Healthcare Professionals

  • Combination therapy may be more effective at preventing preterm birth

    When mice with a genetic predisposition toward preterm birth also experience mild inflammation, preterm birth rates soar. But when those mice are treated with a combination of rapamycin and progesterone preterm birth rates plummet, according to a new study led by scientists at Cincinnati Children’s.

    These findings, published online Aug. 27, 2013, in the Journal of Clinical Investigation, provide evidence that gene-environment interactions are a major contributor to preterm birth and that treatments to prevent preterm birth are possible.

    The study was led by Sudhansu K. Dey, PhD, director of Reproductive Sciences at Cincinnati Children’s, first author Jeeyeon Cha, an MD / PhD graduate student in the Dey lab, and Yasushi Hirota, MD / PhD, a former postdoctoral fellow in the Dey lab and now a faculty member at the University of Tokyo.

    “The results are clinically relevant because aspects of the molecular signatures observed in the mouse studies are consistent with those observed in tissue samples of women who had undergone preterm birth,” Dey says.

    A recent report from the World Health Organization states that while more than 60 percent of preterm births occur in developing countries, the U.S. is among 10 nations with the highest numbers of preterm birth. Dey and colleagues suggest that different factors may be driving preterm birth in developing and developed countries. Infection and inflammation may affect developing countries more, while chronic diseases such as diabetes and hypertension, and the increased use of assisted reproductive technologies in older women may increase prematurity rates in developed countries.

    To conduct their research, the investigators generated a mouse model of preterm delivery in which the Trp53 gene was inactivated in the uterus. Trp53 encodes the p53 protein, which helps regulate cell growth and replication.

    The genetic deletion caused the mice to have a 50 percent preterm birth rate. This occurs because the mice exhibit increased signaling by mammalian target of rapamycin complex 1 (mTORC1) and cyclooxygenase-2 (COX2). The signaling generates fatty acids called prostaglandins that can prematurely trigger uterine contractions. Research also shows that human women who have experienced preterm birth have shown similar increases in mTORC1 and COX2 signaling.

    In this study, Trp53-deficient female mice were subjected to mild inflammation with LPS (endotoxin), which resulted in a 100 percent preterm birth rate.  The team then observed that a combination of rapamycin (an mTORC1 inhibitor) and progesterone, an ovarian hormone necessary for pregnancy success, was effective at preventing preterm birth with no apparent adverse effects on maternal or fetal health.

    Progesterone already is used by some at-risk women to prevent preterm birth. Although further investigation is required, the new findings suggest that adding low doses of an mTORC1 inhibitor may further reduce incidence rates.  

 
  • Sudhansu K. Dey, PhD.
    Sudhansu K. Dey, PhD.
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