Progestogen for Threatened Miscarriage

• Threatened miscarriage is when a mother might be losing her baby at less than 20 weeks' gestation.
• The signs are vaginal bleeding, with or without abdominal pain, while the cervix is closed.
• The use of ultrasound scans in the management of bleeding in early pregnancy has improved the diagnosis and management, as attempts to maintain a pregnancy are likely to be effective only if the fetus is viable and has no chromosomal abnormalities.
• Once the cervix begins to open, pregnancy loss is inevitable.
• Women who continue with their pregnancy after threatened miscarriage were found to have increased risk of antepartum haemorrhage, pre-labour rupture of the membranes, preterm delivery, and intrauterine growth restriction.

Rationale for progestogen

• Progestogen is an essential hormone both for establishing and maintaining pregnancy
• It has been postulated that some miscarriages are due to corpus luteum deficiency/luteal phase defect (LPD) where the corpus luteum produces a suboptimal amount of progesterone, resulting in retarded endometrial development
• Exogenous progesterone supplementation can occur in various forms such as medroxyprogesterone acetate, 17-alpha-hydroxyprogesterone caproate, progesterone and dydrogesterone
• Various meta-analyses have also been done to study the effects of progestational agents in miscarriage prevention in the general population, with conflicting results

Evidence for Use

• The review of trials located four randomised studies involving 421 women that compared the use of progestogens in the treatment of threatened miscarriage with either placebo or no treatment.
• The limited evidence suggests that the use of a progestogen does reduce the rate of spontaneous miscarriage.
• Two trials reported that treatment with progestogens did not increase the occurrence of congenital abnormalities in the newborns and the women did not have any significant difference in incidence of pregnancy-induced hypertension nor antepartum haemorrhage
• 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.

Evidence against use

• There was no evidence of effectiveness of vaginally given progesterone in reducing the risk of miscarriage for women with threatened miscarriage
• 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
• no evidence for an effect favouring the use of progestagens in women with recurrent miscarriage was found when compared to placebo

Medroxyprogesterone

• FDA has considered it to be a category X drug, which means that it is contraindicated in women who are or may become pregnant.
• The older studies also show no reduction in miscarriage rates with medroxyprogesterone.

17-hydroxyprogesterone caproate

• A review revealed that there was no effect in miscarriage prevention, even in patients who had previously suffered from recurrent miscarriages
• considered a category D drug by the FDA,which means that there is positive evidence of human foetal risk,
• While its use in early trimester for the prevention of miscarriage is contraindicated, its use in pregnancy has been resurrected by recent evidence that it reduces the preterm labour rates in those patients at high risk of preterm labour when administered weekly from 16 gestational weeks onwards.

Dydrogesterone

• A small recent RCT on its use in the context of a threatened miscarriage showed that there was an improvement in outcome with more continuing pregnancies in the treatment group
• no reports of foetal abnormalities other than an isolated incident of a non-virilising abnormality of the genitourinary tract, when dydrogesterone was used together with hydroxyprogesterone caproate.

Recommendations

• based on scarce data there is no evidence to support the routine use of progestagens for the treatment of threatened miscarriage.
• information about potential harms to the mother or child, or both, with the use of progestagens is lacking.
• there has been much speculation about progestagens but the results of these meta-analysis show no statistically significant difference between women receiving progestagens for preventing threatened miscarriage or miscarriage when compared to placebo,

References:

1. Progestogen for preventing miscarriage : RHL commentary (last revised: 2 February 2009). The WHO Reproductive Health Library; Geneva: World Health Organization.
2. Progestogen for treating threatened miscarriage. http://www.cochrane.org/CD005943/PREG_progestogen-for-treating-threatened-miscarriage
3. Non-surgical interventions for threatened and recurrent miscarriages. Singapore Med J 2007; 48(12):1074–1090
4. Use of progestagens during early pregnancy. FVV in ObGyn, 2013, 5 (1): 66-71