A University of South Florida Health preclinical study indicates that FKBP51-progesterone receptor binding plays a critical role in stress-induced preterm birth

Babies born before 37 weeks, particularly those born before 34 weeks, have more health problems and may face long-term complications like heart and lung diseases and neurodevelopmental delays.

Tampa, FL (March 8, 2021) — Preterm birth is a leading cause of infant deaths and illness in the U.S. — yet its underlying molecular causes remain largely unclear. About 40 to 50% of preterm births, defined as births before 37 weeks of pregnancy, are estimated to be “idiopathic,” meaning they arise from unexplained or spontaneous labor. And, maternal stress linked to depression and post-traumatic stress disorders as well as fetal stress have been strongly implicated in preterm births with no known cause.

Now, for the first time, a University of South Florida Health (USF Health) preclinical study has uncovered a mechanism to help explain how psychological and/or physiological stress in pregnant women triggers idiopathic preterm birth. A research team at the USF Health Morsani College of Medicine Department of Obstetrics and Gynecology shows how cortisol — the “fight-or-flight” hormone critical for regulating the body’s response to stress — acts through stress-responsive protein FKBP51 binding to progesterone receptors to inhibit receptor function in the uterus. This reduced progesterone receptor activity stimulates labor.

The findings were published online first March 8 in Proceedings of the National Academy of Sciences (PNAS).

“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, MD, senior vice president of USF Health, dean of the USF Health Morsani College of Medicine, and a professor of obstetrics and gynecology specializing in maternal-fetal medicine.

Dr. Lockwood was a co-principal investigator for the study along with the paper’s lead author Ozlem Guzeloglu-Kayisli, PhD, a USF Health associate professor of obstetrics and gynecology. Nihan Semerci, MSc, a senior biological scientist, shares the lead authorship with Dr. Guzeloglu-Kayisli.

The preclinical study providing molecular insights into maternal stress and preterm birth of unknown cause was led by USF Health’s Charles J. Lockwood, MD, (above) and Ozlem Guzeloglu-Kayisli, PhD. | Photos by Freddie Coleman and Allison Long, USF Health Communications

Progesterone reduces contractions of the uterus and sustained levels are essential to prevent a baby from being born too early. Reduced uterine progesterone receptor expression and signaling stimulates labor. In the brain, elevated FKBP51 expression has been strongly associated with increased risk for stress-related disorders.

Previous work by the USF Health team showed that normal human labor starting at term (between 37 and 42 weeks of pregnancy) was associated with reduced expression of progesterone receptors and increased expression of FKBP51, specifically in maternal decidual cells (specialized cells lining the uterus).

For the current study focused on maternal stress-induced idiopathic preterm birth, the researchers combined experiments in human maternal decidual cells and a mouse model in which FKBP5, the gene that makes FKBP51, had been removed, or “knocked out.” Altogether, their results revealed a novel functional progesterone withdrawal mechanism, mediated by maternal stress-induced uterine FKBP51 overexpression and enhanced FKPB51-progesterone receptor binding, that decreased progestational effects and triggered preterm birth. The researchers found that Fkbp5 knockout mice (with depletion of the gene encoding for FKBP51) exhibit prolonged gestation and are completely resistant to maternal stress-induced preterm birth.

Among the USF Health team’s key findings:

– FKPB51 levels were greater and FKPB51 binding to progesterone receptors was significantly increased in the decidual cells of women with idiopathic preterm birth, compared to decidual cells of gestational age-matched controls.

– The study reports for the first time that Fkbp5-deficient (knockout) mice are completely resistant to maternal stress-induced preterm birth and exhibit prolonged pregnancies accompanied by slower decline in systemic progesterone levels. This indicates that FKBP51 plays a crucial role in the length of pregnancy and initiation of labor and delivery.

– In contrast, mice with the FKPB5 gene intact and normal levels of FKPB51 protein (wild type mice) delivered earlier when exposed to maternal stress than either non-stressed wild type mice or FKPB5 knockout mice under nonstressed or stressed conditions.

“Collectively, these results suggest that FKBP51 plays a pivotal role both in term labor and stress-associated preterm parturition (birth) and that inhibition of FKBP51 may prove to be a novel therapy to prevent idiopathic preterm birth,” the study authors conclude.

Dr. Guzeloglu-Kayisli (center) in the Ob-Gyn research team’s laboratory, USF Health Morsani College of Medicine, with MCOM maternal-fetal medicine fellow Anthony Kendle, MD (left) and biological scientist Xiaofang Guo (right), who are isolating tissue samples | Photo by Allison Long, USF Health Communications.

Currently, injectable progesterone is the only drug approved to help prevent preterm birth in high-risk women who have had a previous preterm birth. However, its effectiveness was not confirmed by a recent large clinical trial, sparking debate in the health care community.  The authors finding that progesterone receptor activity was reduced in idiopathic preterm birth may explain the apparent lack of effectiveness of supplemental progesterone.

Babies born before 37 weeks, particularly those born before 34 weeks, have more health problems and may face long-term health complications, including childhood lung or heart disease and neurodevelopmental delays, Dr. Guzeloglu-Kayisli said. The likelihood of poor outcomes decreases as gestational age (length of the pregnancy) increases.

“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,” Dr. Guzeloglu-Kayisli said. “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.”

The USF Health study was supported in part by The March of Dimes Prematurity Research Center Ohio Collaborative grant.

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Tampa, Fla (October 30, 2017) – Pregnant women who consume fish rather than fish oil supplements are just as likely to protect their offspring from developing asthma.

Researchers at the University of South Florida in Tampa, Fla, just published a scientific review of two studies that conclude children whose mothers consume high-dose omega-3 fatty acids daily during the third trimester are less likely to develop such breathing problems.

However, co-authors Richard Lockey, MD, and Chen Hsing Lin, MD suggest pregnant women receive the same benefit following the Food and Drug Administration and Environmental Protection Agency’s recommendation to consume 8-12 ounces (2-3 servings) of low mercury fish a week.

The review published in the Journal of Allergy and Clinical Immunology: In Practice examined two articles. The New England Journal of Medicine study included 346 pregnant women in their 3^d trimester who took omega-3 fatty acids daily and 349 who took a placebo. The investigators also divided the trial population into three groups based on their blood levels of omega-3 fatty acids. The population with the lowest blood levels benefited the most from fish oil supplementation.

The Journal of Allergy and Clinical Immunology randomized pregnant women in their 3^rd trimester into fish oil, placebo and “no oil” groups. The fish oil group took omega-3 fatty acids daily as did the placebo (olive oil) group. The “no oil” group was informed of the trial proposal and therefore could consume fish oil or fish during the 3^rd trimester if they chose to do so. Researchers found the fish oil and the “no oil” groups took less asthma medication as they aged to 24 years old, inferring both groups developed less asthma.

“Omega-3 fatty acids cannot be synthesized by humans and therefore are essential nutrients which are derived exclusively from marine sources,” said Lin. “It may be premature to recommend daily high dose fish oil supplementation during the 3^rd trimester.”

“With almost equal to slightly higher cost, consuming 8-12 ounces (2-3 servings) of fish a week not only may attain the same asthma protection, but strengthens the nutritional benefits to infant growth and development,” said Lockey.

Dr. Maureen Groer heads a group of USF Health researchers in a five-year study examining the relationship between a common parasite and how it affects the brain of pregnant Hispanic women

Tampa, FL (August 31, 2017) – The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) has awarded more than $2.6 million to the University of South Florida College of Nursing to study the correlation between pregnant Hispanic women, depression and a common parasite that affects the brain.

Maureen Groer, PhD, Gordon Keller professor at the USF College of Nursing, will lead a group of USF Health researchers in a five-year study examining whether Hispanic women, who carry the Toxoplasma gondii parasite, have a greater risk of the infection reactivating during pregnancy.

The project is significant because it is the largest study ever done on Hispanic women infected with the parasite. The Toxoplasma parasite is a common organism that can be transferred through eating undercooked meat or touching cat feces.

The study could help pinpoint one of the causes of prenatal and postpartum depression and lead to different treatments for chronic toxoplasmosis.

Maureen Groer, PhD

Pregnant women, who have a weaker immune system, are more susceptible to the infection, which can cause brain and eye damage and result in personality changes. Once infected, the parasite normally lives in the brain in a dormant state.

“It would be the first large study to measure the immune changes in pregnancy and its effects on chronically infected women,” Dr. Groer said. “So we’re looking at immunity in these women across pregnancy.”

Dr. Groer and her team will screen more than 800 women at Tampa General Hospital’s Genesis Women’s Center to find 480 pregnant Hispanic women — half of the women will have tested positive for the parasite, while the remaining 240 women will not.

Researchers will monitor the two groups during pregnancy and for six weeks after giving birth. The women will undergo blood tests to study chemicals related to depression and eye exams to see if the parasite has formed cysts in the retina.  Scientists will also test the infant’s cord blood to see if the parasite was transferred from the mother.

Dr. Groer believes the women who carry the organism will be more likely to experience prenatal and postpartum depression and have the latent parasite reactivate during pregnancy.

“They had it already, and now their immune system is very different. And some defenses they normally had against the organism might be less effective. So if the organism reactivates, it will reactivate likely in the eye,” she said.

The study, titled “Chronic Toxoplasma gondii, Pregnancy Reactivation, and Perinatal Depression,” focuses on Hispanic women, because a previous USF health study Dr. Groer conducted linking depression and the Toxoplasma gondii parasite noticed a high infection rate among Hispanic women.

Dr. Groer will work with a team of USF Health researchers who specialize in ophthalmology, biological chemistry, molecular medicine, psychiatry, neurosciences, and biostatistics.

The study’s co-investigators within the College of Nursing include Allyson Duffy, PhD, assistant professor; Amanda Elliott, PhD, assistant professor; and Ming Ji, PhD, professor.

Dr. Groer will also collaborate with researchers and physicians from USF Health Morsani College of Medicine, including Andreas Seyfang, PhD, associate professor; Jamie Fernandez, MD, associate professor; Steven Cohen, MD, professor; Karen Bruder, MD, associate professor; and Adetola Louis-Jacques, MD, assistant professor.

Teodor Postolache, MD, a psychiatry professor at the University of Maryland School of Medicine, will also be a co-investigator. Dietmar Fuchs, an associate professor of biological chemistry at Innsbruck Medical University in Austria, will consult on the project.

The study is supported by NICHD, part of the National Institutes of Health (NIH). NICHD strives to ensure that every child is born healthy and grows up free from disease and disability. For more information about NIH and NICHD visit www.nichd.nih.gov.

-Story by Elizabeth Brown,  USF College of Nursing Communications

USF public health leader involved in the FDOH investigation comments

Florida’s rate of ectopic pregnancy deaths jumped in 2009-10 – an increase that may be associated with delays in obtaining care and illicit drug use, according to a new report by the U.S. Centers for Disease Control and Prevention.  The state’s rise in ectopic pregnancy deaths, published in the CDC’s Feb. 17 issue of Morbidity & Mortality Weekly Report, runs counter to the national trend of steadily declining deaths.

“It was surprising,” said one of the report’s co-authors Dr. William Sappenfield, director of the Chiles Center for Healthy Mothers and Babies at USF, who was maternal-child health epidemiologist at the Florida Department of Health when the study was conducted.

“Nationwide, ectopic pregnancy death rates are going down, because the condition has become much easier and quicker to diagnose and treat,” said Dr. Sappenfield, chair of Community and Family Health at the USF College of Public Health.

Dr. William Sappenfield of the USF College of Public Health was a co-author of the report published in the CDC’s Mortality & Morbidity Weekly.

Ectopic pregnancy occurs when an egg is fertilized outside the uterus, usually in the fallopian tube.  If it remains undetected the pregnant woman may die if the tube ruptures, leading to rapid blood loss.

Improvements in pregnancy testing, ultrasound examination and outpatient treatments, including laparoscopic surgery and medications, have contributed to the decline in deaths. This success is largely dependent on access to care so women with signs and symptoms of ectopic pregnancy can be identified and treated before tube rupture, shock and severe blood loss.

Dr. Sappenfield helped staff the multidisciplinary team investigating ectopic pregnancy deaths in Florida, based on a review of cause death, risk factors and prevention opportunities.

Florida’s ectopic pregnancy mortality ratio was similar to the national rate of 0.6 deaths per 100,000 live births during 1999–2008, but increased abruptly to 2.5 during 2009-2010.  This four-fold increase appeared to be linked in part to lack of access to care. The researchers found that the 13 women who died in the one year (2009-2010) were more likely to have collapsed from a hemorrhage before seeking care than the 11 women who died the previous decade from ectopic pregnancies. Of the eight women who collapsed during 2009-2010, six tested positive for illicit drug use.

“We clearly have not reached our potential to prevent this life-threatening condition,” Dr. Sappenfield said.

Based on their review, the investigators wrote: “Efforts to prevent ectopic pregnancy deaths need to ensure early access to care, promote awareness about early pregnancy testing and ectopic pregnancy risk, and raise public awareness about substance abuse risks, especially during pregnancy.”

While ectopic pregnancy cannot be prevented, Dr. Sappenfield said, pregnant women and those of childbearing age should not delay seeking medical attention for continuing abdominal or pelvic pain, usually 6 to 8 weeks after a missed period.  Better to quickly rule out an ectopic pregnancy than to risk future fertility and perhaps dangerous complications if the pregnancy ruptures the fallopian tube.

Story by Anne DeLotto Baier, USF Health Communications