Cosmos Study

Progesterone Use Associated with 18% Reduction in Miscarriage Risk Among Women with History of Miscarriages

September 30, 2025

Team A:Kersten Bartelt, RNEric Barkley

Team B:Christopher Alban, MDJacob Gasser

Key Findings

Women with a history of miscarriages who received progesterone in the year before their pregnancy were 18% less likely to experience a miscarriage than those who did not receive progesterone before their pregnancy.

Miscarriage is a common and often emotionally devastating outcome of pregnancy. Women with prior pregnancy losses often seek interventions that might improve their chances of a healthy birth. Because progesterone plays a critical role in maintaining early pregnancy, progesterone supplementation has been considered a treatment for women with recurrent miscarriages. However, evidence from clinical trials and reviews has been mixed, leaving uncertainty for both patients and clinicians.^1,2

To further understand the relationship between progesterone supplementation and miscarriages, we studied 84,009 pregnancies among women who had at least one prior miscarriage or fetal demise. We accounted for maternal age, BMI, race and ethnicity, social vulnerability, comorbidities, fertility treatments, and count of prior pregnancies. Women who were started on progesterone after the pregnancy began were excluded to avoid confounding by indication, since clinicians are more likely to prescribe progesterone to pregnancies already perceived as threatened.

We found that women who received progesterone prior to pregnancy were 18% less likely to experience a miscarriage compared to those who did not receive progesterone.

Figure 1

Miscarriage Likelihood by Progesterone Use

Figure 1. The likelihood of an expectant mother experiencing a miscarriage by whether she was prescribed progesterone.

A sensitivity analysis analyzing the type of progesterone used, based on the pharmaceutical class, found similar results.

These data come from Cosmos, a dataset created in collaboration with a community of Epic health systems representing more than 300 million patient records from 1,700 hospitals and more than 40,000 clinics from all 50 U.S. states, Canada, Lebanon, and Saudi Arabia. This study was completed by two teams that worked independently, each composed of a clinician and research scientists. The two teams came to similar conclusions. Graphics by Brian Olson.

References

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
Devall AJ, Papadopoulou A, Podesek M, et al. Progestogens for preventing miscarriage: a network meta-analysis. Cochrane Database Syst Rev. 2021;4(4):CD013792. doi:10.1002/14651858.CD013792.pub2

Data Definitions

Study period: Pregnancies ending between 2/14/2017 and 7/2/2025

Study population: inclusion

Pregnancies with:

A documented pregnancy start date or a gestational age at delivery
Mothers aged 18 to 45 at the start of the pregnancy
At least one previous miscarriage or fetal demise
At least one outpatient face-to-face encounter prior to the pregnancy start date

Study population: exclusion: Pregnancy with multiples
Pregnancy with no active progesterone order in the year prior to the start of the pregnancy, but an order for progesterone initiated during the pregnancy.

Exposures: Progesterone order active in the year prior to the start of the pregnancy

Outcomes: Fetal demise

Confounders: Maternal age at conception: 18-29, 30-39, 40-45
Maternal pre-pregnancy BMI: <18.5, 18.5-<25, 25-<30, 30-<35, 35+
SVI quintile
Race and ethnicity: Hispanic, non-Hispanic White, non-Hispanic Black, non-Hispanic, Asian, non-Hispanic other
Gravity count
Para count
Prior C-section: Y/N
History of smoking
Diagnoses any time before pregnancy end, including problem list:
IUI fertility treatment: CPT code 58321 or 58322
IVF fertility treatment: CPT 58974, 89280 HCPCS S4011, S4015
Fertility medication: clomid (RxNorm code 2596), letrozole (RxNorm code 72965), or metformin (RxNorm code 6809)

Outpatient face-to-face encounter: Encounters of type “Emergency,” “Office Visit,” “Well Child,” “Follow-up,” “Telemedicine,” “Urgent Care,” “Walk-In,” “Routine Prenatal,” “Postpartum Visit,” “Fetal Care Consult,” or “Hospital Outpatient Visit”

Progesterone: A medication with ATC code G03D[AB]*, RxNorm code 8727 or 7514,
pharmaceutical class of “PROGESTATIONAL AGENTS” or “ESTROGEN-PROGESTIN WITH ANTIMINERALOCORTICOID COMB,” pharmaceutical subclass of “Progestins,” or a simple generic name of “MEDROXYPROGESTERONE ACETATE,” “HYDROXYPROGESTERONE CAPROATE,” or “HYDROXYPROGESTERONE CAPROAT/PF”

Model specifications: Cox PH regression model

Limitations: Different indications and strengths of progesterone were explored as a sensitivity analysis but not in the primary analysis.
We do not have documentation of any suspected causes of the prior miscarriages or fetal demises.