It is well known that progesterone (progesterone for short) is a female hormone that belongs to the progesterone (also known as luteinizing hormone) class. Luteinizing hormone can cause secretory-like changes in the endometrium affected by estrogen, which is one of the essential prerequisites for the successful implantation of a fertilized egg. It is believed that a significant proportion of women who have spontaneous abortions during early pregnancy are due to insufficient secretion of their own luteinizing hormones. Therefore, over the years, progesterone has been quite commonly used clinically in both developed and developing countries, including China, as a drug to prevent and treat miscarriage in early to mid-term pregnancies. So, is progesterone really effective in the prevention and treatment of miscarriage? Professors Haas and Wahab et al. searched all relevant databases worldwide for information on randomized and semi-randomized controlled trials comparing progesterone with placebo (or no treatment) for the prevention and treatment of miscarriage; to obtain the necessary information, the scientists also talked to the authors of some of the published papers; and contacted experts in the field to find any unpublished articles. Based on this information, they made an evidence-based medical evaluation of this. According to the results of the search, 15 randomized controlled trials with 2,118 cases at high risk of miscarriage (pre-eclampsia or previous history of miscarriage, previous surgery involving the uterus such as amniocentesis, etc.) were included in the analysis; in addition, a study was included in which 180 women with previous recurrent miscarriages were randomly assigned to receive either an oral progestin (didrogestrel) group, an intramuscular human chorionic gonadotropin group, or no treatment (control ) group for a trial to observe pregnancy outcomes. The results of the analysis showed that (i) there was no statistically significant difference in the reduction of the risk of miscarriage between the group receiving progestogen and the placebo or no treatment groups [Peto ratio (Peto
OR) was 0.98; 95% confidence interval (CI): 0.78C1.24]. (ii) Similarly, different routes of progestin administration, oral, intramuscular or vaginal, did not show a statistically significant difference in reducing the occurrence of miscarriage. (iii) Interestingly, four small trials (three published 40 years ago and one published in 2005) reported that in subgroups of women with previous recurrent miscarriages, progestin administration resulted in a statistically significant reduction in miscarriage rates compared to the placebo group (OR 0.37; 95%
CI: 0.17C0.91). ④ Progestin application did not have any adverse effects on women. Although a slight increase in subsequent fetal, neonatal adverse outcomes (e.g., fetal malformations and neonatal deaths) has been identified in women treated with progestins, the number of cases is too small (in part because such adverse outcomes are uncommon) to be identified as potentially dangerous. 5 A separate analysis involving only two studies of low methodological quality, 84 cases of preterm abortion (the most common clinical diagnosis requiring progestin therapy), suggested that there was no evidence that progesterone vaginal dosing was effective in reducing the risk of miscarriage in women with preterm abortion (relative risk RR 0.47; 95% CI: 0.17-1.30). Although the four small trials included in this evaluation suggest that progestins may be beneficial for women with previous recurrent miscarriages; however, because of the small number of observed cases, wide confidence intervals, inconsistent definitions of recurrent miscarriage between trials, and inadequate methodology used in three of the older trials, and the 2005 trial was not placebo-controlled, blinded, or adequately randomized; therefore, until a well-designed large trials are confirmed, the results should be interpreted with caution. Finally, these medical experts concluded that progesterone has no preventive or therapeutic effect on miscarriage in early to midterm pregnancies. Also, the medical scientists concluded that all trials included in this evaluation were conducted in developed countries, but the results are applicable to developing countries as well. The results of the above evaluation are most important to raise awareness among policy makers, health care providers and women at risk of miscarriage that there is no evidence-based medical basis for the application of progesterone for the treatment of preterm miscarriage. The evaluation provides guiding recommendations for relevant studies that should be conducted in the future, and further large-scale randomized controlled trials are necessary to answer the following 3 questions: ① What is the effectiveness of progesterone treatment in women with recurrent miscarriage to increase the live birth rate? (ii) Are there any long-term adverse effects of progesterone use in early pregnancy on the mother and the fetus and newborn? (3) What alternatives to progesterone can be used to treat preterm miscarriage, especially recurrent miscarriage?