Immunomodulatory Role of Natural Progesterone in Pregnancy: A Review

Prakash Mehta; Hemant Deshpande; Anjali Deshpande; Reshma Quadros; Shruti Dharmadhikari; Chintan Khandhedia; Gaurav Puppalwar; Amey Mane; Suyog Mehta

doi:10.1111/jog.70342

Immunomodulatory Role of Natural Progesterone in Pregnancy: A Review

Mehta P, Deshpande H, Deshpande A, Quadros R, Dharmadhikari S, Khandhedia C, Puppalwar G, Mane A, Mehta S

Published June 2026 The journal of obstetrics and gynaecology research, 52(6), e70342

DOI 10.1111/jog.70342 PMID 42303279 PMC PMC13271834

RRM Academy Synopsis

Natural progesterone supports pregnancy by shaping immune signaling

A 2026 narrative review reports that natural progesterone appears to support pregnancy by shifting the mother's immune response toward tolerance of the baby. The review addresses miscarriage, preterm birth and luteal phase defect. The authors searched two databases through April 2025.

Key Findings

In a randomized trial of 221 women with threatened miscarriage, progesterone lowered the inflammatory markers IL-6 and TNF-α and raised anti-inflammatory IL-10, with the effect proportional to dose.
In a randomized study of women with recurrent pregnancy loss, the abortion rate (miscarriage) was 3.5% with oral micronized progesterone and 16.7% without it.
In another randomized study of recurrent pregnancy loss, live births occurred in 86.7% of treated women and 46.7% of untreated women (p < 0.005).
In women with impending preterm delivery, progesterone raised progesterone-induced blocking factor (PIBF), and the rise was associated with longer gestation (odds ratio 1.016, 95% CI 1.001–1.03).
Natural micronized progesterone produced no fatal, serious or unexpected adverse events in women with threatened miscarriage. The US FDA withdrew approval of the synthetic progestin 17OHP-C in 2023.

Interpretation

The paper is a narrative review. The authors report no formal appraisal and no pooled analysis. The studies range from randomized trials to cell experiments and one mouse study. The review describes two immune routes by which progesterone supports pregnancy. Directly, it shifts cytokine signaling toward a Th2-dominant profile that tolerates the baby. Indirectly, it acts through progesterone-induced blocking factor (PIBF). The authors conclude that gaps remain and emphasize the need for further research.

RRM Context

Natural progesterone is the hormone the body makes after ovulation. The review reports that luteal phase progesterone deficiency has been linked to recurrent miscarriage and preterm labor. It also keeps natural progesterone apart from synthetic progestins. RRM puts the ovulatory cycle first.

Our editorial summary of this paper, not the article's abstract.

Abstract

Aim

Pregnancy complications such as miscarriage, preterm birth (PTB), and luteal phase defects (LPD) are significant reproductive health issues globally, with both physical and psychological implications. This review aims to examine the role of natural progesterone in pregnancy-related disorders, specifically threatened and recurrent miscarriage, PTB, and LPD. Additionally, it examines how natural progesterone's immune-modulating actions, including both direct and indirect involvement, contribute to maintaining pregnancy.

Methods

This narrative review was conducted using PubMed, Google Scholar, and reference screening to identify English-language studies examining the role of natural progesterone in miscarriage, PTB, and LPD. Emphasis was placed on progesterone's immunomodulatory actions, including cytokine regulation and the activity of the progesterone-induced blocking factor (PIBF), and their relevance to pregnancy maintenance.

Results

Natural progesterone demonstrates clinical benefit in managing threatened miscarriage, recurrent pregnancy loss, preterm labor, and LPD. Evidence shows that it is well-tolerated with manageable side effects, reducing miscarriage rates, preventing PTB, and improving LPD outcomes through its effects on the maternal-fetal interface. This review also highlights progesterone's dual immunomodulatory action, direct cytokine regulation, and indirect influence via PIBF, which together contribute to improved pregnancy maintenance and outcomes.

Conclusion

Natural progesterone supports pregnancy by preventing miscarriages, preterm labor, and LPD through its direct and indirect immunomodulatory mechanisms. Clinically, it is well-tolerated with no serious or unexpected adverse events. However, gaps remain in fully understanding its effectiveness, emphasizing the need for further research.

Prakash Mehta, Hemant Deshpande, Anjali Deshpande, Reshma Quadros, Shruti Dharmadhikari, Chintan Khandhedia, Gaurav Puppalwar, Amey Mane, Suyog Mehta

P Mehta, H Deshpande, A Deshpande, R Quadros, S Dharmadhikari, C Khandhedia, G Puppalwar, A Mane, S Mehta

PMID 42303279 42303279 DOI 10.1111/jog.70342 10.1111/jog.70342 Mehta et al. 2026, Mehta 2026

Keywords

anti‐inflammatory cytokines, natural progesterone, pregnancy, progesterone‐induced blocking factor, pro‐inflammatory cytokines

Immunomodulatory Role of Natural Progesterone in Pregnancy: A Review

Natural progesterone supports pregnancy by shaping immune signaling

Key Findings

Interpretation

RRM Context

Abstract

By this author

Anxiety, Depression, and Quality of Life in Women with Polycystic Ovarian Syndrome

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Keywords