Endocrine interventions and live birth outcomes in women with recurrent pregnancy loss: a meta-analysis

Kiny-Binyumbe Doukaga; Shan Wang

doi:10.18203/2320-1770.ijrcog20263449

Authors

Kiny-Binyumbe Doukaga Department of Reproductive Medicine, Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong First Medical University, Tai’an, Shandong, China https://orcid.org/0009-0009-1285-172X
Shan Wang Department of Reproductive Medicine, Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China https://orcid.org/0000-0002-6783-7599

DOI:

https://doi.org/10.18203/2320-1770.ijrcog20263449

Keywords:

Recurrent pregnancy loss, Progesterone, Levothyroxine, Live birth rate, Endocrine intervention, Meta-analysis

Abstract

Recurrent pregnancy loss (RPL) is a multifactorial reproductive disorder for which endocrine therapies are frequently considered, although their effects on live birth remain uncertain. This meta-analysis assessed the effectiveness of progesterone and levothyroxine on pregnancy outcomes in women with RPL. Following PRISMA 2020 guidance, PubMed, the Cochrane Central Register of Controlled Trials, and Web of Science were searched from January 2015 to the final search date without language restrictions. Eight studies involving 7,749 participants were included in the systematic review; quantitative synthesis was restricted to randomized controlled trials with comparable data. Mantel-Haenszel fixed-effect meta-analyses generated pooled risk ratios (RRs) with 95% confidence intervals (CIs), heterogeneity was assessed using I², and risk of bias was evaluated with Cochrane RoB 2. For progesterone versus placebo, two large trials (PROMISE and PRISM; n=4,864) showed no statistically significant improvement in live birth (RR=1.03, 95% CI=1.00-1.07; I²=0%; p=0.08). For levothyroxine, pooled analysis suggested a non-significant trend toward improved live birth (RR 1.25, 95% CI 0.90-1.73; I²=74%), but substantial heterogeneity limited confidence in the estimate. Differences in thyroid status and study populations may explain part of this variability. Current evidence does not support routine empirical progesterone or levothyroxine use in unselected women with RPL. Progesterone may offer modest benefit in selected higher-risk subgroups, particularly women with multiple previous miscarriages; treatment should therefore be individualized according to clinical characteristics and endocrine profiles.

References

Turesheva A, Aimagambetova G, Ukybassova T, Marat A, Kanabekova P, Kaldygulova L, et al. Recurrent pregnancy loss etiology, risk factors, diagnosis, and management. Fresh look into a full box. J Clin Med. 2023;12(12):4074.

Cao C, Bai S, Zhang J, Sun X, Meng A, Chen H. Understanding recurrent pregnancy loss: recent advances on its etiology, clinical diagnosis, and management. Med Rev. 2023;2(6):570-89.

ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, et al. ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open. 2023;2023(1):hoad002.

Krog MC, Nielsen HS, Christiansen OB, Kolte AM. Reproductive endocrinology in recurrent pregnancy loss. Clin Obstet Gynecol. 2016;59(3):474-86.

Kaur R, Gupta K. Endocrine dysfunction and recurrent spontaneous abortion: an overview. Int J Appl Basic Med Res. 2016;6(2):79-83.

Coomarasamy A, Devall AJ, Cheed V, Harb H, Middleton LJ, Gallos ID, et al. A randomized trial of progesterone in women with bleeding in early pregnancy. N Engl J Med. 2019;380(19):1815-24.

Coomarasamy A, Williams H, Truchanowicz E, Seed PT, Small R, Quenby S, et al. A randomized trial of progesterone in women with recurrent miscarriages. N Engl J Med. 2015;373(22):2141-8.

Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(3):315-89.

Jansen S, Leduc-Robert G, AbdelHafez FF, Albert A, Mayer U, Bedaiwy MA. Temporal trends in thyroid-stimulating hormone and live birth rate in subclinical hypothyroid patients in a recurrent pregnancy loss population. Eur J Obstet Gynecol Reprod Biol. 2022;277:21-6.

van Dijk MM, Vissenberg R, Fliers E, van der Post JAM, van der Hoorn MP, de Weerd S, et al. Levothyroxine in euthyroid thyroid peroxidase antibody-positive women with recurrent pregnancy loss (T4LIFE trial): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2022;10(5):322-9.

Leng T, Li X, Zhang H. Levothyroxine treatment for subclinical hypothyroidism improves the rate of live births in pregnant women with recurrent pregnancy loss: a randomized clinical trial. Gynecol Endocrinol. 2022;38(6):488-94.

Morley LC, Tang T, Yasmin E, Norman RJ, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2017;11(11):CD003053.

Palomba S, Molinaro M, Ingargiola A, Aversa A. Recent developments in drug treatment strategies for infertility in patients with polycystic ovary syndrome. Expert Opin Pharmacother. 2024;25(16):2191-202.

Saadati S, Mason T, Godini R, Vanky E, Teede H, Mousa A. Metformin use in women with polycystic ovary syndrome: opportunities, benefits, and clinical challenges. Diabetes Obes Metab. 2025;27(3):31-47.

Shpakov AO. Improvement effect of metformin on female and male reproduction in endocrine pathologies and its mechanisms. Pharmaceuticals. 2021;14(1):42.

Zhou L, Qu H, Yang L, Shou L. Effects of GLP1RAs on pregnancy rate and menstrual cyclicity in women with polycystic ovary syndrome: a meta-analysis and systematic review. BMC Endocr Disord. 2023;23(1):245.

Ling Q, Xu J, Tian Y, Chen D, Mo C, Peng B. Effect of IVIG therapy on pregnant women with unexplained recurrent spontaneous abortion: a systematic review and meta-analysis. Front Endocrinol. 2024;15:1381461.

Fang T, Ji X, Su Z, Zhang A, Zhu L, Tang J, et al. Risk factors associated with pregnancy outcomes in patients with recurrent pregnancy loss after treatment. BMC Pregnancy Childbirth. 2024;24(1):827.

Zhou X, Lai F, Chen W, Zhou C, Deng Y, Wang T, et al. The landscape of recurrent spontaneous abortion registered on ClinicalTrials.gov. Front Endocrinol. 2024;15:1460968.

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Rev Panam Salud Publi. 2022;46:e112.

Sterne JAC, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.

Agarwal N, Gupta S, Kulshrestha V, Yadav RK, Kriplani A, Kachhawa G, et al. Cytokines and pentraxin 3 levels in unexplained recurrent pregnancy loss: role of oral micronized progesterone therapy as immunomodulator on their levels and pregnancy outcome, a prospective comparative study. J Obstet Gynaecol India. 2025;75(1):59-66.

Xu GL, Hu XF, Han YM, Wei AW. Clinical efficacy of low molecular heparin on unexplained recurrent spontaneous abortion. Clin Lab. 2018;64(6):1037-40.

Kale AR, Kale AA, Yelikar K. A comparative, randomized control trial in patients of per vaginal bleeding comparing efficacy of oral dydrogesterone versus vaginal progesterone in successful pregnancy outcome for patients with recurrent pregnancy loss. J Obstet Gynaecol India. 2021;71(6):591-5.

Dal Lago A, Galanti F, Miriello D, Marcoccia A, Massimiani M, Campagnolo L, et al. Positive impact of levothyroxine treatment on pregnancy outcome in euthyroid women with thyroid autoimmunity affected by recurrent miscarriage. J Clin Med. 2021;10(10):2105.