There was a small reduction in miscarriage for those with 1-2 previous miscarriages and a big reduction in miscarriage for those with 3 or more previous miscarriages.

Introduction

Progesterone is produced by the corpus luteum in the ovaries and helps to prepare the endometrium

for implantation of the embryo. Progesterone is therefore an essential hormone for a successful pregnancy.

Progesterone for prevention of miscarriage

The PROMISE trial,1 which included 836 participants, evaluated the benefit of progesterone supplementation in women with 3 or more unexplained miscarriages.  Successful outcome was considered to be a live birth after 24 weeks of gestation. The findings of the trial were as follows:

  • For those who received progesterone, it was 65.8% (262 of 398 pregnancies) in the progesterone group
  • For those who received placebo, it was 63.3% (271 of 428 pregnancies).
  • A post hoc analysis found that progesterone was of benefit in women with a history of 4 or more miscarriages.

Bullet point guidance

  • Vaginal progesterone (Cyclogestâ or Utrogestanâ 400 mg twice daily) should be offered to women with four or more previous miscarriages from the time of a positive pregnancy test until 16 completed weeks of gestation.
  • In women with a history of RPL being treated for a pregnancy of unknown location, progesterone supplementation should continue until pregnancy viability is determined.
  • Progesterone therapy should be discontinued if there is an ultrasound diagnosis of a miscarriage.
  • Common side effects of vaginal progesterone: breast pain, drowsiness and gastrointestinal discomfort.
  • Contraindications to progesterone treatment: acute porphyria, history during pregnancy of idiopathic jaundice, pemphigoid gestationis or severe pruritus, breast cancer, thromboembolism or thrombophlebitis.3
  • Caution: diabetes, history of depression or migraine. If using Utrogestanâ, check for soy and peanut allergy due to the risk of cross-sensitivity.3

Progesterone as rescue therapy

Results from the PRISM RCT,2 which included 4153 women, showed that progesterone did not reduce the rate of miscarriage for those with no previous miscarriages. There was a small reduction in miscarriage for those with 1-2 previous miscarriages and a big reduction in miscarriage for those with 3 or more previous miscarriages. The overall live birth rate was 75% (1513/2025) in the progesterone group and 72% (1459/2013) in the placebo group. However, when the results were split by the number of previous miscarriages that the participants had suffered, the analysis showed that:

  • No previous miscarriages: the live birth rate was 74% (824/1111) in the progesterone group and 75% (840/1127) in the placebo group, i.e. no benefit
  • 1-2 previous miscarriages: the live birth rate was 76% (591/777) in the progesterone group and 72% (534/738) in the placebo group, i.e. some benefit
  • 3 or more previous miscarriages: the live birth rate was 72% (98/137) in the progesterone group and 57% (85/148) in the placebo group, i.e. substantial benefit

Bullet point guidance

  • Based on the findings of the PRISM trial, offer vaginal micronized progesterone 400 mg twice daily to women with an intrauterine pregnancy confirmed by an ultrasound scan, if they have vaginal bleeding and a history of previous miscarriage. Vaginal progesterone should be taken until 16 completed weeks of pregnancy.2,4
  • If a fetal heartbeat is confirmed, progesterone therapy should be discontinued if there is an ultrasound diagnosis of a miscarriage.4
  • Common side effects of vaginal progesterone: breast pain, drowsiness and gastrointestinal discomfort.3
  • Contraindications to progesterone treatment: acute porphyria, history during pregnancy of idiopathic jaundice, pemphigoid gestationis or severe pruritus, breast cancer, thromboembolism or thrombophlebitis.3
  • Caution: diabetes, history of depression or migraine. If using Utrogestanâ, check for soy and peanut allergy due to the risk of cross-sensitivity.3

References: 

  1. Coomarasamy A et al. A Randomized Trial of Progesterone in Women with Recurrent Miscarriages. New England Journal of Medicine 2015;373: 2141-2148.
  2. Coomarasamy A, Devall AJ, Cheed V, Harb HM et al. A Randomized Trial of Progesterone in Women with Early Pregnancy Bleeding. New England Journal of Medicine 2019; 380:1815-1824
  3. Joint Formulary Committee (2021). British National Formulary. Available at: bnf.nice.org.uk.
  4. National Institute for Health and Care Excellence (NICE). Ectopic pregnancy and miscarriage: diagnosis and initial management. Published 17 April 2019. Updated 24 November 2021. Available at: www.nice.org.uk/guidance/ng126