“Further research is needed to explore the possible interaction between folate-associated status (FAS) and progesterone use on the risk of malformations,” the authors stated.
The study, led by Jiang-Nan Wu and colleagues from the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, was published in the European Journal of Medical Research. It evaluated the potential link between early pregnancy bleeding, progesterone supplementation, and folic acid use, aiming to clarify whether their combination influences the risk of congenital malformations.
Progesterone supplementation is commonly used to prevent miscarriage, especially in cases of threatened abortion. Meanwhile, folic acid is well-established for its role in reducing the risk of neural tube defects and supporting early fetal development. Although animal research has indicated that folic acid supplementation may improve progesterone activity, little evidence exists on how these two interventions interact in human pregnancies complicated by early bleeding.
To explore this, researchers conducted a large multicenter prospective cohort study involving 17,713 pregnant women recruited between 11 and 13 weeks of gestation from 23 tertiary hospitals across 12 provinces in China. The study investigated how different treatments for early pregnancy bleeding—including progesterone administered either orally or by injection—and folic acid supplementation affected pregnancy outcomes.
The key findings of the study were as follows:
- Women who experienced vaginal bleeding during early pregnancy had a higher risk of delivering infants with congenital malformations compared to those without bleeding (HR 1.37).
- Treatment for bleeding, including progesterone therapy, was not significantly associated with an increased risk of malformations compared with no treatment (HR 1.05).
- The interaction between folic acid supplementation and progesterone use was not statistically significant in the overall study population (HR 1.55).
- Among women who experienced bleeding, the interaction between folic acid use and progesterone therapy remained insignificant (HR 3.22).
- In women without a history of adverse pregnancy outcomes, progesterone injections were not significantly linked to malformations compared to those untreated (HR 1.18).
- When compared with women who had no bleeding, the association between progesterone injections and malformations approached borderline statistical significance (HR 1.61).
The researchers concluded that while vaginal bleeding in early pregnancy is an independent risk factor for fetal malformations, routine use of progesterone injections—particularly in women without an adverse pregnancy history—should be approached with caution. They emphasized the need for additional studies to better understand the potential combined effect of folic acid supplementation and progesterone therapy on congenital malformation risk.
These findings highlight the importance of individualized treatment decisions in managing early pregnancy bleeding and the necessity for further research to optimize both maternal and fetal outcomes.
Reference:
Wu, JN., Yin, LL., Deng, XD. et al. Association of combined folic acid and progesterone use with congenital malformations in women with vaginal bleeding during early pregnancy: a multicenter cohort study. Eur J Med Res 30, 1057 (2025). https://doi.org/10.1186/s40001-025-03370-0
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