Progesterone Gel May Lower Risk for Early Preterm Birth

Laurie Barclay, MD

April 12, 2011

April 12, 2011 (UPDATED April 22, 2011) — In women with a sonographic short cervix in the midtrimester, vaginal progesterone gel is linked to a 45% decrease in birth rate before 33 weeks' gestation and better neonatal outcomes, according to the results of a multicenter, randomized, double-blind, placebo-controlled trial reported online April 6 in Ultrasound in Obstetrics & Gynecology.

"Women with a sonographic short cervix in the mid-trimester are at increased risk for preterm delivery," write Sonia S. Hassan, MD, from the Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health (NIH)/Department of Health and Human Services in Bethesda, Maryland, and colleagues from the PREGNANT Trial. "This study was undertaken to determine the efficacy and safety of micronized vaginal progesterone gel to reduce the risk of preterm birth and associated neonatal complications in women with a sonographic short cervix."

Asymptomatic women (n = 465) with a singleton pregnancy and a cervical length of 10 to 20 mm measured sonographically at 19 to 23 and 6/7 weeks of gestation were randomly selected to receive daily vaginal progesterone gel or placebo beginning at 20 to 23 and 6/7 weeks. Randomization sequence was stratified by center and by history of a previous preterm birth. Study medication was continued until 36 and 6/7 weeks, rupture of membranes, or delivery, whichever occurred first. Analysis was by intent-to-treat, with a main outcome measure of preterm birth before 33 weeks of gestation.

For women with a very short cervix in the mid second trimester, vaginal progesterone may help reduce the risk of preterm birth and adverse outcomes such as neonatal respiratory distress syndrome," David M. Haas, MD, MS, director of PREGMED, the Indiana University Center for Pharmacogenetics and Therapeutics Research in Maternal and Child Health in Indianapolis, told Medscape Medical News when asked for independent comment. "This is one of the first studies of its kind to show improved neonatal outcomes."

Dr. Haas is also the director of clinical research and assistant professor of obstetrics and gynecology at Indiana University School of Medicine, Wishard Memorial Hospital in Indianapolis.

Study Findings

Seven women randomly selected were lost to follow-up, leaving 458 with analyzable data, of whom 235 were assigned to vaginal progesterone gel and 223 to placebo. Compared with the placebo group, the vaginal progesterone group had a lower rate of preterm birth before 33 weeks (8.9% [n = 21] vs 16.1% [n = 36]; relative risk [RR], 0.55; 95% confidence interval [CI], 0.33 - 0.92; P = .02). Adjustment for covariables did not abolish this effect (adjusted RR, 0.52; 95% CI, 0.31 - 0.91; P = .02).

Compared with placebo, rates of preterm birth before 28 weeks and 35 weeks were also significantly decreased with vaginal progesterone (5.1% vs 10.3%; RR, 0.50; 95% CI, 0.25 - 0.97; P = .04; and 14.5% vs 23.3%; RR, 0.62; 95% CI, 0.42 - 0.92; P = .02, respectively). The vaginal progesterone group also fared better than the placebo group in lower rates of respiratory distress syndrome (3.0% vs 7.6%; RR, 0.39; 95% CI, 0.17 - 0.92; P = .03), any neonatal morbidity or mortality event (7.7% vs 13.5%; RR, 0.57; 95% CI, 0.33 - 0.99; P = .04), and birth weight of less than 1500 g (6.4% [15/234] vs 13.6% [30/220]; RR, 0.47; 95% CI, 0.26 - 0.85; P = .01). The groups did not differ significantly in the incidence of treatment-related adverse events.

"Our study demonstrates that progesterone gel reduces the rate of early preterm delivery — less than 33 weeks — in women with a short cervix," said second author Roberto Romero, MD, program head for Perinatology Research and Obstetrics and chief of the Perinatology Research Branch at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, in a news release. "Women with a short cervix can be identified through routine ultrasound screening. Once identified, they could be offered treatment with progesterone."

Strengths and Limitations

Limitations of this study include use of a primary endpoint that is a surrogate for infant outcome, and insufficient power to detect differences in the outcome according to risk strata (presence or absence of a previous preterm birth).

"One of the limitations is that we are still using this therapy that seems to work, but we do not yet know the specific mechanism of action," said Dr. Haas. "This is not a limitation of this particular study per se but of the therapy in general. That being said, this is a large study, well designed and executed."

Other study strengths noted by Dr. Haas include central randomization, double-masking, strict allocation concealment, intent-to-treat and other prespecified analyses, and the size of the trial.

However, only 2.3% of the population screened had the eligible cervical length for inclusion in this study.

"The large amount of screening transvaginal ultrasounds that would have to be done routinely to find these women (particularly the ones without a history of preterm birth) may lessen some of the enthusiasm," Dr. Haas pointed out. "However, if women are found to be in this cervical length range, then this therapy is an option that appears to be effective and without immediate adverse effects."

Dr. Haas recommended additional research in several areas, including clarification of the exact mechanism of how the progestin works to prevent preterm birth, a full cost-effectiveness analysis, and longer follow-up of the offspring.

"The long-term impact on the fetus is not clearly known," Dr. Haas said. "Are there long-term behavioral or neurodevelopmental effects of prolonged administration of progestins to the developing baby? Long-term follow-up studies are needed."

Comparisons With Makena

Makena (hydroxyprogesterone caproate injection; KV Pharmaceutical; Ther-Rx Corporation) is the first and only treatment approved by the US Food and Drug Administration (FDA) to reduce the risk for preterm singleton birth in women before 37 weeks of gestation who are at increased risk because of a history of preterm delivery, as previously reported by Medscape Medical News.

Makena is not intended for use in women with multiple gestations or other risk factors for preterm birth. Hence, it appears to target a somewhat different population than vaginal progesterone gel, which is intended for women at risk for preterm birth because of a short cervix. Unlike vaginal progesterone gel, which is administered daily into the vagina, Makena is administered once a week by intramuscular injection. Treatment should begin at 16 weeks of pregnancy, or no later than at 21 weeks, and continue until 37 completed weeks or delivery.

"The progesterone gel is self-administered vaginally and may be more tolerable to subjects than the weekly intramuscular injections [of Makena], but I am not aware of data comparing tolerability," Dr. Haas said.

On February 4, 2011, the FDA approved Makena under accelerated approval regulations, based on an NIH-sponsored, multicenter, randomized double-blind study of 463 women with singleton pregnancy and a history of a previous spontaneous preterm birth. Preterm birth (< 37 weeks) occurred in 37% of the women treated with Makena vs 55% of women in the control group. In trials to date, the most common adverse effects with Makena were pain, swelling, or itching at the injection site; hives; nausea; and diarrhea. Serious adverse reactions were rare (1 pulmonary embolism and 1 injection site infection).

On March 30, as reported by Medscape Medical News, the FDA announced that it would continue to permit pharmacies to compound a generic version of hydroxyprogesterone caproate, available for $10 to $20 per injection.

KV Pharmaceutical announced on April 1 that it would lower the list price of Makena from $1500 to $690 per injection, after considerable pressure from organized medicine, politicians, and the March of Dimes Foundation, as reported by Reuters Health.

Dr. Haas noted that a full cost-effectiveness analysis of vaginal progesterone as well as an analysis of Makena would help determine whether either of the therapies, and the population screening that may be needed to identify women eligible for treatment, are cost effective in a population.

"This drug is likely to compete with Makena for women who have a known short cervix," Dr. Haas concluded. "Currently Makena is prescribed to anyone with a history of prior preterm birth, so the indications do not necessarily overlap. Until the data is clear that the reported therapy is indicated in the population of all women with a history of prior preterm birth, there may be some women who have an indication for one drug over the other."

The Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health and Columbia Laboratories, Inc, supported this study. Some of the study authors have disclosed various financial relationships with Columbia Laboratories, Inc. Dr. Haas has disclosed no relevant financial relationships.

Ultrasound Obstet Gynecol. Published online April 6, 2011. Full text

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