Abstract
Miscarriage, or spontaneous abortion, is an extremely distressing experience. 1,2 Most sources report that 10% to 15% of pregnancies result in miscarriage; however, the true prevalence may be much higher, as many pregnancies terminate before being clinically recognized. 1,3 Physiologic studies have suggested that low progesterone levels may be associated with miscarriage, resulting in the use of progestins in the first trimester of pregnancy to try to prevent this common complication. 1,4
This article provides a brief overview of the use of progestins for the prevention of miscarriage, with the aim of addressing some of the common questions that pharmacists may need to discuss with patients.
Case
Sherrie is a 29-year-old female who presents with a prescription for progesterone 100 mg vaginal suppositories to be used twice daily for eight weeks. After talking with her, you determine that she has had three previous miscarriages and has just found out that she is pregnant. The doctor at the fertility clinic told her that she is at high risk of miscarrying again, and that this drug might help prevent another spontaneous abortion. Sherrie is quite anxious and wants to know if this is a safe and effective therapy.
Rationale
During the luteal phase of the menstrual cycle, progesterone is responsible for inducing endometrial changes that are required for successful embryo implantation. 1,4 It is also accepted that progesterone is crucial to the maintenance of an established pregnancy. 2 Therefore, it would seem logical that exogenous progesterone replacement would help sustain a pregnancy in cases where endogenous secretion is inadequate.
Efficacy
A recent systematic review and meta-analysis examined the efficacy and safety of using progestins for the prevention of miscarriage. Fourteen trials (which included 1098 women) were assessed in the meta-analysis. 4
Overall, there was no significant difference in the miscarriage rate between women who received a progestin and those who received a placebo (OR 1.05, 95% CI 0.83 to 1.34). Nor was a benefit shown for women receiving a progestin via any specific route of administration (i.e., oral, intramuscular, or vaginal) when a subgroup analysis of results was carried out. However, a statistically significant decrease in the rate of miscarriage, albeit small, was demonstrated for women taking progestin when a subgroup analysis was performed on those with a history of three or more consecutive miscarriages (OR 0.39, 95% CI 0.17 to 0.91). This positive finding is tempered by the fact that the number of women in this subgroup analysis was small (n = 93), and the confidence interval was wide.
Fetal effects
Despite early reports of several adverse fetal effects (e.g., cardiac malformations; penile, urethral, and psychosexual developmental abnormalities in males) associated with exposure to progestins in utero, current evidence does not confirm such risks. 4 –6 However, progestins that are 19-nortestosterone derivatives (e.g., norethindrone, norgestrel) may be associated with an increased risk of transient clitoral hypertrophy in females. 5,6
Indications for use
Based on available data, the routine use of progestins to prevent miscarriage is not justified. 4 Women who may benefit from therapy are those with a history of unexplained recurrent miscarriage, especially when progesterone levels in early pregnancy are low. 2,4 Nonetheless, evidence from large, randomized, controlled trials is required to confirm a positive effect in this subgroup of patients.
Dose and administration
Given the lack of conclusive data, it remains unclear if any particular progestin (e.g., progesterone, medroxyprogesterone) has advantages over another. It is also unclear what the most appropriate route, dose, and duration of progestin should be in women who may benefit from therapy.
A vaginal progesterone gel (Crinone) is approved and commercially marketed for use in women who require luteal phase support during induced cycles (e.g., in vitro fertilization). 7 The recommended dose is 90 mg once or twice daily, which may be continued for 10 to 12 weeks after pregnancy occurs. 7 Although the specific indication for this product is not completely analogous to women with unexplained recurrent miscarriage, similar dosing may be reasonable in both situations.
Pharmacist's role
Explain to Sherrie that the existing information regarding the use of progesterone to prevent miscarriage is not definitive, but that there is some information to suggest that it may be beneficial for women who have experienced recurrent miscarriage. Sherrie should be told that progesterone does not appear to increase the risk of having a child with a birth defect, although the use of synthetic progestins has been associated with transient enlargement of the clitoris in females. In the current situation, the potential benefits of therapy likely outweigh the risks. Close follow-up with her obstetrician/gynecologist should be encouraged.