Preterm birth is when a baby is born before the 37th week of pregnancy (The American College of Obstetricians and Gynecologists and the Society for Maternal Fetal Medicine describe a full term as 39 weeks through 40 weeks and 6 days). The liver, lungs, and brain undergo a crucial development period between 37 and 39 weeks, and preterm babies that miss that time have a host of short-and long-term complications and are at higher risk of chronic health issues. Researchers have been looking for the cause of preterm birth.
Recent work reported in the Proceedings of the National Academy of Sciences (PNAS) has suggested that imbalances in progesterone signaling may be causing some women to go into labor too early or late. Progesterone reduces uterine contractions; progesterone levels have to be maintained or labor can start too soon.
Another PNAS study investigated the link between spontaneous or unexplained early labor and stress. Both maternal stress and fetal stress have been linked to preterm birth without a known cause. Cortisol is a hormone that plays a crucial role in the body's response to stress, and the FKBP51 gene responds to stress. FKBP51 expression in the brain has been linked to a higher risk of stress-related disorder.
Previous work by this team has shown that full-term pregnancies are associated with an increase in FKBP51 expression, and a reduction in progesterone receptor expression in cells lining the uterus. FKBP51 seems to be attaching to progesterone receptors, which prevents these receptors from binding to progesterone. The reduction in progesterone receptor activity may be inducing labor.
"This new study fills in some longstanding mechanistic gaps in our understanding of how normal labor begins and how stress causes preterm birth," said the paper's senior author Charles J. Lockwood, M.D., senior vice president of USF Health, among other appointments.
Using human cells and a mouse model, the researchers found that maternal stress causes uterine cells to increase FKBP51 expression, which binds to progesterone receptors and lowers the effects of progesterone, causing preterm birth. In mice that did not express Fkbp51 protein, gestation was longer, and maternal stress did not cause preterm birth.
The authors are hopeful that this study will enable the development of therapeutics to prevent preterm birth, aimed at inhibiting FKBP51. Right now, progesterone injections are the only approved option, and the effectiveness of this approach has been called into question by a recent, large clinical trial. This latest study may help explain that finding; supplemental progesterone won't have much of an impact if the progesterone receptors are busy attaching to another molecule.
The complications that pre-term babies face are reduced as the length of the pregnancy increases (until it goes too long and other risks rise).
"Prevention of idiopathic preterm birth by extending gestation even two or three weeks can benefit the newborn because it provides critical time needed for the fetus's lungs and brain to mature," said first study author Ozlem Guzeloglu-Kayisli, Ph.D. "Our research indicates the importance of investigating the potential use of FKBP51 inhibitors as a targeted therapy to reduce the risk of stress-related preterm birth."