Progestogen for preventing miscarriage
Progestogen therapy in early-to-mid pregnancy does not prevent miscarriage. Four small studies included in this review suggest that progestogen therapy may be beneficial for women who have experienced recurrent miscarriages. This finding should be interpreted with caution until it is confirmed in large, well-designed trials.
RHL Commentary by Thach TS
Progesterone plays a key part in preparing the uterus for implantation of the newly fertilized egg. It has been suggested that some women who experience spontaneous abortions may not be producing enough progesterone, so by administering exogenous progesterone it may be possible to prevent miscarriage. In Viet Nam, where induced abortion is available on request since 1960, unsafe abortion and miscarriage are together still the fourth leading cause of maternal mortality (1). Doctors in Viet Nam widely prescribe progestogens for the treatment of threatened miscarriage. Widespread use of progestogens is not limited to under-resourced settings. In France, for example, progesterone is among the most frequently prescribed drug during pregnancy (2), and almost one third of women with threatened abortion are prescribed progestogen in Italy (3). Unlike in developed countries, most health-care workers and policy-makers in developing countries do not have easy access to the latest reliable information on effective care (4). Therefore, it is likely that in developing countries the extent of progestogen use during pregnancy is much greater than in developed countries. The objective of this review was to determine the efficacy and safety of progestogens as a preventative therapy against miscarriage.
The review authors searched all relevant databases for randomized and quasi-randomized controlled trials that had compared progestogens with placebo or no treatment for preventing miscarriage. Where necessary the review authors contacted authors of papers to obtain information. They also contacted experts in the field to identify any unpublished works. Two review authors independently assessed the quality of the available trials.
The current updated review (5) was published in April 2008. It analysed data from 15 randomized controlled trials involving 2118 women who were perceived to be at an increased risk of miscarriage (previous miscarriage, threatened abortion, having undergone a uterine procedure such as amniocentesis, etc.). In this update, new data were included from a trial (6) in which 180 women with recurrent miscarriage were randomized to receive oral dydrogesterone, intramuscular human chorionic gonadotrophin or no treatment (controls).
Overall, there was no statistically significant difference in the risk of miscarriage between groups receiving a progestogen or a placebo/no treatment [Peto odds ratio (Peto OR) 0.98; 95% confidence interval (CI) 0.78–1.24]. Also, the route of administration of progestogen (oral, intramuscular, or vaginal) appeared not to be associated with a statistically significant difference in miscarriage rates. Interestingly, four small trials (three of them published 40 year ago and one published in 2005) reported that progestogen administration was associated with a statistically significant decrease in miscarriage rate compared with placebo (OR 0.37; 95% CI 0.17–0.91) in a subgroup of women who had experienced recurrent miscarriage. The confidence interval suggests that the difference in miscarriage rate between progestogen administration and placebo may be either small or large.
Progestogen therapy was not associated with any adverse effects on the woman. Although slightly more fetal/neonatal adverse events (fetal abnormalities and neonatal deaths) were identified among women receiving progestogen, the numbers were far too small − partly because of the rarity of such events − to qualify as a potential risk.
Threatened miscarriage − the most common clinical diagnosis necessitating progestogen treatment − was analysed separately in another review (7), which includes only 84 participants from two rather methodologically poor studies. There was no evidence of effectiveness of vaginally given progesterone in reducing the risk of miscarriage for women with threatened miscarriage (RR 0.47; 95% CI 0.17−1.30).
Progestogens do not prevent miscarriage in early-to-mid pregnancy. Results from the four small trials showing a positive effect of progestogens in the subgroup of women with recurrent miscarriage should be interpreted with caution because of the small number of subjects in those trials and the wide confidence interval. Moreover, the methods used in the three older trials were inadequate and the 2005 trial (6) was neither placebo-controlled nor blinded nor well randomized. Also, the operative definition of recurrent miscarriage was not consistent between the trials. Finally, the Le Vine trial (8) had a post-randomization dropout rate of 46.4%.
4.1 APPLICABILITY OF THE RESULTS
Despite the fact that all trials included in the review were conducted in developed countries, there is no biological basis to believe that the findings of this review may not be applicable to developing countries.
4.2 IMPLEMENTATION OF THE INTERVENTION
Progestogen should be removed from the treatment list for preventing miscarriage. To do that, the most important step will be to increase awareness among policy-makers, health-care providers and patients about the fact that the practice is not based on evidence. Furthermore, proper counselling will need to be provided to all women presenting with threatened miscarriage. To institute the use of progestogen therapy for recurrent miscarriage, treatment protocols for reproductive health care will need to be standardized and periodically updated by appropriate authorities, using an evidence-based approach.
4.3 IMPLICATIONS FOR RESEARCH
Even though the endocrinological basis of recurrent miscarriage has been studied extensively, there are still gaps in knowledge about physiopathological mechanisms of miscarriage. The long-term maternal and neonatal/fetal adverse effects of progestogen administration in early pregnancy also warrant further investigation. Further large randomized controlled trials are needed to answer to the following questions: What is the efficacy of progesterone treatment in terms of increasing live birth rate among women with recurrent miscarriage? What alternative treatments may be used to treat threatened abortion, especially recurrent miscarriage?
- Maternal mortality in Viet Nam 2000–2001: an in-depth analysis of cause and determinants. Manila: World Health Organization Regional Office for Western Pacific; 2005.
- Beyens MN, Guy C, Ratrema M, and Ollagnier M. Prescription of drugs to pregnant women in France: the HIMAGE study. Therapie 2003;58:505–511.
- Donati S, Baglio G, Spinelli A, and Grandolfo ME. Drug use in pregnancy among Italian women. European Journal of Pharmacology 2000;56:323–328.
- Villar J, Gulmezoglu AM, Khanna J, Carroli G, Hofmeyr GJ, Schulz K, et al. Evidence-based reproductive health in developing countries. The WHO Reproductive Health Library, No. 8. Geneva: World Health Organization.
- Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database of Systematic Reviews 2008; Issue 2. Art. No.: CD003511; DOI: 10.1002/14651858.
- El-Zibdeh MY. Dydrogesterone in the reduction of recurrent spontaneous abortion. Journal of Steroid Biochemistry & Molecular Biology 2005;97(5):431–434
- Wahabi HA, Abed Althagafi NF, Elawad M. Progestogen for treating threatened miscarriage. Cochrane Database of Systematic Reviews 2007; Issue 3. Art. No.: CD005943; DOI: 10.1002/14651858.
- LeVine L. Habitual abortion. A controlled clinical study of progestational therapy. Western Journal of Surgery 1964;72:30–36.
This document should be cited as: Thach TS. Progestogen for preventing miscarriage : RHL commentary (last revised: 2 February 2009). The WHO Reproductive Health Library; Geneva: World Health Organization.