NIH Study at UH Rainbow Aims to Mitigate Alcohol as a Factor in Congenital Heart Diseases

Innovations in Pediatrics | Spring 2025

As many as 40% of infants born with fetal alcohol spectrum disorder (FASD) have congenital heart disease (CHD), the most common being valvuloseptal and outflow tract defects. However, the role of alcohol exposure in these life-threatening and life-altering conditions has not been widely studied.

Stephanie Ford, MD

At UH Rainbow Babies & Children’s Hospital, neonatologist Stephanie Ford, MD, is looking to change that. She’s studying how prenatal alcohol exposure induces changes at times critical to human heart development, using hearts of quail and mouse embryos as a model. Her goal is to identify where within the 3D heart, such as the forming valves, gene expression is changing in response to alcohol --- and whether compounds administered during pivotal periods of embryonic heart development could ultimately be used to prevent CHDs.

Dr. Ford’s research is funded by the National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health.

What kind of compound might make the difference? Dr. Ford says she and her team are exploring whether choline and glutathione can prevent the effects of prenatal alcohol exposure. Both are available as over-the-counter supplements.

“Choline and glutathione are known to promote methylation in one-carbon metabolism,” she says. “Choline has been shown in preliminary human studies to prevent early neurologic effects of prenatal alcohol exposure. What’s more, we’ve shown in an avian model that glutathione prevents the CHDs and abnormal DNA methylation seen after prenatal alcohol exposure. We’re using both avian and mouse models to determine the effects of alcohol + choline or glutathione on cardiac structure, DNA methylation, and gene expression. We hypothesize that by maintaining normal methylation, and therefore DNA expression, our chosen compounds will prevent the CHDs that result from prenatal alcohol exposure.”

With appointments at UH Rainbow in both neonatology and pediatric cardiology, Dr. Ford is ideally suited to lead this work. Already, her published research has shown that prenatal alcohol exposure reduced global DNA methylation in the developing heart and that glutathione is effective in protecting the embryo from this hypomethylation. Furthermore, using optical coherence tomography and novel LIMPID 3D FISH protocols, she can image and measure embryonic cardiac structure and link congenital heart disease subtypes to 3D gene expression and DNA methylation.

Dr. Ford says she first got interested in these topics as a basic scientist, curious to learn more about how and why CHDs develop. The development of the human heart, from something early in the embryonic stage that’s C-shaped, to a fully formed four-chamber organ, she says, requires complex cell signaling -- everything must go just right. Her research has found that with blood flow going backward more than normal, known as regurgitant blood flow, the negative effects on the developing heart can be profound. Dr. Ford has shown regurgitant blood flow to be important in CHD formation in multiple animal models, including prenatal alcohol exposure.

“What we found in some of our previous experiments is if we take some of these hearts that are just past the equivalent of five weeks gestation and you change the blood flow so it’s more backwards blood flow than is normal, you can very drastically change how the heart forms,” she says. “You end up with clinically relevant congenital heart defects like those we see in kids.”

By better understanding this cardiac embryonic process, she says, it provides a greater foundation to try to intervene, such as with compounds to combat prenatal alcohol exposure.

Research is ongoing, but Dr. Ford says it’s already quite clear from her research that just one binge drinking episode by a pregnant woman during the critical period of gastrulation – the early embryonic phase around four to five weeks gestation during which the blastula reorganizes into a two-layered or three-layered gastrula – can contribute to CHDs.

“If you give alcohol during that time, then the cells get abnormal signals,” she says. ”Essentially, their gene expression is different, and we have shown in in our work that this can  lead to the congenital heart defects that we see in kids.”

That’s why her ongoing NIAAA study is so crucial, she says.

“Compounds that could prevent prenatal alcohol exposure-induced CHDs could help thousands of children and their families each year,” Dr. Ford says.

For more information on this study, please email Peds.Innovations@UHhospitals.org.

Contributing Expert:
Stephanie Ford, MD
Neonatologist
UH Rainbow Babies & Children’s Hospital
Associate Professor of Pediatrics
Case Western Reserve University School of Medicine