A Randomized Trial of Progesterone in Women with Recurrent Miscarriages

Abstract

BACKGROUNDProgesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain. METHODSWe conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twicedaily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation. RESULTSA total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, −4.0 to 9.0). There were no significant between-group differences in the rate of adverse events. CONCLUSIONSProgesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages.

Author's reply re: Changes in anti‐müllerian hormone levels as a biomarker for ovarian reserve after ultrasound‐guided high‐intensity focused ultrasound treatment of adenomyosis and uterine fibroid

“…2,3 To alleviate the uncertainty, we reported a preliminary observation on the changes in AMH levels from 12 women before and up to 12 months after HIFU treatment, and this article was published in April 2016. 4 We are pleased to see that Lee et al's conclusion confirms our previous observation, despite our patients having received an overall higher treatment energy (median 575 521.5 joules). 4 However, it was commented that our study only included women over 40 years of age, and hence the AMH levels were generally low and might not be applicable to younger patients.…”

“…4 We are pleased to see that Lee et al's conclusion confirms our previous observation, despite our patients having received an overall higher treatment energy (median 575 521.5 joules). 4 However, it was commented that our study only included women over 40 years of age, and hence the AMH levels were generally low and might not be applicable to younger patients. In the study by Lee et al, the women's ages were between 24 and 45 years.…”

Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation

“…Although natural and synthetic progestogens have been extensively used in pregnant patients or patients undergoing infertility treatments for various indications such as prevention of unexplained recurrent pregnancy loss and threatened abortion (34,35), it remained controversial whether P4 supplementation would increase the chance of successful implantation and ongoing pregnancy among women with a history of unexplained recurrent miscarriages (35,36). Debate is still ongoing with regard to the best administration timing (luteal phase or first trimester of pregnancy) and method of P4 supplementation for better implantation rate and term pregnancy outcomes in these patients (36 Genomic deletions of the respective genes in Ishikawa cells employing the CRISPR/Cas9 system were performed as previously described (46).…”

“…Debate is still ongoing with regard to the best administration timing (luteal phase or first trimester of pregnancy) and method of P4 supplementation for better implantation rate and term pregnancy outcomes in these patients (36 Genomic deletions of the respective genes in Ishikawa cells employing the CRISPR/Cas9 system were performed as previously described (46). The Cas9 and sgRNA plasmid pX458 were obtained from Addgene (plasmid number 48138).…”

Oral Allylestrenol: A Pregnancy-supporting Progestogen

“…Results from a subsequent double-blind definitive trial [PROMISE trial, (Table 1)] conducted in women with a history of recurrent miscarriage, 6 and given vaginal suppositories of micronized progesterone (432 women), progesterone showed no benefit in increasing the rate of live birth after 24 weeks of gestation. Norman et al 7 conducted a large double-blind, randomized, placebo-controlled study [OPPTIMUM trial, (Table 1)] on pregnancy and infant outcomes in women at risk of preterm birth after being treated with vaginal progesterone taken daily from 22, 23, or 24 to 34 weeks of gestation.…”