Is oral progesterone an option?
In the 1980s and 1990s, oral micronized progesterone was widely used in France at doses of 900 to 1,200 mg/d for women at risk for PTD. The practice was stopped when secondary hepatic effects, including cholestasis of pregnancy, were reported at a higher rate in treated women.24 A rise in the serum concentration of progesterone metabolites has been associated with impaired biliary excretion and subsequent accumulation of bile acids.25 In other reports, elevated serum transaminase activity was found in pregnant women treated with oral micronized progesterone, and withdrawal of treatment frequently has led to improvement in transaminase levels.26 The synthesis of endogenous progesterone during normal pregnancy is between 250 and 500 mg/d,26 and experts have expressed concern that exogenous progesterone supplementation may impose an additional load on the hepatic transport of sulfated metabolites. Unlike orally administered progesterone, progestins given by the vaginal route avoid the hepatic first-pass effect. For this reason, they may be associated with less hepatic dysfunction.
Although not recommended by professional guidelines, oral progesterone administration for the prevention of PTD has been used in the United States. A 2015 survey of Wisconsin prenatal care providers found that of those who prescribed any progesterone for PTD prevention, oral progesterone was prescribed by 13.1% of obstetricians, 24.4% of midwives, and 40.7% of family medicine practitioners.27
Some limited recent evidence from a meta-analysis of 3 trials investigating oral progesterone versus placebo suggests effectiveness in the prevention of recurrent PTD and reduction in perinatal morbidity and mortality.15 However, the number of cases included in the meta-analysis (386) was too small to support definitive clinical recommendations. Furthermore, questions have been raised in the literature about the reliability of the largest trial included in that meta-analysis.28
Case 3 Two previous spontaneous PTDs
A 29-year-old G3P0201 presents for her first prenatal appointment at 10 weeks’ gestation. With her first pregnancy she had a spontaneous PTD at 23 weeks, and the neonate did not survive. In her second pregnancy, she was treated with 17-OHPC from 16 weeks’ gestation. She had a spontaneous PTD at 29 weeks, and that child is developing normally by her report. She believes that 17-OHPC helped her in her last pregnancy and is anxious about the risk for still another PTD. Consistent with the concept of shared decision-making, you inform her of the results of the recent PROLONG trial and statements on the subject released by professional organizations such as ACOG and the Society for Maternal-Fetal Medicine (SMFM). What options does she have?
17-OHPC may be a possibility in very high-risk women
According to a SMFM statement released in the wake of the PROLONG trial publication, “. . . SMFM believes that it is reasonable for providers to use 17-OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial”.29 Only a few women will have a recurrence risk of PTD over 50%, as was the background event rate in the Meis trial.30 Such a risk level may be suspected, as an example, in women with 2 or more prior early (before 34 weeks) PTDs without intervening term deliveries. Even in those cases, if treatment with 17-OHPC is decided upon, ultrasound cervical surveillance should be added as an additional safety measure. ●