Fonseca and colleagues then explored the benefit of progesterone therapy in preventing preterm birth in women who had a shortened cervical length between 20 and 25 weeks’ gestation.14 They screened more than 24,000 women and found 413 who had a cervical length of less than 15 mm. Of these women, 250 were randomized to micronized progesterone (200 mg in a vaginal suppository), starting at 24 weeks. This was twice the dosage given in the Brazilian trial involving women who had a history of preterm birth,3 but the authors thought that women who had a short cervix were at higher risk of preterm birth and, therefore, needed a higher dosage of progesterone. Although all women in this trial had a short cervix, the population overall was more heterogeneous than in other trials, including women who had a history of preterm birth (30% of participants) and women carrying a multiple gestation (19% of participants).
Progesterone reduced the risk of preterm birth in the overall cohort, with 19% of the women who received progesterone delivering preterm, versus 34% of those who received placebo (odd ratio [OR], 0.56; 95% CI, 0.36–0.86). Progesterone did not reduce the rate of perinatal mortality or neonatal morbidity. A subgroup analysis of only the nulli parous women was conducted, given that 30% of the study population had a history of preterm birth. That analysis showed no benefit.
DeFranco and associates17 published a secondary analysis of 46 women from a large randomized trial4 who had a cervical length of less than 28 mm. Of these women, 19 received progesterone and 27 received placebo. Of the 19 who received progesterone, 15 had a history of preterm birth. Of the 27 who received placebo, 22 had such a history. The authors found that progesterone significantly reduced preterm birth at less than 37, 35, and 32 weeks. However, again because of the small sample size and the inclusion of women with a history of preterm birth, these findings are not definitive.
Randomized trials designed to test the effect of progesterone in women who have a short cervix are called for. Numerous studies are under way.15
POPULATION 4: Women who experience preterm labor
Two recent trials explored the use of progesterone in this context. In one, progesterone was administered during the episode of preterm labor; in the other, it was given after successful tocolysis.
In the first trial, Facchinetti and colleagues studied 60 women who were pregnant with a singleton fetus and who were in active preterm labor.18 These women were randomly assigned to 341 mg of intramuscular 17α-hydroxyprogesterone caproate or placebo twice weekly, with cervical length monitored weekly. Women in the progesterone group were less likely to deliver by 7 or 21 days, and their cervical length was longer at both time points.
Borna and Sahabi evaluated use of progesterone as maintenance therapy after successful tocolysis.19 Seventy women were randomly assigned to progesterone (400-mg suppository) or no treatment. Women who received progesterone had a longer latency period (36 versus 24 days; P=.03), less respiratory distress (11% versus 36%), and a lower rate of low birth weight (27% versus 52%) than did women receiving no treatment.
What are the long-term effects of progesterone exposure?
Therapeutic interventions during pregnancy affect two people—one of them during a period of intense development that can have a lifelong impact. Although studies of progesterone to prevent preterm birth involve administration of the hormone after 16 weeks—well beyond the major period of organogenesis—concerns about potential teratogenic and other long-term effects have been raised. It is notable that progesterone has been widely used for decades during the first trimester—the period of organogenesis—in women who have a poor pregnancy history and early loss, to treat the “luteal phase defect.”
A Cochrane review of 14 studies of progesterone in the prevention of stillbirth and miscarriage20 and a systematic review of 14 cohort and case-control studies21 involving first-trimester exposure found no harm related to progesterone use. These findings are consistent with those of a meta-analysis by Coomarasamy and colleagues, which also found no harm related to the use of progesterone.1
Numerous studies have explored the long-term effects of progesterone on offspring, including a review of outcomes of pregnancies treated before 199022 and data from animal studies.23 Children from a trial by Meis22 were followed up at around 4 years of age to assess any differences in physical health and the achievement of developmental milestones between children who were exposed to progesterone and those who were not.24 Investigators used the Ages and Stages Questionnaire score, assessment of developmental milestones, and physical exams to evaluate the 348 children. No differences were seen in height, weight, and head-circumference percentiles; achievement of developmental milestones; gender roles; and physical health.