Abstract This guideline was written on the basis of research and clinical examination. Thus, its seems appropriate to use all the encouraging evidence obtained, and the European expert group formulated the guidelines in the form of a summary outline, aiming to give guidance to gynecologists, obstetricians, and reproductive medicine specialists in the prevention or treatment of miscarriage to benefit pregnancies at risk. A large number of statements, opinions and guidelines have been published on this topic, which are not entirely consistent. Terminology and definitions The guidelines describe two types of miscarriage: (1) Pre-eclampsia (2) Recurrent (habitual) miscarriage (1) Pre-eclampsia is the diagnosis of a patient with a pregnancy that occurs before 20 weeks of gestation with vaginal bleeding and no cervical dilation or loss. These patients may present with spotting or heavy vaginal bleeding lasting from a few hours to a few days. The time span is up to 24 weeks of gestation. (2) Recurrent (habitual) miscarriage is defined as a history of 2 or more consecutive spontaneous obstetric abortions (RCOG, or defined as 3 or more consecutive recurrent spontaneous abortions. Hormonal and biochemical background Progesterone is a dominant hormone in the human body during pregnancy. It is necessary not only for conception and implantation, but also for the entire period of pregnancy until termination. Early pregnancy is characterized by luteal activity (until the 8th week), after which progesterone production and secretion shifts to the placenta, forming the so-called luteal to placental transition between the 8th and 12th week of gestation. During this period, circulating endogenous progesterone may be stable or even decreased. At this time, most of the clinical signs of pre-eclampsia or recurrent (habitual) miscarriage may occur. Biologically speaking: endogenous progesterone levels are low during this period, especially when luteal function is limited or delayed and/or when placental progesterone production and secretion are inadequate resulting in luteal transplacental disturbances. Also in the case of ovulation induction, most of the progesterone may be very high at the beginning, with a rapid decrease in progesterone leading to bleeding with progesterone withdrawal, the clinical sign underlying preterm abortion. Overall, spontaneous abortions in early pregnancy are as high as 10C20% . Women with multiple risk factors (e.g., luteal insufficiency, all women undergoing ART operations (e.g., IVF and ICSI)), women with a history of recurrent (habitual) miscarriages, and women with somewhat stressed pregnancies present with reduced endogenous progesterone. Treatment of women with pre-eclampsia pregnancies The Cochrane review by Wahabi et al. for progesterone for pre-eclampsia and subsequent updates was reviewed.The Wahabi Cochrane review on progesterone for pre-eclampsia included only two vaginal progesterone studies (84 participants). The first study was conducted by Gerhard et al. This study compared vaginal progesterone suppositories 25 mg twice daily with placebo, given to pregnant women until 14 days after miscarriage or cessation of bleeding. Only 34/56 women had ultrasonographically confirmed fetal viability and were therefore included in the meta-analysis. The progesterone used followed pharmaceutical procedures since 1976. The second study compared progesterone vaginal particulate gel 90 mg once daily with placebo, both used for 5 days, and all participants met the inclusion criteria for the meta-analysis. The final conclusion was reached that there was no evidence of effectiveness of vaginal progesterone administration in reducing the risk of miscarriage compared with placebo (relative risk 0.47; 95% confidence interval [CI] 0.17-1.30). Therefore, there is no evidence to support the routine use of vaginal progesterone for the treatment of preterm abortion. The authors concluded, based on limited data from two methodologically inferior trials, that there was no evidence to support the routine use of progesterone for the treatment of preterm abortion. Wahabi updated the Cochrane review in 2011 to include two additional recently published dydrogesterone trials, and [19] increased the number of participants from 84 to 421. The incidence of spontaneous abortion was reduced with progestogen compared with placebo or no treatment (risk ratio [RR] 0.53; 95% confidence interval [CI] 0.35-0.79). It was concluded that progestogen was effective in treating preterm abortion without evidence of increased incidence of gestational hypertension, antepartum hemorrhage, or congenital malformations in the newborn. However, the degree of certainty of the meta-analysis was limited by the study. The third systematic review conducted by Carp [20] included the largest number of participants (n=660 from five dydrogesterone trials) and provided more robust findings compared to the two previous systematic reviews. The results demonstrated a statistically significant reduction in miscarriage rates with a ratio of 0.47 for didrogestrel compared with standard care (confidence interval [CI] = 0.31-0.7). Notably, it was not possible to assess bias as both included trials were published as early as 1967. However, excluding both trials from the meta-analysis still showed that the incidence of miscarriage was lower in the treatment group compared with standard care (ratio of 0.42, [CI] = 0.25-0.69). In conclusion, for women with a clinical diagnosis of preterm abortion, there are now meta-analytic data from several small studies showing superiority of progestin (i.e., dydrogesterone) over placebo or no treatment in reducing the rate of spontaneous abortion. This covers the critical area of luteinizing-placental progesterone conversion. Additional well-designed studies are recommended to corroborate these findings.