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

Results

From 30 March 2016 through May 2018, 1135 women were assessed for eligibility, of which 729 women were excluded and 406 consented to participate (Figure 1). Two hundred and three women were randomly assigned to the progestogen group and another 203 randomly assigned to the placebo group; 47 of them in total were lost to follow-up. Baseline characteristics were similar in the two groups (Table I). The mean (± SD) duration of treatment was 4.9 ± 1.6 weeks in the progestogen group and 4.8 ± 1.6 weeks in the placebo group. The results showed that 70.9% (144 out of 203) and 53.7% (109 out of 203) of women in the progestogen and placebo groups had drug compliance of >80%, respectively.

Figure 1.

CONSORT flowchart for a randomized double-blind controlled trial of oral progestogen versus placebo in women with threatened miscarriage in the first trimester.

Primary Outcome

The primary outcome is the miscarriage rate before 20 weeks of gestation. There were 21 and 26 women who defaulted all follow-ups in the progestogen and placebo groups, respectively. We included all 406 women in the analysis for the primary outcome as an ITT analysis. The primary outcomes of those who defaulted all follow-ups were traced from the electronic patient record system if available, and those where the primary outcomes were not traceable or ended up in termination of pregnancy were counted as miscarriage in the analysis. The miscarriage rates were 12.8% and 14.3% in the progestogen and placebo groups, respectively (RR 0.897, 95% CI 0.548–1.467; P = 0.772) (Table II). Analysis of the primary outcome with PP (n = 331) showed similar results.

Of those who had miscarriage, only 10 women could save tissue mass for chromosomal analysis of which four were found to have chromosomal abnormality, four of them revealed no villus for further testing, and two of them showed normal results.

Subgroup analyses of women aged ≥35 years, having positive foetal cardiac pulsations on ultrasound, those with drug compliance of >80% and exclusion of abnormal foetal karyotypes did not show a significant difference in the miscarriage rate between the two groups (Table II).

The primary outcome was not available in nine and eight women in the progestogen group and the placebo group, respectively. There are four possible hypothetical outcomes (Supplementary Table SI). A significant difference in the primary outcome between the two groups in favour of the progestogen group was only found when all nine women in the progestogen group did not have miscarriage and all eight women in the placebo group had miscarriage.

Secondary Outcomes

There were 334 live births in total, and the live birth rates were similar in both groups (Table III). There was one intrauterine death in the placebo group, which was an intrauterine death of the first twin at 28 weeks of gestation in a twin pregnancy, and the remaining twin was delivered by lower segment Caesarean section at term. There were no significant differences in all secondary outcomes by ITT or PP analysis (Table III).

Side Effects and Adverse Drug Reactions

There were no significant differences between the two groups in the side effects, including nausea and vomiting, headache and dizziness (Table IV). Three cases of adverse drug reactions/drug allergy were noted. One woman in the progestogen group developed a skin rash over her face, trunk and upper limbs after 13 days of medications and her condition resolved after stopping the medication. Another woman in the placebo group developed an itchy skin rash on limbs after 1 day of medication and the condition resolved after cessation of medication. The third woman in the progestogen group developed an oral ulcer 3 days after commencement of dydrogesterone. She was subsequently managed by the medical team for severe oral ulcers with impression of drug-induced oral mucositis or Herpes simplex virus infection.

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