What is the issue?
Spontaneous miscarriage occurs in about 15% to 20% of pregnancies. Threatened miscarriage occurs when a mother might be losing her baby at less than 20 weeks' gestation. The symptoms of threatened miscarriage are vaginal bleeding, with or without abdominal pain, while the cervix of the womb is closed and the baby inside the womb is alive. Progesterone is a hormone that is known to prepare the uterus for implantation of the fertilized egg and suppress uterine contractions until term. Medications that mimic the action of progesterone are known as progestogens. Treatment with progestogens may be effective in reducing the rate of miscarriage in women who have threatened miscarriage. This Cochrane Review examines whether progestogens could reduce miscarriage for women with threatened miscarriage, and also addresses the safety of these medications for mother and baby.
Why is this important?
We were interested to investigate if progestogens are effective and safe in the treatment of threatened miscarriage, which may increase the women's chances of having a successful pregnancy and a live birth.
What evidence did we find?
In this review of the literature, up to August 2017, we identified seven randomised trials involving 696 women that compared the use of progestogens in the treatment of threatened miscarriage with either placebo or no treatment. We found that the use of a progestogen probably reduces the rate of spontaneous miscarriage and this was supported by moderate-quality evidence. Five trials, involving 588 women, reported on the effectiveness of progestogens given for threatened miscarriage in reducing the rate of preterm delivery and showed little or no effect, with low-quality evidence. Two trials, involving 337 women, reported on the effect of treatment with progestogens given for threatened miscarriage on the rate of occurrence of congenital abnormalities in the newborns. The evidence on congenital abnormalities is uncertain, because the quality of the evidence for this outcome was based on only two small trials with very few events and was found to be of very low quality.
What does this mean?
The evidence suggests that progesterone probably reduces the rate of spontaneous miscarriage but may make little or no difference to the number of preterm deliveries. The evidence for congenital abnormalities is uncertain because the quality of the evidence for this outcome was based on only two small trials with very few events and was found to be of very low quality.
The results of this Cochrane Review suggest that progestogens are probably effective in the treatment of threatened miscarriage but may have little or no effect in the rate of preterm birth. The evidence on congenital abnormalities is uncertain, because the quality of the evidence for this outcome was based on only two small trials with very few events and was found to be of very low quality.
Miscarriage is a common complication encountered during pregnancy. It is defined as spontaneous pregnancy loss before 20 weeks' gestation. Progesterone's physiological role is to prepare the uterus for the implantation of the embryo, enhance uterine quiescence and suppress uterine contractions, hence, it may play a role in preventing rejection of the embryo. Inadequate secretion of progesterone in early pregnancy has been linked to the aetiology of miscarriage and progesterone supplementation has been used as a treatment for threatened miscarriage to prevent spontaneous pregnancy loss. This update of the Cochrane Review first published in 2007, and previously updated in 2011, investigates the evidence base for this practice.
To determine the efficacy and the safety of progestogens in the treatment of threatened miscarriage.
Randomised, quasi-randomised or cluster-randomised controlled trials, that compared progestogen with placebo, no treatment or any other treatment for the treatment of threatened miscarriage in women carrying singleton pregnancy.
At least two review authors assessed the trials for inclusion in the review, assessed trial quality and extracted the data and graded the body of evidence.
We included seven trials (involving 696 participants) in this update of the review. The included trials were conducted in different countries, covering the full spectrum of the World Bank's economic classification, which enhances the applicability of evidence drawn from this review. Two trials were conducted in Germany and Italy which are high-income countries, while four trials were conducted in upper-middle income countries; two in Iran, one in Malaysia and the fourth in Turkey, and the seventh trial was conducted in Jordan, which is a lower-middle income country. In six trials all the participants met the inclusion criteria and in the seventh study, we included in the meta-analysis only the subgroup of participants who met the inclusion criteria. We assessed the body of evidence for the main outcomes using the GRADE tool and the quality of the evidence ranged from very low to moderate. Downgrading of evidence was based on the high risk of bias in six of the seven included trials and a small number of events and wide confidence intervals for some outcomes.
Treatment of miscarriage with progestogens compared to placebo or no treatment probably reduces the risk of miscarriage; (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.47 to 0.87; 7 trials; 696 women; moderate-quality evidence). Treatment with oral progestogen compared to no treatment also probably reduces the miscarriage rate (RR 0.57, 95% CI 0.38 to 0.85; 3 trials; 408 women; moderate-quality evidence). However treatment with vaginal progesterone compared to placebo, probably has little or no effect in reducing the miscarriage rate (RR 0.75, 95% CI 0.47 to 1.21; 4 trials; 288 women; moderate-quality evidence). The subgroup interaction test indicated no difference according to route of administration between the oral and vaginal subgroups of progesterone.
Treatment of preterm birth with the use of progestogens compared to placebo or no treatment may have little or no effect in reducing the rate of preterm birth (RR 0.86, 95% CI 0.52 to 1.44; 5 trials; 588 women; low-quality evidence).
We are uncertain if treatment of threatened miscarriage with progestogens compared to placebo or no treatment has any effect on the rate of congenital abnormalities because the quality of the evidence is very low (RR 0.70, 95% CI 0.10 to 4.82; 2 trials; 337 infants; very-low quality evidence).