Vaginal micronised progesterone for the prevention of hypertensive disorders of  pregnancy: A systematic review and meta-analysis

Pedro Melo; Adam Devall; Andrew H Shennan; Manu Vatish; Christian M Becker; Ingrid Granne; Aris T Papageorghiou; Ben W Mol; Arri Coomarasamy

doi:10.1111/1471-0528.17705

Therapeutics · Hormonal Agents

Vaginal micronised progesterone for the prevention of hypertensive disorders of pregnancy: A systematic review and meta-analysis

Melo P, Devall A, Shennan AH, Vatish M, Becker CM, Granne I, Papageorghiou AT, Mol BW, Coomarasamy A

Published May 2024 BJOG : an International Journal of Obstetrics and Gynaecology, 131(6), 727-739

DOI 10.1111/1471-0528.17705 PMID 37941309

RRM Academy Synopsis

First-Trimester Vaginal Progesterone May Lower Preeclampsia Risk

This review of 11 trials against placebo took in 11,640 women at risk of miscarriage or preterm birth. Vaginal progesterone started in the first trimester may lower preeclampsia risk. Out of 1,000 women, the estimate was 14 cases with an early start and 23 with placebo. Progesterone started after the first trimester was not linked to less preeclampsia.

Key Findings

First-trimester vaginal progesterone lowered the risk of any hypertensive disorder of pregnancy versus placebo (RR 0.71, 95% CI 0.53–0.93; 2 trials, 4431 women; moderate certainty).
First-trimester vaginal progesterone also lowered the risk of preeclampsia versus placebo (RR 0.61, 95% CI 0.41–0.92; 3 trials, 5267 women; moderate certainty).
Second- or third-trimester starts were not associated with a reduction in hypertensive disorders (RR 1.19, 95% CI 0.67–2.12) or preeclampsia (RR 0.97, 95% CI 0.71–1.31). Low certainty.
Estimated risk of a hypertensive disorder with first-trimester progesterone was 37 per 1000 (95% CI 28–49), against 52 per 1000 on placebo. For preeclampsia: 14 per 1000 (9–21), against 23.
Every first-trimester trial enrolled women with recurrent miscarriage or threatened miscarriage. None of the 11 trials studied blood pressure disorders as a main outcome.

Interpretation

This is a systematic review and meta-analysis. The review pools placebo-controlled randomized trials, where chance decided who got vaginal progesterone. Even so, the authors conclude only that early progesterone may reduce risk. The authors rated the first-trimester finding moderate certainty. They rated the later-start finding low certainty, since its estimates were wide. The first-trimester results come from three trials, all in women with recurrent miscarriage or early pregnancy bleeding. The review does not cover pregnant women in general. No trial reported whether women had high blood pressure in a past pregnancy, or made it a main outcome. The authors could not adjust for age, body mass index, twins or aspirin use.

RRM Context

Restorative reproductive medicine starts with how the body works. After ovulation, the corpus luteum makes the progesterone an early pregnancy relies on. Studies that removed the corpus luteum showed early pregnancy needs it (Csapo and Pulkkinen 1978). The authors call it plausible that added vaginal progesterone may partly correct abnormal implantation. The added progesterone may work by fixing a possible low-progesterone state. Charting methods such as the Creighton Model track the days after Peak. That count can give an early clue to how the corpus luteum works before conception.

Our editorial summary of this paper, not the article's abstract.

Abstract

Background

Treatment with vaginal progesterone reduces the risk of miscarriage and preterm birth in selected high-risk women. The hypothesis that vaginal progesterone can reduce the risk of hypertensive disorders of pregnancy (HDP) is unexplored.

Objectives

To summarise the evidence on the effectiveness of vaginal progesterone to reduce the risk of HDP.

Search Strategy

We searched Embase (OVID), MEDLINE (OVID), PubMed, CENTRAL and clinicaltrials.gov from inception until 20 June 2023.

Selection Criteria

We included placebo-controlled randomised trials (RCTs) of vaginal progesterone for the prevention or treatment of any pregnancy complications.

Data Collection and Analysis

We extracted absolute event numbers for HDP and pre-eclampsia in women receiving vaginal progesterone or placebo, and meta-analysed the data with a random effects model. We appraised the certainty of the evidence using GRADE methodology.

Main Results

The quantitative synthesis included 11 RCTs, of which three initiated vaginal progesterone in the first trimester, and eight in the second or third trimesters. Vaginal progesterone started in the first trimester of pregnancy lowered the risk of any HDP (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53-0.93, 2 RCTs, n = 4431 women, I(2) = 0%; moderate-certainty evidence) and pre-eclampsia (RR 0.61, 95% CI 0.41-0.92, 3 RCTs, n = 5267 women, I(2) = 0%; moderate-certainty evidence) when compared with placebo. Vaginal progesterone started in the second or third trimesters was not associated with a reduction in HDP (RR 1.19, 95% CI 0.67-2.12, 3 RCTs, n = 1602 women, I(2) = 9%; low-certainty evidence) or pre-eclampsia (RR 0.97, 95% CI 0.71-1.31, 5 RCTs, n = 4274 women, I(2) = 0%; low-certainty evidence).

Conclusions

Our systematic review found first-trimester initiated vaginal micronised progesterone may reduce the risk of HDP and pre-eclampsia.

Topics

Therapeutics › Hormonal Agents › Progesterone and Progestins · Pregnancy › Pregnancy Complications › Hypertensive Disorders · Birth and Delivery › Birth Outcomes › Maternal Morbidity

Pedro Melo, Adam Devall, Andrew H Shennan, Manu Vatish, Christian M Becker, Ingrid Granne, Aris T Papageorghiou, Ben W Mol, Arri Coomarasamy

P Melo, A Devall, Andy Shennan, Drew Shennan, A Shennan, M Vatish, C Becker, I Granne, A Papageorghiou, Benjamin Mol, B Mol, A Coomarasamy

PMID 37941309 37941309 DOI 10.1111/1471-0528.17705 10.1111/1471-0528.17705 Melo et al. 2024, Melo 2024