New Hope in Recurrent Miscarriage: Micronized Progesterone

Bleeding in early pregnancy is a worrisome and distressing event for expectant women because of its associations with threatened abortion and ectopic pregnancy. For the clinician, bleeding can also be a frustrating event because little can be offered to stop it. Many treatments (progesterone, estrogen, vitamins, hemostatic drugs) have been attempted, but none have been shown to improve the outcomes of pregnancies complicated by early bleeding.

Exogenous Progesterone

A recent randomized trial^[1] sought to determine whether exogenous progesterone supplementation in early pregnancy complicated by vaginal bleeding results in higher live birth rates. Progesterone is a key hormone for maintenance of pregnancy. In the first trimester it is primarily secreted by the corpus luteum. At week 7-8 of gestation there is a shift in synthesis to the placenta.^[2] Supplementing with progesterone is a requirement during assisted reproduction and has often been used to manage bleeding during early pregnancy, based on small studies.

In the largest study of its kind ever conducted, Coomarasamy and colleagues enrolled more than 4000 women (aged 16-39) with early pregnancy (< 12 weeks) vaginal bleeding and an intrauterine pregnancy confirmed by ultrasound. The women were randomly assigned to receive either 400 mg micronized vaginal progesterone or matching placebo up to week 16 of gestation. Randomization was balanced for maternal age (< 35 vs ≥ 35 years), body mass index (< 30 vs ≥ 30 kg/m²), gestational age (< 42 vs ≥ 42 days) and amount of bleeding. The primary outcome was the rate of live birth after 34 weeks.

Baseline characteristics of the two groups were similar. The following key findings were obtained:

The incidence of live birth was similar: 75% (progesterone) vs 72% (placebo).
Miscarriage rates were comparable: 20% vs 22%.
Live birth rates of women who received progesterone and who had up to two previous miscarriages were comparable to the birth rates of women who took placebo.
Live birth rates of women who received progesterone and who had three or more previous miscarriages were 15% higher (72% vs 57%) than those of women who took placebo.
Subgroup analyses (based on age, BMI, gestational age, amount of bleeding, etc.) revealed no differences.

The study's conclusion was that vaginal micronized progesterone did not increase the chance of live birth among women with first-trimester vaginal bleeding and documented intrauterine pregnancy.

Viewpoint

Progesterone has important roles in preparing the endometrium for implantation and maintaining the maternal-fetal connection. Progesterone can be supplemented as oral, subcutaneous, or vaginal products. Exogenously administered progesterone can entirely replace the physiologic secretion as seen in artificial frozen embryo transfer cycles.^[3]

Bleeding in early pregnancy may indicate a problem with the embryo or could be a sign of insufficient progesterone supply to maintain the embryo-uterus connection. The latter can also be the consequence of an abnormal pregnancy, which isn't able to maintain sufficient progesterone secretion. Whether cause or consequence, inadequate progesterone is the salient factor in early bleeding.

Progesterone supplementation in the setting of bleeding may be beneficial for its uterine-relaxing and immunomodulatory effects.^[4] The use of progesterone to prevent recurrent miscarriages is controversial, with a recent large randomized controlled trial not finding a benefit.^[5] To the contrary, this study found a benefit with progesterone, but only among those with bleeding and history of three or more miscarriages.

In summary, this study offers three important conclusions: Most early pregnancies complicated by bleeding will progress to delivery even without active treatment. Progesterone overall does not increase the chance of having a live birth. Women with three or more pregnancy losses may benefit from vaginal progesterone supplementation.

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