Abstract and Introduction
Abstract
Study Question: In women with threatened miscarriage, does progesterone supplementation until the completion of the first trimester of pregnancy increase the probability of live birth?
Summary Answer: In women with threatened miscarriage, 400 mg vaginal progesterone nightly, from onset of bleeding until 12 weeks, did not increase live birth rates.
What is Known Already: Limited evidence has indicated that vaginal micronized progesterone may make little or no difference to the live birth rate when compared with placebo in women with threatened miscarriage. Subgroup analysis of one recent randomized trial reported that in women with bleeding and at least one previous miscarriage, progesterone might be of benefit.
Study Design, Size, Duration: We performed a randomized, double-blinded, placebo-controlled trial between February 2012 and April 2019. Eligible pregnant women under 10 weeks gestation, experiencing a threatened miscarriage as apparent from vaginal bleeding were randomized into two groups in a 1:1 ratio: the intervention group received 400 mg progesterone as vaginal pessaries, the control group received placebo vaginal pessaries, both until 12 weeks gestation. The primary endpoint was live birth. We planned to randomize 386 women (193 per group). The study was stopped at a planned interim analysis for futility after randomization of 278 women.
Participants/Materials, Setting, Methods: This trial was conducted at the Mater Mothers' Hospital, a tertiary centre for maternity care in South Brisbane, Queensland, Australia. We randomized 139 women to the intervention group and 139 women to the placebo group. Primary outcome data were available for 136 women in the intervention group and 133 women in the placebo group.
Main Results and the Role of Chance: The live birth rates were 82.4% (112/136) and 84.2% (112/133) in the intervention group and placebo group, respectively (risk ratio (RR) 0.98, 95% CI 0.88 to 1.09; risk difference −0.02, 95% CI −0.11 to 0.07; P = 0.683). Among women with at least one previous miscarriage, live birth rates were 80.6% (54/67) and 84.4% (65/77) (RR 0.95, 95% CI 0.82–1.11; P = 0.550). No significant effect was seen from progesterone in women with two (RR 1.28, 95% CI 0.96–1.72; P = 0.096) or more (RR 0.79, 95% CI 0.53–1.19; P = 0.267) previous miscarriages. Preterm birth rates were 12.9% and 9.3%, respectively (RR 1.38; 95% CI 0.69 to 2.78; P = 0.361). Median birth weight was 3310 vs 3300 g (P = 0.992). There were also no other significant differences in obstetric and perinatal outcomes.
Limitations, Reasons for Caution: Our study was single centre and did not reach the planned sample size because it was stopped prematurely at an interim analysis.
Wider Implications of the Findings: We did not find evidence supporting the treatment effect of vaginal progesterone in women with threatened miscarriage. Progesterone in this setting should not be routinely used for threatened miscarriage. The treatment effect in women with threatened miscarriage after previous miscarriages warrants further research.
Study Funding/Competing Interest(S): Mothers' and babies Golden Casket Clinical Fellowship (L.A.M.). Progesterone and placebo pessaries were provided by Perrigo Australia.
B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work.
Trial Registration Number: ACTRN12611000405910
Trial Registration Date: 19 April 2011
Date of First Patient's Enrolment: 06 February 2012
Introduction
Threatened miscarriage, apparent from vaginal bleeding with or without lower abdominal pain, affects ~25% of all clinical pregnancies (Hasan et al., 2009). Around one-quarter of threatened miscarriages will proceed to a complete miscarriage over the ensuing weeks of pregnancy (Dede et al., 2010; Duan et al., 2011). When the pregnancy continues, women who experience a threatened miscarriage are at increased risk of adverse pregnancy outcomes including pregnancy loss, antepartum haemorrhage, preterm delivery, perinatal mortality and low-birthweight babies (Jauniaux et al., 2010; Saraswat et al., 2010).
Miscarriage can be a significant loss for a woman and her partner and can be related to longer-term sequelae such as depression, anxiety, and delay in pursuing pregnancy (Thapar and Thapar, 1992). With the exception of anticoagulants for women with persistent antiphospholipid antibodies (Hamulyák et al., 2020) and perhaps progesterone for women with multiple miscarriages (Haas et al., 2019), there is presently no agreed therapeutic approach which has been shown to reduce the risk of pregnancy loss in women who present with a threatened miscarriage.
Progesterone is important for the establishment and maintenance of pregnancy. Its presence creates a mature endometrium and a favourable immune environment for early embryonic development. Women with recurrent miscarriage have particularly low endometrial progesterone levels (Salazar and Calzada, 2007). Also, progesterone levels have been observed to be lower in pregnancies that subsequently end in miscarriage (Arck et al., 2008), but it is not known whether the lower levels are merely predicting a poor pregnancy outcome or are causative (Duan et al., 2011).
Caution needs to be exercised in using hormones in the early embryological and organogenesis stage of development. There has been concern regarding the use of progestins in pregnancy, particularly with respect to the potential for genital (hypospadias in males and female virilization) and non-genital anomalies (Carmichael et al., 2005). On the other hand, progesterone could be effective in decreasing the miscarriage rate.
A recent Cochrane review that included only two placebo-controlled randomized trials found that in women with threatened miscarriage vaginal micronized progesterone increased the live birth rate, although the treatment effect was small and non-significant (risk ratio (RR) 1.03, 95% CI 1.00 to 1.07) (Devall et al., 2021). The treatment effect was more evident in women with one or more previous miscarriages. These findings were predominantly driven by one large randomized trial that yielded the same conclusions (Coomarasamy et al., 2019).
We performed a placebo-controlled randomized trial to further elucidate the treatment effect of vaginal progesterone in women with threatened miscarriage.
Hum Reprod. 2023;38(4):560-568. © 2023 Oxford University Press
