ATLANTA – Vaginal progesterone confers no obstetrical or neonatal benefit, and no long-term benefit with respect to cognitive and neurosensory outcomes in children when used to prevent preterm birth, according to findings from the randomized, controlled, double-blind OPPTIMUM trial.
The findings from OPPTIMUM – the largest trial to date looking at progesterone for the prevention of preterm birth – have important implications for current practice. Vaginal progesterone is not currently approved for the prevention of preterm birth in the United States, but is commonly used off label for this purpose.
Dr. Jane E. Norman
Prior studies have demonstrated a benefit with respect to progesterone for the prevention of preterm birth, particularly in women with a short cervix, but no studies have looked at long-term outcomes, Dr. Jane E. Norman of the University of Edinburgh reported at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.
In OPPTIMUM, the rate of the primary obstetric outcome of preterm birth or fetal death before 34 weeks’ gestation did not differ significantly for 618 women at risk for preterm birth who were randomized to receive 200 mg of vaginal progesterone daily starting at 22-24 weeks and continuing to 34 weeks’ gestation, compared with 600 women who received placebo (16% vs. 18%; odds ratio, 0.86), Dr. Norman said.
The rate of the primary neonatal composite outcome of death or major morbidity (brain injury or bronchopulmonary dysplasia) also did not differ significantly between the progesterone and placebo groups after a prespecified multiple comparisons procedure (6% vs. 10%; odds ratio, 0.62).
A secondary analysis looking at the individual components of the composite neonatal outcomes showed that progesterone reduced the risk of brain injury and neonatal death, but not bronchopulmonary dysplasia, she said.
Further, no difference was seen in Bayley III cognitive scores (with values imputed for deaths) at 2 years of age in 439 and 430 children born to mothers in the progesterone and placebo groups, respectively (average scores, 97.7 and 97.3; odds ratio, 0.48).
On secondary analyses, some safety signals were noted with respect to neurodevelopmental outcomes.
“We were really surprised that we didn’t show that progesterone prevented preterm birth, and we became concerned that perhaps our cutoff of 34 weeks was just the wrong time to choose a cutoff,” Dr. Norman said, noting that a post hoc survival curve analysis was performed to look at the trajectory to delivery, and a “very marginal benefit” was seen with progesterone, but the difference was not statistically significant.
In addition, subgroup analyses showed no significant benefit of progesterone on obstetrical, neonatal, or childhood outcomes. For example, in women with a short cervix, no evidence was seen that progesterone was more or less effective than in women with a longer cervix. Other subgroups studied included fibronectin-positive and fibronectin-negative women and women with a history of preterm birth. Progesterone was no more or less effective in any of the subgroups, Dr. Norman said.
OPPTIMUM study subjects were women at risk of preterm birth because of a positive fetal fibronectin test result, a history of spontaneous preterm birth at or before 34 weeks’ gestation, or a short cervix (25 mm or less).
All outcomes were adjusted for a previous pregnancy of 14 weeks’ gestation or greater, with study center as a random effect.
“OPPTIMUM is the largest trial of progesterone to prevent preterm birth, and after adjusting for multiple comparisons as we planned, we did not disprove the null hypothesis that progesterone doesn’t prevent preterm birth, it doesn’t reduce adverse neonatal outcomes, and it doesn’t have a beneficial effect on childhood outcomes,” Dr. Norman said, concluding that “there is a remaining unmet need for a safe and effective agent to prevent preterm birth.”
Asked about the safety of progesterone given the findings from secondary analyses in OPPTIMUM, she said, “I would not advise my daughter to take progesterone if she’s pregnant.”
The study drug and placebo were donated by Besins, but the company was not involved in study design or analysis. Funding was provided by the Medical Research Council. Dr. Norman reported having no relevant financial disclosures.