By Ahizechukwu C. Eke, MD, PhD, MPH
Assistant Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: In this double-blind, randomized clinical trial, 406 pregnant women were randomized to dydrogesterone or placebo. There were no statistically significant differences in the primary outcome (miscarriage before 20 weeks of gestation; relative risk, 0.897; 95% confidence interval, 0.548-1.467; P = 0.772), which occurred in 12.8% and 14.3% in the dydrogesterone and placebo arms, respectively. The use of dydrogesterone in women with threatened miscarriage for the prevention of early pregnancy loss in the first trimester failed to decrease the miscarriage rate or increase the live birth rate.
SOURCE: Chan DMK, Cheung KW, Ko JKY, et al. Use of oral progestogen in women with threatened miscarriage in the first trimester: A randomized double-blind controlled trial. Human Reprod 2020: Dec 17;deaa327. doi: 10.1093/humrep/deaa327. [Online ahead of print].
Miscarriage (early pregnancy loss), the loss of an intrauterine confirmed pregnancy before 20 weeks of gestation, occurs in approximately 10% to 25% of all pregnancies.1 A miscarriage usually is a distressing experience, and can be associated with enormous psychologic effect.2 Although there are no proven effective medical therapies to prevent miscarriage, studies have suggested that some women who experience miscarriage have insufficient serum progesterone in early pregnancy.3 Therefore, progestogen supplementation in these women has been suggested for the prevention of early pregnancy loss.3
Progestogens (medications identical to endogenous progesterone) in the form of vaginal suppositories have been studied extensively for the prevention of miscarriage. The rationale for the use of progestogens in the prevention of miscarriage is based on their uterine-relaxant, anti-estrogenic, immunomodulatory, and anti-inflammatory effects. However, there are sparse data to support the use of oral progestogens that are stable in plasma for the prevention of miscarriage. To answer this research question, Chan and colleagues conducted a double-blind, randomized controlled trial in three public hospitals in Hong Kong: Queen Mary, Kwong Wah, and Pamela Youde Nethersole Eastern hospitals.4 Inclusion criteria included women between 18 and 40 years of age presenting with threatened miscarriage (vaginal bleeding with or without abdominal pain, with a viable intrauterine pregnancy determined by gestational sac diameter and crown-rump length) between five weeks and 12 weeks of gestation; absence of fever (temperature ≥ 38.5°C); singleton gestations; and women with a history of one or two prior miscarriages.4 Exclusion criteria included heavy vaginal bleeding; history of recurrent miscarriage (three or more consecutive spontaneous miscarriages); history of known parental chromo-somal abnormalities; severe abdominal pain requiring surgical intervention; absence of fetal tones in a fetus with crown-rump length of ≥ 7 mm on transvaginal ultrasound; use of human chorionic gonadotrophin (hCG)/progestogens for threatened miscarriage prior to recruitment; and women with current or suspected breast or genital cancers, hepatic disease, or tumors.4
Using computer randomization, the participants were randomized to dydrogesterone (Duphaston, Abbott, Chicago) and placebo groups. The dose of the medications (dydrogesterone and placebo) was a 40-mg loading dose, followed by 10 mg three times daily (according to prescription instructions). The primary outcome was miscarriage before 20 weeks of gestation, while secondary outcomes included gestational weight at delivery, live birth rate, Apgar score, and obstetric complications, including antepartum hemorrhage, placenta previa, pregnancy-induced hypertension, preeclampsia, preterm labor, low birthweight at term, and congenital abnormality.4 The participants had weekly follow-up with pelvic ultrasounds until 12 weeks of gestation, missed abortion, severe vaginal bleeding requiring surgical management, or one week after vaginal bleeding ceased, whichever came last. A sample size of at least 171 women per group was sufficient to demonstrate statistically significant differences between the treatment and placebo groups based on a baseline miscarriage prevalence rate of 14.8% in the progestogen group and 27.1% in the control group, assuming 80% power and a type 1 error rate of 5%.
From March 2016 to May 2018, a total of 406 pregnant women met inclusion criteria. A total of 203 women were randomized to the dydrogesterone arm, and 203 were randomized to the placebo group. The baseline characteristics were similar in both groups. The primary outcome (miscarriage at < 20 weeks of gestation) was 12.8% and 14.3% in the dydrogesterone and placebo groups, respectively (relative risk, 0.897; 95% confidence interval, 0.548-1.467; P = 0.772). Subgroup analyses of women aged ≥ 35 years, those with positive fetal heart tones on ultrasound, those with drug compliance of > 80%, and exclusion of abnormal fetal karyotypes did not show a significant difference in the miscarriage rate between the two groups. There were no significant differences in all secondary outcomes by intention-to-treat or by per-protocol analysis. There were no differences in adverse effects between the groups.
COMMENTARY
Progesterone is essential for both implantation and continued maintenance of pregnancy. For a long time, vaginal progesterone was used off-label for the prevention of miscarriages, but data from the progesterone in recurrent miscarriage (PROMISE)5 and the progesterone in early pregnancy bleeding (PRISM)6 trials did not show vaginal progesterone as a promising drug for preventing early pregnancy loss.
The PROMISE trial was a double-blind, placebo-controlled, multicenter, randomized clinical trial involving more than 800 women with a history of miscarriage to evaluate the efficacy of vaginal progesterone (when compared to placebo) in increasing live-birth rates and neonatal survival in women with unexplained miscarriage, while the PRISM trial is a multicenter, randomized, double-blind, placebo-controlled trial involving more than 4,000 women with threatened miscarriage.
Both trials demonstrated that vaginal progesterone suppositories were not effective in preventing early pregnancy loss when compared to placebo. Therefore, the research question of the efficacy of oral progestogens in the prevention of early pregnancy loss is pertinent and relevant.
Because of the extensive hepatic first-pass effect of oral progestogens, the bioavailability of most orally administered progestogens is low (4% to 8%). Although this is true for most progestogens, dydrogesterone is an exception. Dydrogesterone, a synthetic pregnane retro-progesterone derivative, is rapidly absorbed from the intestines, achieving a bioavailability of 28% within one to three hours of ingestion, with a steady-state concentration achieved after 72 hours of therapy.7 Metabolism of dydrogesterone to its active metabolite, 20-dihydrodydrogesterone, increases its half-life from five to seven hours (dydrogesterone) to 14 to 17 hours (20-dihydrodydrogesterone).7 These pharmacokinetic properties confer on 20-dihydrodydrogesterone longer pharmacodynamic effects compared to other oral progestogens. In this study by Chan et al, no significant differences were demonstrated in the primary and secondary outcomes between participants treated with dydrogesterone compared to placebo. It is possible that plasma concentrations of dydrogesterone and 20-dihydrodydrogesterone were below the minimum trough concentration (Ctrough) needed to prevent miscarriage in these participants. However, it is difficult to tell, because plasma dydrogesterone or 20-dihydrodydrogesterone concentrations were not assayed in the trial participants. Based on these data, oral progestogens are not recommended for prevention of early pregnancy loss.
REFERENCES
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- Chan DMK, Cheung KW, Ko JKY, et al. Use of oral progestogen in women with threatened miscarriage in the first trimester: A randomized double-blind controlled trial. Human Reprod 2020; Dec 17. doi: 10.1093/humrep/deaa327. [Online ahead of print].
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- Coomarasamy A, Devall AJ, Cheed V, et al. A randomized trial of progesterone in women with bleeding in early pregnancy. N Engl J Med 2019;380:1815-1824.
- Stanczyk FZ, Hapgood JP, Winer S, Mishell DR Jr. Progestogens used in postmenopausal hormone therapy: Differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev 2013;34:171-208.
