Progestogen for preventing miscarriage
The use of progestogens in early-to-mid pregnancy does not prevent a threatened miscarriage. However, a small study has found that progestogen administration may decrease the risk of miscarriage in women who have experienced recurrent miscarriages.
RHL Commentary by Thach TS
1. EVIDENCE SUMMARY
The review analysed data from 14 randomized controlled trials involving 1988 women. Most rials included women at some level of perceived increased risk of miscarriage (previous miscarriage, threatened abortion, uterine procedure such as amniocentesis).
There was no statistically significant difference in the risk of miscarriage between groups receiving progestogen or a placebo. 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, progestogen administration showed a small but statistically significant decrease in the miscarriage rate compared with placebo (OR 0.37; 95%CI 0.17–0.91) in a sub-group of women who had experienced recurrent miscarriages, defined as patients who had suffered three or more consecutive miscarriages. These result should be interpreted with caution because the number of subjects was small and the confidence interval wide.
The findings of the review remain unchanged when the data from a recent trial (1) are also taken into account.
No maternal adverse effect was identified. While slightly more fetal/neonatal adverse events, namely fetal abnormalities and neonatal deaths were identified among women receiving progestogen, the number was far too small—partly because of the rarity of such events—to qualify as a potential risk.
Threatened miscarriage—the most common clinical situation necessitating progestogen treatment—was not separately analysed in the review. In a recent meta-analysis, Sotiriadis and colleagues (2) did not find statistically significant reduction in miscarriage rate among threatened miscarriages who received progestogen treatment (OR 1.1; 95%CI 0.92–1.31). A sub-group analysis for those having sonographic evidence of fetal heart activity at presentation yielded a similar result (2).
2. RELEVANCE TO UNDER-RESOURCED SETTINGS
2.1. Magnitude of the problem
In Viet Nam, where induced abortion has been legal and available on request since 1960, unsafe abortion and miscarriage are still the fourth leading cause of maternal mortality (3). The administration of progestogen for the treatment of threatened miscarriage is an example of empirical treatment despite sound evidence. It is almost impossible to estimate the accurate percentage of physicians who prescribe progestogens in case of threatened abortion. Apart from the widespread use of progestogens for luteal support in assisted reproduction technique schemes, these drugs are still being given for threatened miscarriage and to prevent preterm birth (4). Progestogen is among the most commonly used drug in pregnancy in France (5), and almost one third of women with threatened abortion are prescribed progestogen in Italy (6). Unlike in industrialized countries, most health workers and policy-makers in developing countries do not have easy access to the latest reliable information on effective care (7); therefore, it is likely that in developing countries the extent of this practice may be even wider.
2.2. Applicability of the results
There is no biological basis to believe that the findings of this review may not be applicable to developing countries, despite the fact that all trial included in the review were conducted in developed countries.
There may be some subgroups of women such as those with recurrent miscarriage who might benefit from progestogen treatment although that needs confirmation through further research as well.
2.3. Implementation of the intervention
To remove progestogen from the treatment list for threatened miscarriage, 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 any women presenting with threatened miscarriage.
To institute the use of progestogen therapy for recurrent miscarriage, treatment protocol for reproductive health care will need to be standardized and periodically updated by appropriate authorities, using an evidence-based approach.
Better knowledge of physiopathological mechanisms of miscarriage, in particular of recurrent miscarriage, needs to be generated in order to develop appropriate therapies. The long-term maternal and neonatal/fetal adverse effects of progestogen administration in early stage of pregnancy also warrant further investigation. Additionally, randomized controlled trials are needed to respond to the following problems:
(1) What is the efficacy of progesterone treatment in terms of increasing live birth rate among women with recurrent miscarriage?
(2) What alternative treatments may be used to treat threatened abortion, especially recurrent miscarriage?
- Kalinka J and Szekeres-Bartho J. The impact of dydrogesterone supplementation on hormonal profile and progesterone-induced blocking factor concentrations in women with threatened abortion. American journal of Reproductive Immunology 2005;53:166–171.
- Sotiriadis A, Papatheodorou S and Makrydimas G. Threatened miscarriage: evaluation and management. British Medical Journal 2004;329:152–155.
- World Health Organization Regional Office for Western Pacific. Maternal mortality in Vietnam 2000–2001: an in-depth analysis of cause and determinants. ;2005.
- Dodd JM, Flenady V, Cincotta R, Crowther CA. Prenatal administration of progesterone for preventing preterm birth. The Cochrane Database of Systematic Reviews;2006, Issue 1.
- 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, and Lumbiganon P. Evidence-based reproductive health in developing countries. The WHO Reproductive Health Library, No. 8. Geneva: World Health Organization.
This document should be cited as: Thach TS. Progestogen for preventing miscarriage: RHL commentary (last revised: 8 March 2006). The WHO Reproductive Health Library; Geneva: World Health Organization.