Rationale use of Progesterone in Abortions

OBG-Speculum:    2024                       ISSN no.

Vol -2, Issue -1  

Dr Sumaira Sadeed, PG 3, Department of OBGYN, JNMC, Aligarh

Prof Tamkin Khan, Department of OBGYN, JNMC, Aligarh

Progesterone plays a crucial role in initiating and sustaining pregnancy.1 Progesterone is essential for secretory transformation of the endometrium that permits implantation and maintenance of early pregnancy.2 Luteal phase insufficiency has been implicated as one of the reasons for implantation failure and is considered to be responsible for miscarriage.3 In addition to its well-known role in preparation of the endometrium for implantation, endometrial decidualization, and inhibition of uterine contractility, progesterone also has an immunomodulatory effect by suppression of T-cell activation4, 5 and controlling cytokine production during pregnancy.6 These characteristics have led to its current widespread use in managing recurrent miscarriage. Therefore, support with progesterone may help to establish a sufficient immune response in early pregnancy and prevent miscarriage.7 It is known that drugs with antiprogesterone effects are potent in inducing abortions.8 Due to the pivotal function of progesterone in early pregnancy, there has been a hypothesis among clinicians and researchers that a deficiency in progesterone might contribute to miscarriages. This theory has prompted numerous clinical trials involving progesterone supplementation for women with a high risk of miscarriage, particularly those with a history of recurrent miscarriage or experiencing bleeding in early pregnancy.

However, these trials utilized different progestogens, were relatively small, and had methodological limitations, resulting in diverse and unreliable outcomes.9,10 Consequently, policymakers face challenges in providing evidence-based recommendations regarding the use of progesterone supplementation to enhance outcomes in these specific groups of women. Following are few of the noteworthy trials:

The PROMISE (PROgesterone in recurrent MIScarriage, 2015) Trial, a robust randomized study focusing on women experiencing recurrent miscarriage. The trial specifically targeted women with unexplained recurrent miscarriages, involving either three consecutive or non-consecutive miscarriages, who are attempting to conceive naturally. The intervention in this trial involved the administration of 400 mg of micronized progesterone vaginally twice daily, commencing no later than 6 weeks and continuing until 12 weeks of gestation. A placebo is used for comparison. The primary outcome assessed was the occurrence of live births beyond 24 weeks of gestation. Findings showed that women with a history of unexplained RM do not benefit from first-trimester progesterone therapy for any of the clinical outcome.11

The PRISM (PRogesterone In Spontaneous Miscarriage, 2020) trial was a well-conducted randomized study focused on women experiencing threatened miscarriage. It was a double blind placebo controlled trial, maintaining an excellent follow-up rate, with a pre-specified statistical analysis plan. In the primary analysis of the PRISM trial, the investigation revealed that the live birth rate was similar in both the groups. Additionally, the trial included a prespecified subgroup analysis based on the number of previous miscarriages:  women with no history of miscarriage, women with 1 or 2 previous miscarriages, and women with 3 previous miscarriages. A noteworthy increase in live births was noted specifically in the subgroup of women with a history of previous miscarriages.  In women with three or more previous miscarriages, the live birth rate was 72% (98/137) with progesterone, compared with 57% (85/148) in the placebo group (relative risk 1.28, 95% CI 1.08 to 1.51; p = 0.004).12

The STOP (Progesterone for women with threatened miscarriage, 2023) trial, another randomized, double-blinded, placebo-controlled trial, aimed to investigate the use of progesterone in women with threatened miscarriage. In this, eligible pregnant women under 10 weeks of gestation experiencing a threatened miscarriage, as indicated by vaginal bleeding, were randomly assigned to two groups in a 1:1 ratio. The intervention group received 400 mg of progesterone in the form of vaginal pessaries, while the control group received placebo vaginal pessaries. Both treatments were administered until 12 weeks of gestation. The findings of the STOP trial revealed that progesterone supplementation did not result in an increased rate of live births among women with threatened miscarriage. Furthermore, there were no significant differences observed in the rates of miscarriage, preterm birth, and perinatal outcomes between the progesterone intervention group and the placebo control group.13

The conclusions drawn from the trials, particularly considering the lack of significant benefits observed in certain scenarios and the potential side effects of progesterone, suggest a cautious approach to its use.14,15 In light of this, it is recommended to carefully consider the decision to use progesterone in everyday clinical practice.

Specifically, the use of progesterone may be more justified in pregnancies with a history of recurrent abortions and are currently presenting with bleeding in this pregnancy.16 This targeted approach aligns with the idea that progesterone supplementation may have a more discernible impact in certain subgroups of pregnant women, as suggested by the trial findings. It emphasizes the importance of individualized treatment decisions based on the patient's specific medical history and circumstances. However, it's crucial for healthcare providers to stay updated on the latest research and guidelines as medical knowledge evolves.

References:

1.               Wahabi HA, Fayed AA, Esmaeil SA, et al. Progestogen for treating threatened miscarriage. Cochrane Database Syst Rev. 2018(8):CD005943.

2.               Coulam, 2016, Luesley and Kilby, 2016

3.               Swyer GI, Daley D. Progesterone implantation in habitual abortion. Br Med J. 1953; 1: 1073-1077.

4.               Society for Maternal-Fetal Medicine Publications Committee, with assistance of Vincenzo Berghella. Progesterone and preterm birth prevention: translating clinical trials data into clinical practice. Am J Obstet Gynecol. 2012; 206: 376-386.

5.               Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003; 348: 2379-2385.

6.               Szekeres-Bartho J, Par G, Dombay G, Smart YC, Volgyi Z. The antiabortive effect of progesterone-induced blocking factor in mice is manifested by modulating NK activity. Cell Immunol. 1997; 177: 194-199.

7.               Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol. 2012; 206(124): e1-e19.

8.                Le, Tao; Bhushan, Vikas; Qiu, Connie; Chalise, Anup; Kaparaliotis, Panagiotis (2023). First Aid. McGraw Hill.

9.               Hussain M, El-Hakim S, Cahill DJ. Progesterone supplementation in women with otherwise unexplained recurrent miscarriages. J Hum Reprod Sci. 2012; 5: 248-251

10.             Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database Syst Rev. 2013;(10):CD003511.

11.             Coomarasamy A, Williams H, Truchanowicz E, et al. A randomized trial of progesterone in women with recurrent miscarriages. N Engl J Med. 2015; 373: 2141-2148.

12.             Coomarasamy A, Harb HM, Devall AJ, et al. Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT. Southampton (UK): NIHR Journals Library; 2020 Jun. (Health Technology Assessment, No. 24.33.) Chapter 3, Results. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558717/

13.             Lucas A McLindon, Gabriel James, Michael M Beckmann, Julia Bertolone, Kassam Mahomed, Monica Vane, Teresa Baker, Monique Gleed, Sandra Grey, Linda Tettamanzi, Ben Willem J Mol, Wentao Li, Progesterone for women with threatened miscarriage (STOP trial): a placebo-controlled randomized clinical trial, Human Reproduction, Volume 38, Issue 4, April 2023, Pages 560–568

14.             Siemienowicz KJ, Wang Y, Marečková M, Nio-Kobayashi J, Fowler PA, Rae MT, Duncan WC.2020Early pregnancy maternal progesterone administration alters pituitary and testis function and steroid profile in male fetuses. Scientific Reports 10 21920. (10.1038/s41598-020-78976-x) 

15.             Davidovitch M, Chodick G, Shalev V, Eisenberg VH, Dan U, Reichenberg A, Sandin S, Levine SZ.2018Infertility treatments during pregnancy and the risk of autism spectrum disorder in the offspring. Progress in Neuro-Psychopharmacology and Biological Psychiatry 86175–179. (10.1016/j.pnpbp.2018.05.022)

16.             Duncan WC. Did the NICE guideline for progesterone treatment of threatened miscarriage get it right? Reprod Fertil. 2022 Apr 7;3(2):C4-C6. doi: 10.1530/RAF-21-0122. PMID: 35514538