The role of progesterone in miscarriage

The origin of the name progesterone is based on the “progestational” activity of this steroid hormone. Indeed, progesterone exerts several progestational effects throughout pregnancy.

Before pregnancy, progesterone secreted by the corpus luteum promotes the development of a secretory endometrium characterized by immunomodulatory, paracrine, and endocrine effects supporting the implantation of an embryo.¹ In early pregnancy, progesterone is critical for the maintenance of pregnancy. Excising the corpus luteum early in pregnancy (luteectomy) results in decreased progesterone levels.

Subsequently miscarriage occurs,² unless exogenous progesterone is administered. Between 7 and 9 weeks of gestation, a “luteal placental shift” occurs when the placenta takes over as the main progesterone-producing organ. As a result, luteectomy conducted following 9 weeks of gestation does not result in a miscarriage.³

In the second and third trimesters of pregnancy, progesterone maintains uterine quiescence and acts as an immune modulator, decreasing immune responses that could result in preterm labor.¹ However, the role of progesterone supplementation in reducing miscarriages remains unclear.

The aim of our review is to summarize the evidence regarding the role of exogenous progesterone in the prevention of early pregnancy loss.

Early pregnancy loss affects 10% to 15% of clinical pregnancies and up to 31% of pregnancies in total.⁴ It can result in medical or surgical morbidity as well as in psychological sequelae including posttraumatic stress disorder, depression, and anxiety.^5,6

Women with a history of early pregnancy loss or who present with bleeding in early pregnancy are a subgroup of patients at increased risk of miscarriage.⁷ Consequently, studies evaluating the role of progesterone in preventing miscarriage mainly focus on these 2 groups.

Threatened miscarriage

Vaginal bleeding in the presence of a closed uterine cervix and with sonographic visualization of a viable intrauterine pregnancy is termed threatened miscarriage.

Low progesterone levels have been associated with an increased rate of miscarriage, but whether these low levels are the cause or solely the consequence of a failed pregnancy is unclear.

A Cochrane review that included 7 randomized controlled trials, with a total of 696 participants, concluded that progesterone “probably reduces the risk of miscarriage” with a relative risk (RR) of 0.64 and a confidence interval CI of 0.47 to 0.87.8

The quality of evidence was considered moderate, and the trials included those with a small sample size (the largest trial included 191 participants; the smallest trial, 35 participants). In addition, the route of progesterone administration and the dosage varied widely. A subgroup analysis indicated that treatment with oral progesterone reduced the miscarriage rate when compared with no treatment, whereas treatment with vaginal progesterone did not. A subgroup interaction analysis, however, showed no difference when comparing the route of administration.

The same question was addressed in the 2019 PRISM trial (ISRCTN14163439),⁹ a large multicenter, randomized, double-blind, placebo-controlled trial. The study involved 4153 women aged 16 to 39 years, who presented with vaginal bleeding in the presence of an intrauterine pregnancy of less than 12 weeks gestation. The RR of ongoing pregnancy at 12 weeks with 400 mg of twice-daily vaginal micronized progesterone was 1.04 (95% CI, 1.01-1.07) and of live births after at least 34 weeks, 1.03 (95% CI, 1.00-1.07; P = .08). A more pronounced effect was seen in those with a history of 3 or more miscarriages (RR, 1.28; 95% CI, 1.08-1.51; P = .007).

The live birth rates in this subgroup were 72% in the treated group and 57% in the placebo group. Because the analysis was done on a prespecified study subgroup of 285 women, the authors stated that their observation required validation.

A subsequent meta-analysis comprising 8 studies, including the PRISM trial, and 4833 patients found the RR of miscarriage to be lower in women taking progesterone (RR, 0.7, 95% CI, 0.52-0.94).¹⁰

The quality of evidence, however, was considered very low, and when limiting the analysis to only studies reporting live birth rates, no significant difference was found with or without progesterone supplementation.

Current guidelines reflect the lack of certainty regarding progesterone treatment in threatened miscarriage. The American College of Obstetricians and Gynecologists (ACOG) guidelines state: “For threatened early pregnancy loss, the use of progestins is controversial and conclusive evidence supporting their use is lacking.”¹¹

Similarly, the United Kingdom’s National Institute for Health and Care Excellence guidelines affirm that the evidence is inconclusive but “data from meta-analysis of several small studies suggest that progestogens are better than placebo.”¹² Note that a persistent limitation of these studies is the inability to control for the presence of better-established causes of pregnancy loss such as aneuploidy.

Recurrent pregnancy loss

The American Society for Reproductive Medicine (ASRM) and the European Society of Human Reproduction and Embryology (ESHRE) define recurrent pregnancy loss (RPL) as the spontaneous loss of 2 or more pregnancies.^13,14 Previous definitions required 3 or more pregnancy losses, and thus studies comparing etiology, treatment, and treatment outcome differ with regard to RPL definition.

The most common cause of early pregnancy loss is chromosomal abnormalities. They account for approximately 60% of early miscarriages, with a lower prevalence in women with more advanced gestation and among those with RPL.¹⁵

Other possible etiologies of RPL include anatomical factors, immunological factors such as the antiphospholipid syndrome, and endocrinological factors.^14,16 Yet even after comprehensive examinations, the cause for RPL can be determined only in less than 50% of couples.^14.16

As progesterone is required for both implantation and the maintenance of pregnancy, it has been postulated that a dysfunction in progesterone secretion or action could contribute to RPL. The condition related to insufficient progesterone action is known as luteal phase deficiency.

It could be primary, in which no cause is found (idiopathic), or secondary to other pathologies including thyroid or prolactin disorders.

ASRM guidelines suggest a clinical diagnosis of luteal phase deficiency when a luteal phase lasts for 10 days or less.¹⁷ The guidelines also state that short luteal phases have been diagnosed in fertile women and luteal phase deficiency has not been proved as a cause of RPL.

Even if the luteal phase is of adequate length, supplemental progesterone might maintain an adequate immune environment in women with a dysregulated response to the pregnancy.

Several studies have evaluated the effect of progesterone supplementation in women with RPL. Kumar et al evaluated dydrogesterone (20 mg/day orally) in 360 women with a history of 3 or more pregnancy losses in a double-blind, randomized, placebo-controlled study.¹⁸

The risk for another miscarriage was higher in the placebo group (RR, 2.4; 95% CI, 1.3-5.9). The largest trial (PROMISE; ISRCTN14163439), evaluated 836 women between the ages of 18 and 39 with a history of 3 or more pregnancy losses.¹⁹

Patients in the study group received 400 µg of micronized progesterone twice daily from the time of a positive urinary pregnancy test until 12 gestational weeks. The RR for live births after 24 weeks of gestation in the progesterone-treated group was 1.05 (95% CI, 0.94-1.15).

The live birth rate in the progesterone group was 66% and in the placebo group 63%. The neonatal outcomes were comparable. No effect was found in the subgroups defined according to maternal age or number of previous miscarriages (3 or >4). A post hoc subgroup analysis by the number of previous miscarriages (3, 4, 5, or >6) showed a nonsignificant trend toward increased efficacy with increasing number of previous miscarriages.

A Cochrane review on progesterone for preventing miscarriage in women with RPL included 10 trials (1684 women).²⁰ This meta-analysis revealed an RR of 0.73 (95% CI, 0.54-1.00) for miscarriage among women taking progesterone. However, the quality of evidence was moderate. A subgroup analysis resulted in an RR of 0.59 (95% CI, 0.34-1.01) in those with a history of 3 or more miscarriages.

Clearly, no universal agreement exists regarding the use of progesterone in women with a history of RPL. The ASRM 2012 guidelines on the evaluation and treatment of RPL state that “in patients with 3 or more consecutive miscarriages immediately preceding their current pregnancy, empiric progesterone administration may be of some potential benefit.”¹⁶

ACOG guidelines state that “women who have experienced at least 3 prior pregnancy losses may benefit from progesterone therapy in the first trimester.”¹¹ ESHRE guidelines on RPL state that “vaginal progesterone does not improve live birth rate in women with unexplained RPL” and “there is insufficient evidence to recommend the use of progesterone to improve live birth rate in women with RPL and luteal phase insufficiency.”¹⁴

Safety of progesterone in pregnancy

One factor that plays a role in a clinician’s decision-making process, apart from the specific treatment, is treatment safety. In a case control study, progesterone supplementation was associated with an increased risk of hypospadias (odds ratio [OR], 3.7; 95% CI, 2.3-6.0).

The risk remained elevated even among cases that did not report any additional subfertility procedures or treatment (OR, 2.2; 95% CI, 1.0-5.0).²¹

However, the history of progestin intake was evaluated by maternal interviews after birth with a risk of recall bias. In addition, in 30 of the 42 cases of hypospadias, the type (progesterone or a synthetic progestin) and duration of progestin treatment were unknown. The risks associated with natural progesterone are unclear, and using synthetic progestins in pregnancy is not advisable. In another case control study involving 402 patients, the use of dydrogesterone was associated with congenital heart defects (adjusted OR, 2.71; 95% CI, 1.54-4.24).²²

The study also was at risk of a recall bias and did not control for the indication for dydrogesterone treatment.

The PROMISE and PRISM trials found no evidence for an increased risk of congenital malformations in women taking micronized vaginal progesterone. Although the studies were not powered to do so, this finding is reassuring. Despite limited data and low quality, both Cochrane reviews regarding threatened abortion and RPL found no increase in congenital anomalies in women treated with progesterone.

In addition, controlled trials have shown no increased risk of congenital anomalies, including genital abnormalities resulting from progesterone exposure in early pregnancy.

The ASRM concluded that there is no evidence indicating that maternal exposure to progesterone increased the risk of birth defects.²³

In an overview of birth defects reported between 1977 and 2005, 28 cases of a potential link between dydrogesterone use and congenital birth defects were reported.²⁴ The type of defects showed no specific pattern, suggesting that an association between dydrogesterone use and birth defects is unlikely.

More importantly, an estimated 10 million pregnant women received dydrogesterone during this period, also supporting the safety of dydrogesterone in pregnancy. Clinical studies of progesterone use during pregnancy, both oral and vaginal, support its tolerability and relatively minimal adverse effects.

Conclusion

Current evidence regarding the role of progesterone in early pregnancy is inconclusive.

It is likely that progesterone has no role in the treatment of threatened miscarriage in women without a history of previous miscarriages. It is plausible that in cases of unexplained RPL, especially among those who present with vaginal bleeding and a history of multiple pregnancy losses, progesterone may be of benefit.

Considering the apparent safety profile, it is not surprising that many experts still recommend and administer such treatment.

Unfortunately, the evidence remains unclear, and many questions, such as the most appropriate indication, preferred dose, duration, route of administration, number needed to treat, and cost-effectiveness, need further study.

References

1. Carp HJA. Progestogens and pregnancy loss. Climacteric. 2018;21(4):380-384. doi:10.1080/13697137.2018.1436166

2. Csapo AI, Pulkkinen MO, Ruttner B, Sauvage JP, Wiest WG. The significance of the human corpus luteum in pregnancy maintenance: I. preliminary studies. Am J Obstet Gynecol. 1972;112(8):1061-1067. doi:10.1016/0002-9378(72)90181-0

3. Csapo AI, Pulkkinen MO, Wiest WG. Effects of luteectomy and progesterone replacement therapy in early pregnant patients. Am J Obstet Gynecol. 1973;115(6):759-765. doi:10.1016/0002-9378(73)90517-6

4. Wilcox AJ, Weinberg CR, O’Connor JF, et al. Incidence of early loss of pregnancy. N Engl J Med. 1988;319(4):189-194. doi:10.1056/NEJM198807283190401

5. Trinder J, Brocklehurst P, Porter R, Read M, Vyas S, Smith L. Management of miscarriage: expectant, medical, or surgical? Results of randomised controlled trial (miscarriage treatment (MIST) trial). BMJ. 2006;332(7552):1235-1240. doi:10.1136/bmj.38828.593125.55

6. Farren J, Jalmbrant M, Falconieri N, et al. Posttraumatic stress, anxiety and depression following miscarriage and ectopic pregnancy: a multicenter, prospective, cohort study. Am J Obstet Gynecol. 2020;222(4):367.e1-367.e22. doi:10.1016/j.ajog.2019.10.102

7. Magnus MC, Wilcox AJ, Morken NH, Weinberg CR, Håberg SE. Role of maternal age and pregnancy history in risk of miscarriage: prospective register based study. BMJ. 2019;364:l869. doi:10.1136/bmj.l869

8. Wahabi HA, Fayed AA, Esmaeil SA, Bahkali KH. Progestogen for treating threatened miscarriage. Cochrane Database Syst Rev. 2018;8(8):CD005943. doi:10.1002/14651858.CD005943.pub5

9. 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(19):1815-1824. doi:10.1056/NEJMoa1813730

10. Yan Y, Chen Z, Yang Y, et al. Efficacy of progesterone on threatened miscarriage: an updated meta-analysis of randomized trials. Arch Gynecol Obstet. 2021;303(1):27-36. doi:10.1007/s00404-020-05808-8

11. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Gynecology. ACOG practice bulletin no. 200: early pregnancy loss. Obstet Gynecol. 2018;132(5):e197-e207. doi:10.1097/AOG.0000000000002899

12. Ectopic pregnancy and miscarriage: diagnosis and initial management. National Institute for Health and Care Excellence. April 17, 2019. Accessed July 24, 2021. https://www.nice.org.uk/guidance/ng126

13. Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril. 2020;113(3):533-535. doi:10.1016/j.fertnstert.2019.11.025

14. Guideline on the management of recurrent pregnancy loss. European Society of Human Reproduction and Embryology. Accessed July 18, 2021. https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Recurrent-pregnancy-loss.aspx

15. Ozawa N, Ogawa K, Sasaki A, Mitsui M, Wada S, Sago H. Maternal age, history of miscarriage, and embryonic/fetal size are associated with cytogenetic results of spontaneous early miscarriages. J Assist Reprod Genet. 2019;36(4):749-757. doi:10.1007/s10815-019-01415-y

16. Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5):1103-1111. doi:10.1016/j.fertnstert.2012.06.048

17. Practice Committees of the American Society for Reproductive Medicine and the Society for Reproductive Endocrinology and Infertility. Diagnosis and treatment of luteal phase deficiency: a committee opinion. Fertil Steril. 2021;115(6):1416-1423. doi:10.1016/j.fertnstert.2021.02.010

18. Kumar A, Begum N, Prasad S, Aggarwal S, Sharma S. Oral dydrogesterone treatment during early pregnancy to prevent recurrent pregnancy loss and its role in modulation of cytokine production: a double-blind, randomized, parallel, placebo-controlled trial. Fertil Steril. 2014;102(5):1357-1363.e3. doi:10.1016/j.fertnstert.2014.07.1251

19. Coomarasamy A, Williams H, Truchanowicz E, et al. A randomized trial of progesterone in women with recurrent miscarriages. N Engl J Med. 2015;373(22):2141-2148. doi:10.1056/NEJMoa1504927

20. Haas DM, Hathaway TJ, Ramsey PS. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology. Cochrane Database Syst Rev. 2019;2019(11):CD003511. doi:10.1002/14651858.CD003511.pub5

21. Carmichael SL, Shaw GM, Laurent C, Croughan MS, Olney RS, Lammer EJ. Maternal progestin intake and risk of hypospadias. Arch Pediatr Adolesc Med. 2005;159(10):957-962. doi:10.1001/archpedi.159.10.957

22. Zaqout M, Aslem E, Abuqamar M, Abughazza O, Panzer J, De Wolf D. The impact of oral intake of dydrogesterone on fetal heart development during early pregnancy. Ped Cardiol.2015;36(7):1483-1488. doi:10.1007/s00246-015-1190-9

23. Practice Committee of the American Society for Reproductive Medicine. Progesterone supplementation during the luteal phase and in early pregnancy in the treatment of infertility: an educational bulletin. Fertil Steril. 2008;89(4):789-792. doi:10.1016/j.fertnstert.2008.02.012

24. Queisser-Luft A. Dydrogesterone use during pregnancy: overview of birth defects reported since 1977. Early Hum Dev. 2009;85(6):375-377. doi:10.1016/j.earlhumdev.2008.12.016