Use of Oral Progestogen in Women With Threatened Miscarriage in the First Trimester

A Randomized Double-blind Controlled Trial

Diana Man Ka Chan; Ka Wang Cheung; Jennifer Ka Yee Ko; Sofie Shuk Fei Yung; Shui Fan Lai; Mei Ting Lam; Dorothy Yuet Tao Ng; Vivian Chi Yan Lee; Raymond Hang Wun Li; Ernest Hung Yu Ng

Disclosures

Hum Reprod. 2021;36(3):587-595. 

In This Article

Abstract and Introduction

Abstract

Study Question: Will use of oral progestogen in women with threatened miscarriage in the first trimester reduce the miscarriage rate when compared with placebo?

Summary Answer: Use of oral progestogen in women with threatened miscarriage in the first trimester did not reduce miscarriage before 20 weeks when compared with placebo.

What is Known Already: Miscarriage is a common complication of pregnancy and occurs in 15–20% of clinically recognized pregnancies. Use of vaginal progestogens is not effective in reducing miscarriage but there is still no good evidence to support use of oral progestogen for the treatment of threatened miscarriage.

Study Design, Size, Duration: This was a randomized double-blind controlled trial. A total of 406 women presenting with threatened miscarriage in the first trimester were recruited from 30 March 2016 to May 2018.

Participants/Materials, Setting, Methods: Women attending Early Pregnancy Assessment Clinics because of vaginal bleeding during the first trimester were recruited and randomly assigned to use dydrogesterone 40 mg orally, followed by 10 mg orally three times a day or placebo until 12 completed weeks of gestation or 1 week after the bleeding stopped, whichever was later. The primary outcome was the miscarriage rate before 20 weeks of gestation.

Main Results and the Role of Chance: The two groups of women had comparable age, BMI, number of previous miscarriages, gestation and ultrasound findings at presentation. The miscarriage rate before 20 weeks of gestation was similar in both groups, being 12.8% (26/203) in the progestogen group and 14.3% (29/203) in the placebo group (relative risk 0.897, 95% CI 0.548–1.467; P = 0.772). The live birth rate was 81.3% in the progestogen group versus 83.3% in the placebo group (P = 0.697). No significant differences were found between the two groups in terms of obstetric outcomes and side effects.

Limitations, Reasons for Caution: The primary outcome was the miscarriage rate, rather than the live birth rate. Women were recruited from Early Pregnancy Assessment Clinics and those with heavy vaginal bleeding might be admitted into wards directly instead of attending Early Pregnancy Assessment Clinic. The severity of vaginal bleeding was subjectively graded by women themselves. The sample size was not adequate to demonstrate a smaller difference in the miscarriage rate between the progestogen and placebo groups. We did not exclude women with multiple pregnancy, which increased the risk of miscarriage although there was only one set of twin pregnancy in the placebo group.

Wider Implications of the Findings: Use of oral progestogen is not recommended in women with threatened miscarriage in the first trimester.

Study Funding/Competing Interest(S): This study was funded by the Health and Medical Research Fund, HKSAR (reference number 12132341). All authors declared no conflict of interest.

Trial Registration Number: ClinicalTrials.gov with an identifier NCT02128685.

Trial Registration Date: 1 May 2014.

Date of First Patient's Enrolment: 30 March 2016.

Introduction

Miscarriage is a common complication of pregnancy. It occurs in 15–20% of clinically recognized pregnancies (National Guideline Alliance, 2019) and is associated with significant physical and psychological sequelae (Marcinko et al., 2011; Cheung et al., 2013); In the first trimester, the most common cause of miscarriage is chromosomal abnormalities of foetuses (Stephenson et al., 2002), although in some cases the cause cannot be identified.

Progesterone plays a crucial role in the maintenance of pregnancy. It is secreted by the corpus luteum, which provides early pregnancy support until placental production takes over at around 10 weeks of gestation. Low levels of serum progesterone have been linked to impending miscarriage (Osmanağaoğlu et al., 2010). It has been postulated, therefore, that lack of progesterone is a cause of miscarriage rather than a secondary signal of failing pregnancy.

Threatened miscarriage is manifested by vaginal bleeding, with or without abdominal pain, whereas the cervix is closed and the foetus remains viable inside the uterine cavity (Cunningham, 2001). A Cochrane review which was first published in 2007 and last updated in 2018 (Wahabi et al., 2018) showed that treatment of threatened miscarriage with progestogens compared to placebo or no treatment reduced the risk of miscarriage, with risk ratio (RR) of 0.64 (95% CI 0.47–0.87). The subgroup analysis found that treatment with oral progestogen reduced the miscarriage rate, while treatment with vaginal progesterone had little or no effect in reducing the miscarriage rate. Another recent meta-analysis including more randomized controlled trials reached a similar conclusion (Li et al., 2020).

A recent large randomized double-blind placebo-controlled trial (Coomarasamy et al., 2019) confirmed that that administration of vaginal progestogen for first-trimester threatened miscarriage did not increase live births compared with placebo. However, use of oral progestogen in women with threatened miscarriage during early pregnancy is still controversial and conclusive evidence in supporting its efficacy is needed due to the poor methodological quality of some of the trials and the small number of women (range 72–191) included in the meta-analyses (Wahabi et al., 2018).

Dydrogesterone, a retro-progesterone with very good oral bioavailability, is structurally and pharmacologically very similar to natural progesterone. It is considered suitable for women with threatened miscarriage as, in contrast to other available synthetic progestogens, it does not have androgenic side effects in the mother (e.g. hirsutism, acne) or oestrogenic effects in the foetus (El-Zibdeh and Yousef, 2009). It does not inhibit the formation of progesterone in the placenta (Pandian, 2009).

This randomized double-blind controlled study aimed to compare the miscarriage rate in women presenting with threatened miscarriage in the first trimester with use of oral progestogen versus placebo. The hypothesis is that use of oral progestogen will reduce the miscarriage rate in women presenting with threatened miscarriage in the first trimester.

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