NICE supports vaginal progesterone to prevent threatened pregnancy loss

Published 02 December 2021

The UK agency has updated its guidance on the management of miscarriage to recommend micronised progesterone for women with a previous miscarriage who bleed in a new early pregnancy - but only after ultrasound confirmation of the intrauterine location of the pregnancy.

NICE, the UK’s National Institute for Health and Care excellence, has updated its guidance on the management of miscarriage to ‘offer vaginal micronised progesterone 400 mg twice daily to women with an intrauterine pregnancy confirmed by a scan, if they have vaginal bleeding and have previously had a miscarriage’.(1)

In its explanation of why the update was introduced NICE notes that there was ‘good evidence that 400 mg twice daily of micronised vaginal progesterone increases the number of live births in women with early pregnancy bleeding and a previous miscarriage’. The recommendation thus came with the caveats that there was ‘evidence of no benefit’ in women with early pregnancy bleeding but no previous miscarriage, nor in women with previous miscarriage but no early pregnancy bleeding in the current pregnancy. The recommendations emphasised that progesterone should only be given to women with intrauterine pregnancy confirmed with a scan.

Evidence in support of the move clearly came from the multicentre PRISM trial in the UK coordinated by the Tommy’s National Centre for Miscarriage Research.(2) The results showed that, while treatment with micronised progesterone did not reduce the rate of miscarriage for those with no previous miscarriages, there was a small reduction in miscarriage for those with one or two previous miscarriages and a big reduction in miscarriage for those with three or more previous miscarriages (72% LBR in the progesterone group and 57% in the placebo group).

The study’s first author, Arri Coomarasamy from the University of Birmingham and Director of the Tommy’s programme, said at the time: ‘Women who are at risk of a miscarriage because of current pregnancy bleeding and a history of a previous miscarriage could benefit from progesterone treatment, and this has huge implications for practice. This treatment could save thousands of babies who may have otherwise been lost to a miscarriage. We hope that this evidence will be considered by the National Institute for Health and Care Excellence (NICE) and that it will be used to update national guidelines for women at risk of miscarriage.’ And this now is what has happened.

A recent Cochrane review on progestogen for treating threatened miscarriage – which included seven eligible trials – found that progestogens are ‘probably effective’ in the treatment of threatened miscarriage but may have little or no effect on the rate of preterm birth. However, this review found that benefits were derived from oral progestogens, and ‘treatment with vaginal progesterone compared to placebo, probably has little or no effect in reducing the miscarriage rate’.(3)

Commenting on the NICE update, Laurentiu Craciunas, Junior Deputy of ESHRE’s SIG Early Pregnancy, notes that the use of progesterone in this context has been debated over the last 60 years - indeed, since the publication of the first trial attempting to prevent miscarriage with progesterone.(4)

Craciunas adds: ‘NICE is very prescriptive in this update and only recommends treatment for women who bleed in early pregnancy after having had a scan to confirm the intrauterine location of the pregnancy. Once the viability is subsequently confirmed by the presence of a heartbeat, vaginal micronised progesterone is recommended until 16 weeks of pregnancy.

‘In addition, the new guideline acknowledges the lack of evidence of benefit for any other forms of progesterone, such as dydrogesterone or 17-hydroxyprogesterone, or for preparations administered orally or intramuscularly. The bulk of evidence favouring vaginal micronised progesterone was provided by the recently published PRISM trial where 400 mg of vaginal micronised progesterone administered twice a day appeared to increase the chance of a live birth for women who suffered previous miscarriages and presented with bleeding in a new pregnancy diagnosed by ultrasound.(2) This note is particularly important because other forms of progesterone are associated with adverse events, such as genital malformations or childhood cancer.(5,6) NICE has made future research recommendations to include direct comparisons between various progesterone preparations and to include adverse events as outcomes to be reported.’

1. See https://www.nice.org.uk/guidance/ng126/chapter/Recommendations#management-of-miscarriage
2. 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.
3. Wahabi HA, Fayed AA, Esmaeil SA, et al. Progestogen for treating threatened miscarriage. Cochrane Database of Systematic Reviews 2018, Issue 8. CD005943. doi:10.1002/14651858.CD005943.pub5.
4. Swyer GI, Daley D. Progesterone implantation in habitual abortion. Br Med J 1953; 1: 1073-1077. doi:10.1136/bmj.1.4819.1073
5. Carmichael SL, Shaw GM, Laurent C, et al. Maternal progestin intake and risk of hypospadias. Arch Pediatr Adolesc Med 2005; 159: 957-962.
6. Murphy CC, Cirillo PM, Krigbaum NY, Cohn BA. In utero exposure to 17α-hydroxyprogesterone caproate and risk of cancer in offspring. Am J Obstet Gynecol 2021: S0002-9378(21)01184-4. doi:10.1016/j.ajog.2021.10.035

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