Findings in The American Journal of Pathology open avenues for development of therapeutic strategies to enhance membrane repair and prevent preterm birth

Philadelphia, September 23, 2025 – When a pregnant woman's water breaks too early, it often leads to preterm birth, with no effective method to prevent or treat it. Researchers have discovered that the lipid molecule prostacyclin plays a key role in the repair of fetal membrane rupture. The findings from a novel study in The American Journal of Pathology, published by Elsevier, provide new insights into the mechanisms of fetal membrane healing and may open avenues for the development of therapeutic strategies to enhance membrane repair and prevent preterm birth.

“Preterm birth is a major challenge in obstetrics, and it poses both medical and social problems. Infants born preterm have a significantly higher risk of perinatal mortality and morbidity,” explains lead investigator Haruta Mogami, MD, PhD, Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine.

Preterm prelabor rupture of membranes (pPROM) is one of the leading causes of preterm birth, occurring in approximately 1% of all pregnancies, and 25% to 30% of preterm births follow pPROM. Although spontaneous healing of fetal membranes is rare and occasionally observed in clinical settings, the underlying mechanisms remain poorly understood. The current research investigated the mechanisms of repair and regeneration of ruptured fetal membranes to address this gap in clinical care, focusing on the role of prostaglandins—a family of hormone-like substances—and prostacyclin, a specific member of this family known to relax blood vessels and prevent clotting.

Using a mouse model of fetal membrane rupture, investigators examined the molecular and cellular responses at the rupture site, with a focus on prostaglandin signaling.

The most significant finding is that prostacyclin signaling through the prostacyclin receptor (IP) plays a crucial role in the repair of fetal membranes by promoting healing through the proliferation and migration of amnion mesenchymal cells.

Other key findings include:

• In ruptured membranes, genes responsible for activating prostaglandin signaling and prostacyclin itself were significantly elevated at the site of the tear.
• The number of amnion mesenchymal (repair) cells at the rupture site increased as well as the enzymes creating prostacyclin.
• Pharmacological inhibition of the prostacyclin receptor (IP) impaired the repair of the amnion and led to reduced proliferation of amnion mesenchymal cells.
• When the repair signal was activated again via treatment with an IP receptor agonist, it led to partially rescued membrane repair.
• IP-deficient mouse fetuses exhibited compromised membrane healing and significantly fewer proliferating mesenchymal cells at the rupture site compared to wild-type controls.
• Complementary in vitro experiments with cultured human amnion mesenchymal cells demonstrated that IP activation enhanced both proliferation and migration of these cells, while IP antagonism had inhibitory effects, confirming the same repair mechanism exists in humans.

“We used to think that prostaglandins were only involved in inducing uterine contraction and cervical ripening during pregnancy. In this study, we clarified that prostacyclin not only relaxes the myometrium and maintains pregnancy but—when locally synthesized at the ruptured amnion—it also helps the wound heal,” notes lead author Masahito Takakura, MD, Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine.

Dr. Mogami concludes, “We were surprised to find that among various prostaglandins, only prostacyclin was specifically upregulated at the rupture site, highlighting a more selective and targeted role than we had expected. This discovery provides new insight into the mechanisms of fetal membrane healing, which could eventually lead to new therapeutic strategies for managing pPROM and reducing the risk of preterm birth and infant mortality.”