Another trial fails to find benefit of progesterone in preventing threatened pregnancy loss

Published 07 March 2023

Following a large multicentre trial and meta-analyses over the past few years, another RCT has found no benefit from vaginal progesterone in preventing pregnancy loss in women with vaginal bleeding and pain in the first trimester. ESHRE updates its guideline on recurrent pregnancy loss.

The threat of miscarriage, suggested in the early weeks of pregnancy by vaginal bleeding and abdominal pain, has been reported to be evident in one quarter of all pregnancies - of which some 20% will end in complete pregnancy loss over the following weeks. Even those which do progress beyond the threats may result in complications, such as preterm delivery or low birth weight.

However, despite the devastation which miscarriage might bring and the many numbers at risk, there is no clear intervention or approach which might mitigate the threat. A Cochrane review from 2019 examined the possibility that progestogens prescribed in the first trimester of pregnancy might help prevent spontaneous loss, a widespread approach based on the knowledge that progesterone induces secretory changes in the endometrium essential for successful implantation.(1) Ten trials contributed to the analysis, which concluded that ‘there may be a reduction’ in the number of miscarriages for women given progestogen supplementation compared to placebo/controls (RR 0.73). However, there have since been questions raised over the validity of one (retracted) and other trials in this meta-analysis with the result that an updated Cochrane review from 2021, which now included seven RCTs, concluded that ‘progestogens probably make little or no difference to live birth rate for women with threatened or recurrent miscarriage’.(2)

This conclusion - and the continuing uncertainty about progestogens in threatened miscarriage - has now been underlined in a new RCT from Australia which similarly found no evidence that vaginal progesterone increases live birth rate in women with threatened miscarriage.(3) The trial was conducted between 2012 and 2019 and planned to recruit 386 women within ten weeks’ gestation and showing signs of a threatened miscarriage as apparent from vaginal bleeding.

By the close of the trial, however, no more than 278 women had been randomised, the intervention group to 400 mg nightly progesterone as vaginal pessaries, the control group to placebo pessaries, until 12 weeks’ gestation. With a primary endpoint of live birth, results were 82.4% in the progesterone group and 84.2% in the placebo group, prompting the authors to conclude: ‘Progesterone in this setting should not be routinely used for threatened miscarriage.’ There were also no significant differences in the rates of miscarriage, preterm birth and perinatal outcomes. LBRs were similar among women with at least one previous miscarriage.

It should be noted that the trial failed to reach its intended number of recruits and was stopped early following interim analysis by the data monitoring committee, because of ‘the low likelihood to achieve statistical significance for the comparison and the difficulty of further recruitment’. Interim results, the authors reported, already indicated ‘the futility of the intervention’.

Although much smaller in its scope, this study bears comparison with the much larger PRISM trial reported in 2019.(4) This study, a multicentre RCT, was performed at 48 UK hospitals in more than 4000 women with vaginal bleeding in early pregnancy. Again, the intervention group received 400 mg vaginal progesterone (though twice daily and up to 16 weeks’ gestation) and again there was no difference in LBR between the two groups, 75% in the progesterone group and 72% in the placebo group. However, in a subgroup analysis of this and the earlier PROMISE trial there was ‘a suggestion’ of benefit among those who had had three or more previous miscarriages.

Similarly neutral results were reported from a smaller trial (n = 406) of women with threatened miscarriage given oral progestogens for up to 12 weeks’ gestation.(5) Their advice was that the ‘use of oral progestogen is not recommended in women with threatened miscarriage in the first trimester’.

ESHRE’s first guideline on recurrent pregnancy loss, published in 2018, advised that ‘vaginal progesterone does not improve live birth rates in women with unexplained RPL’. However, the updated guideline, published in February this year, suggests as a ‘conditional’ recommendation that ‘vaginal progesterone may improve live birth rate in women with 3 or more pregnancy losses and vaginal blood loss in a subsequent pregnancy’. This recommendation was specifically for improving LBR in ‘unexplained’ recurrent pregnancy loss and presents an update on the earlier recommendation. The guideline explains the change based on results of the most recent ‘high-quality’ trials, notably PRISM. However, the guideline notes ‘insufficient evidence’ to recommend the use of progesterone to improve LBR in women with recurrent pregnancy loss and luteal phase insufficiency. ESHRE defines pregnancy loss as loss from the time of conception until 24 weeks’ gestation, and recurrent after the loss of two or more pregnancies.

1. Haas DM, Hathaway TJ, Ramsay PS. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology. Cochrane Database of Systematic Reviews 2019; 11: CD003511.
2. Devall AJ, Papadopoulou A, Podesek M, et al. Progestogens for preventing miscarriage: a network meta‐analysis. Cochrane Database of Systematic Reviews 2021; 4: CD013792.
3. McLindon LA, James G, Beckmann MM, et al. Progesterone for women with threatened miscarriage (STOP trial): a placebo-controlled randomized clinical trial. Hum Reprod 2023;
4. 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.
5. 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. Hum Reprod 2021; 36: 587-595.
6. See
7. Busnelli A, Garolla A, Tersigni C, et al. Sperm human papillomavirus infection and risk of idiopathic recurrent pregnancy loss: insights from a multicenter case–control study. Fertil Steril 2023; 119: 410-418.

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