According to two new studies from the University of Birmingham and Tommy's National Centre for Miscarriage Research, women who have bleeding during early pregnancy and who have had earlier miscarriages could benefit from a course of progesterone, with about 8,500 babies being saved each year.
Female hormone progesterone. Molecular chemical formula on blue background. Image Credit: Linda Kar
Progesterone in pregnancy
Progesterone is a natural hormone produced from the ovaries in every menstrual cycle and also from the placenta in early pregnancy. It is important in pregnancy, from the point of preparing the uterus for implantation of the newly conceived zygote, to nourishing the early pregnancy and sustaining it to full term.
From 1 in 4 to 1 in 5 pregnancies miscarry, an event which is not only a major clinical event in terms of the investigations and treatment required, but also causes profound mental distress to the women and their families. The UK National Health System alone spends about £350 million per year to manage miscarriage and its complications.
Progesterone has been a traditional drug of choice for these women in the next pregnancy, in the first trimester. However, its role has been controversial, with over 60 ears of debate failing to settle the issue. Evidence on the usefulness of progesterone in this context has also been woefully inadequate, making it difficult to evolve a broad-based policy on this management.
The PROMISE and PRISM trials were designed to help provide evidence towards this end.
In one study published January 31, 2020, in the American Journal of Obstetrics and Gynecology, two major clinical trials on the use of progesterone in early pregnancy are summarized. The trials, called PROMISE and PRISM, were both led by researchers at these two institutions.
PROMISE was based on the findings in almost 840 women who had a history of recurrent miscarriage (2 or more pregnancy losses in succession) without any explanation being found. The women were being seen at 45 hospitals at various locations in the UK and the Netherlands. The study concluded that progesterone supplementation produced a 3% higher live birth rate, but the significance in statistical terms is doubtful.
PRISM studied over 4,000 women aged 16-39 years who had bleeding in early pregnancy, seen at 48 UK hospitals. Progesterone given to mothers who had lost one or more early pregnancies earlier increased the live birth rate in this group to 75%, compared to 72% in a control group who received a placebo. 20% and 22% of women in the progesterone and placebo groups, respectively, suffered miscarriages. No increase in significant serious adverse effects were noted in mothers or babies in either groups. The researchers concluded there was no benefit in women with early pregnancy bleeding.
If the analysis was restricted to mothers who had lost 3 or more pregnancies in succession, there was a 15% increase in the live birth rate compared to similar women who received the placebo.
The second study published on the same date in the BJOG: an international Journal of Obstetrics & Gynecology, took a look at the PRISM results from the perspective of financial viability. The researchers found that with an average cost of £204 per pregnancy, the use of progesterone was cost-effective.
The response to the findings of PRISM has been one of widespread acceptance. Before these results were published, only 13% of a small group of 130 medical professionals in the UK (surveyed by the University of Birmingham, results unpublished) prescribed progesterone for women with early pregnancy bleeding. Post-publication of PRISM results, the figure rose to 75%.
Researcher Adam Devall, Manager of Tommy's National Centre for Miscarriage Research, says, “The PRISM and PROMISE Trials found a small but positive treatment effect, dependent on the number of previous miscarriages. We believe that the dual risk factors of early pregnancy bleeding and a history of one or more previous miscarriages identify high risk women in whom progesterone is of benefit. The question is, how should this affect clinical practice?”
The scientists estimate that this practice could save about 8,500 babies a year in the UK. Despite the small benefit shown in the trials, the researchers favour the use of progesterone based on the possible positive effects. Researchers like Arri Coomarasamy, Director of the Center, agree: “Our suggestion is to consider offering to women with early pregnancy bleeding and a history of one or more previous miscarriages a course of treatment of progesterone 400mg twice daily, started at the time of presentation with vaginal bleeding and continued to 16 completed weeks of gestation.”
The need for balance
An alternative is counseling such women and giving them special attention in the next pregnancy to pick up early pregnancy complications for appropriate management. Compared to this expensive process, says Economics expert Tracy Roberts, “progesterone is likely to be considered good value for money in preventing miscarriage.”
Coomarasamy says, “We now urge policy makers and guideline developers to consider the evidence carefully to make a balanced recommendation.” Jane Brewin, Tommy's Chief Executive, goes further, calling the studies “thorough” and the use of progesterone “an effective treatment option which women should be routinely offered.”
The Vice President of The Royal College of Obstetricians and Gynaecologists, Pat O'Brien, sums up: “This treatment offers an increased chance of a successful birth and appears to be cost effective for the NHS, so we hope NICE will consider this important research in their next update of the guidance.” However, she adds a note of balance: “For women with no prior history of miscarriage, there does not appear to be any benefit of the treatment. Reassuringly, most women who have had a miscarriage will have a successful pregnancy and birth in the future.”
The PRISM trial report itself concludes: “Treatment with progesterone did not result in significant improvement in the incidence of live births among women with vaginal bleeding during the first 12 weeks of pregnancy.” Even with only one previous miscarriage, the benefit was very small. Progesterone use should therefore be possibly reserved for women with 3 or more previous miscarriages, since the benefit is highest in this group.
Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence Coomarasamy, Arri et al. American Journal of Obstetrics & Gynecology, https://www.ajog.org/article/S0002-9378(19)32762-0/fulltext
Okeke Ogwulu, CB, Goranitis, I, Devall, AJ, Cheed, V, Gallos, ID, Middleton, LJ, Harb, HM, Williams, HM, Eapen, A, Daniels, JP, Ahmed, A, Bender‐Atik, R, Bhatia, K, Bottomley, C, Brewin, J, Choudhary, M, Deb, S, Duncan, WC, Ewer, AK, Hinshaw, K, Holland, T, Izzat, F, Johns, J, Lumsden, M, Manda, P, Norman, JE, Nunes, N, Overton, CE, Kriedt, K, Quenby, S, Rao, S, Ross, J, Shahid, A, Underwood, M, Vaithilingham, N, Watkins, L, Wykes, C, Horne, AW, Jurkovic, D, Coomarasamy, A, Roberts, TE. The cost‐effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM Trial. BJOG 2020; https://doi.org/10.1111/1471-0528.16068.