested that progesterone may increase preterm delivery or intrauterine death in women with dichorionic pregnancies, but this was not statistically significant.
• For maternal outcomes, the only differences were reduced odds of cesarean delivery (OR, 0.53; P = .006), operative delivery (OR, 0.42; P = .013), and nausea (OR, 0.43; P = .035) in the progesterone group, but the authors attributed the reduction in cesarean delivery and operative delivery to chance.
• The rate of adverse effects such as vaginal discharge, irritation, discomfort, itching, nausea, fluid retention, and breast tenderness did not differ between the 2 groups.
• The meta-analysis generated 198 results, of which only 2 met criteria for inclusion.
• Both studies had high Jadad scores for quality, and the pooled OR for preterm delivery or intrauterine death before 34 weeks was 1.16 (not significant) for progesterone.
• The authors concluded that use of intravaginal progesterone from 24 weeks in women with twin pregnancies was not associated with a reduction in preterm delivery or intrauterine death before 34 weeks.

Clinical Implications

• Use of intravaginal progesterone in women with twin pregnancies is not associated with a reduction in preterm delivery or intrauterine death before 34 weeks' gestation.
• Use of intravaginal progesterone in women with twin pregnancies is not associated with increased adverse events.

Source : http://cme.medscape.com/viewarticle/704610?sssdmh=dm1.488649&src=nldne