Progesterone for Threatened Miscarriage
This randomized controlled trial compares live birth rates in women taking vaginal progesterone vs. placebo after first-trimester threatened miscarriage.
Study Background
WHAT
Comparison on impact to live birth rates using progesterone vs. placebo for threatened miscarriage in first trimester
WHY
Threatened miscarriage increases odds of true miscarriage
Mixed data for use of vaginal progesterone to treat threatened miscarriage
WHERE
Department of Obstetrics and Gynaecology,* Mater Mothers’ Hospitals, Brisbane, Australia
*Fertility Assessment and Research Clinic staff coordinated the study
WHEN
Screened for recruitment February 2012 - April 2019
WHO
Inclusion Criteria:
Female < 10 weeks pregnant
Singleton pregnancy with heartbeat detected on ultrasound
(+) for threatened miscarriage “as apparent from bleeding with or without pain”
Exclusion Criteria:
Bleeding due to trauma or lesions
Use of assisted reproductive technology (due to luteal phase/early pregnancy hormonal support)
HOW
Patients received flyer about trial and joined on day of or day after diagnosis
Randomized by computer program and statistician in 1:1 ratio to vaginal progesterone pessary or placebo
Patients administered 400 mg progesterone or identical placebo every night from time of randomization until 12th week of pregnancy or earlier (if no longer pregnancy)
Medication compliance passively verified via prescription refill dispenses
Statistics (Briefly)
Calculated N = 139 per group for Power 80% and Type-1 error 0.05
Intention to treat (ITT) analysis
Subgroup analyses conducted on: history of miscarriage, prior infertility, maternal age, gestational age at time of recruitment
Results
1364 screened —> 278 consented and randomized to 139 in each group
Baseline characteristics largely similar
Ages 30 +/- 5 years
18% baseline infertility in both groups
Few prior miscarriages (0-1 in progesterone group, 0-2 in placebo group)
More smokers in placebo vs. progesterone but small Ns (5 and 10, respectively)
Study prematurely halted due to third-party monitoring committee recommendation at time of interim analysis
Rates of miscarriage and of live birth similar between groups
Recruitment difficulties
No significant differences seen in rates of pre-term birth, small for gestational age, or obstetric outcomes; similar results seen in subgroup analyses and intention-to-treat vs. per-protocol comparisons
Authors’ Thoughts
Vaginal progesterone has no benefit on live birth rates in threatened miscarriage
Cannot draw conclusions on utility of other routes and forms of progesterone use
Future research on progesterone preventing miscarriages should focus on women who may have a benefit, such as those who had 2+ miscarriage history and stayed on progesterone through week 16, as per the PRISM trial results
This Pharmacist’s Thoughts
Seven years to recruit 300 (of 400 intended) participants - site/research staff should have made efforts to add on additional partner sites to improve enrollment —-> faster enrollment would have enabled a more timely understanding of impact of vaginal progesterone
Compliance issues (only 55% compliant) were not further addressed in Discussion section; would have been easier to assess compliance if original dispense was x 14 nights vs. 20 nights per-protocol
Conclusions
Women taking vaginal progesterone 400 mg nightly from < 10 weeks until 12 weeks for threatened miscarriage did not have additional benefits in terms of miscarriage prevention, improved rates of live birth, etc. Further research is needed for which women with threatened miscarriages would benefit from this treatment.
Resources
Bordewijk EM, Li W, Gurrin LC, Thornton JG, van Wely M, Mol BW. An investigation of seven other publications by the first author of a retracted paper due to doubts about data integrity. Eur J Obstet Gynecol Reprod Biol. 2021;261:236-241. doi:10.1016/j.ejogrb.2021.04.018
Carmichael SL, Shaw GM, Laurent C, Croughan MS, Olney RS, Lammer EJ. Maternal progestin intake and risk of hypospadias. Arch Pediatr Adolesc Med. 2005 Oct;159(10):957-62. doi: 10.1001/archpedi.159.10.957. PMID: 16203941.
Casarramona G, Lalmahomed T, Lemmen C, et al. The efficacy and safety of luteal phase support with progesterone following ovarian stimulation and intrauterine insemination: A systematic review and meta-analysis. Front Endocrinol (Lausanne). 2022;13:960393. Published 2022 Sep 2. doi:10.3389/fendo.2022.960393 Specifically for IUI
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(19):1815-1824. doi:10.1056/NEJMoa1813730. British PRISM trial
Devall AJ, Papadopoulou A, Podesek M, et al. Progestogens for preventing miscarriage: a network meta-analysis. Cochrane Database Syst Rev. 2021;4(4):CD013792. Published 2021 Apr 19. doi:10.1002/14651858.CD013792.pub2
McLindon LA, James G, Beckmann MM, et al. Progesterone for women with threatened miscarriage (STOP trial): a placebo-controlled randomized clinical trial [published online ahead of print, 2023 Feb 20]. Hum Reprod. 2023;dead029. doi:10.1093/humrep/dead029
Meurer WJ, Tolles J. Interim Analyses During Group Sequential Clinical Trials. JAMA. 2021;326(15):1524-1525. doi:10.1001/jama.2021.10174
Oripro (progesterone pessary used in clinical trial) accessible at https://www.healthdirect.gov.au/medicines/brand/amt,124041000036109/oripro
Şükür YE, Göç G, Köse O, et al. The effects of subchorionic hematoma on pregnancy outcome in patients with threatened abortion. J Turk Ger Gynecol Assoc. 2014;15(4):239-242. Published 2014 Dec 1. doi:10.5152/jtgga.2014.14170
Yan X, Xu H, Li J, Xu Z, Niu Y, Wang Y. Subchorionic hematoma and risk of preterm delivery: a systematic review and meta-analysis. Am J Obstet Gynecol MFM. 2023;5(1):100791. doi:10.1016/j.ajogmf.2022.100791
