Abstract
Study question
In women with threatened miscarriage, does progesterone supplementation increase the probability of live birth?
Summary answer
In women with threatened miscarriage, 400 mg progesterone nightly, from onset of bleeding until 12 weeks, did not increase live birth rates.
What is known already
Women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg. A recently published large randomised clinical trial indicated no overall benefit for progesterone until 16 weeks, although subgroup analysis in women with bleeding and at least one previous miscarriage, progesterone might be of benefit (Coomarasamy et al; N Engl J Med 2019;380:1815-1824).
Study design, size, duration
We performed a single centre placebo-controlled randomised clinical trial. After informed consent, women with threatened miscarriage as apparent from vaginal bleeding under 10 weeks, were randomised to 400 mg vaginal micronized progesterone or placebo. The primary endpoint was livebirth. Secondary endpoints were perinatal outcomes, including preterm birth and birthweight. The planned sample size was 386 women. At a planned interim analysis randomisation was halted at 278 women due to lack of effectiveness and slow recruitment.
Participants/materials, setting, methods
Between February 2012 and April 2019 we randomised 139 women to 400 mg vaginal micronized progesterone and 139 women to placebo. Primary outcome data are available for 134 women in the progesterone arm and 130 women in the placebo arm. Mean age was 30.7 and 30.4 years. The number of women without a previous miscarriage was 68 (51%) and 55 (42%), while 66 (49%) and 75 (58%) women had at least one previous miscarriage.
Main results and the role of chance
The live birth rates were 113/134 (84.3%) and 112/130 (86.2%), respectively (RR 0.98, 95% CI 0.89-1.08). Among women with at least 1 miscarriage live birth rates were 55/66 (83.3%) and 65/75 (86.7%) (RR 0.96, 95% CI 0.84-1.11). The number of women with more than 1 miscarriage was limited (26 vs 33 in total), but no effect was seen from progesterone in these women. Preterm birth rates were 12.9% and 9.3% (RR 1.38; 95% CI 0.69 to 2.78). There were five pregnancy losses between 20 and 23 weeks, all in the progesterone arm. Mean birth weight was 3310 vs 3300 gram (p=.99). There were also no other differences in obstetric and perinatal outcomes. Anxiety, stress and depression scores did not differ between the groups.
Limitations, reasons for caution
Our study was single centre and did not reach the planned sample size. We stopped study medication at 12 weeks which might explain the difference between our study and studies that continued progesterone till 16 weeks.
Wider implications of the findings
In women with threatened miscarriage, 400 mg vaginal progesterone did not improve live birth rates.
Trial registration number
ACTRN12611000405910
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