Progesterone Supplementation for Bleeding in Early Pregnancy–Dr. Ken Moghadam

Many women present with bleeding in early pregnancy.  The term ‘threatened miscarriage’ is used to describe bleeding that presents with a closed cervix on examination.  Ultrasound demonstration of pregnancy location and progression, documentation of blood type (with administration of Rhogam for Rh negative patients), and continued observation are usually sufficient interventions, since the bleeding will often resolve and the pregnancy will continue to flourish in the majority of women experiencing a threatened miscarriage.

Independent of previous fertility treatment, checking hormone levels (hCG, estradiol, and progesterone) is common in the first trimester.  It is also a frequent practice, though not without controversy, to supplement progesterone in patients with a visible gestational sac on ultrasound and a low progesterone level when a threatened miscarriage occurs. The authors of a recent study in the New England Journal of Medicine (Coomarasamy A, n engl j med 380;19 nejm.org May 9, 2019) address this controversy in their latest publication from the PRISM (Progesterone in Spontaneous Miscarriage) trial:

• 48 hospitals in the United Kingdom
  • Pregnant women aged 16 to 39
  • Bleeding at less than 12 weeks of pregnancy (gestation)
  • Visible pregnancy (gestational) sac in the uterus on ultrasound
• Randomized to receive 400mg progesterone twice daily administered vaginally or placebo until 16 weeks gestation
• Both the women and the caregivers were unaware of the randomization (double-blinded study)
• Primary outcome was live birth after at least 34 weeks gestation

It is interesting to note that of the 12,862 women eligible for the study from May 2015 thru July 2017, the majority (8709 women) declined to participate.  This emphasizes both how common and sensitive an issue threatened miscarriage is to research.  Among the remaining 4150 women that were randomized into each group, there was no statistical difference in the primary outcome of live birth (75% with progesterone administration compared with 72% with placebo administration).  Of the secondary outcomes, the only subgroup that seemed to benefit from progesterone over placebo was the group with three or more previous miscarriages (72% live birth with progesterone compared to 57% with placebo).   The authors emphasized that earlier (before a gestational sac is seen) or later (beyond 16 weeks) administration of progesterone was not a focus of their study or conclusions.  They also did not directly comment on fertility patients, although it is possible that many of these women would be excluded due to early use of progesterone.

So how does this study help us?  In general, it is reassuring to note that most threatened miscarriages in the first trimester will flourish regardless of progesterone supplementation.  This is consistent with what we expect once the physiological changes of the first trimester have passed and placental function is better established.   The study may also provide confidence to women who experience bleeding that has either resolved during or after progesterone supplementation and, in the absence of other obstetric indications, are reluctant to discontinue the medication.  It would also seem that women with recurrent miscarriage remain a special subset of pregnant women with first trimester bleeding in which treatment should still be individualized.