CHOP's prenatal surgeons work to refine and advance the techniques used to treat fetal conditions.Credit: Children's Hospital of Philadelphia
“Delivery day is really quite overwhelming,” reflects paediatric and fetal surgeon Holly Hedrick. For the past 25 years, Hedrick has worked at the Children’s Hospital of Philadelphia (CHOP) as one expert among a large ensemble of specialists, all of whom play a unique role in caring for families affected by birth defects. “To see 30 adults gathered around this little bitty bed,” Hedrick continues, “it just impresses upon you the importance of what we’re doing.”
Birth defects affect approximately 3% of children born in the United States and account for roughly 20% of infant deaths1. Although many birth defects require no intervention, major birth defects that will impact survival or negatively affect quality of life, like congenital diaphragmatic hernia, spina bifida, twin-twin transfusion syndrome, or large tumors like sacrococcydeal teratomas, require intense multidisciplinary care before birth2. For this level of care, families from around the world come to the Richard D. Wood Jr. Center for Fetal Diagnosis and Treatment at CHOP, an international leader in prenatal diagnosis, fetal surgery and complex care. CHOP specialises in open fetal surgery, minimally invasive fetoscopic surgery and ex utero intrapartum therapy. Its robust basic and translational fetal research team work to advance therapies for those affected with birth defects and genetic conditions.
Comprehensive care
CHOP is the world’s first children’s hospital to have a delivery unit specifically designed for mothers carrying babies with genetic and structural birth defects. “The Garbose Family Special Delivery Unit (SDU) allows mothers to remain close while their babies are treated immediately,” explains Julie Moldenhauer, medical director of the SDU. “Having this comprehensive care in one location is critical to the well-being of both mothers and babies with complex congenital conditions.”
Myelomeningocele, the most common form of spina bifida, is frequently treated at CHOP’s fetal centre. Children with spina bifida can experience many long-term disabilities, including paralysis, bowel and bladder dysfunction, and learning difficulties. “One option is to wait until the baby is born and then do surgery to close the neural tube defect,” explains Moldenhauer. “The alternative is to perform prenatal surgery in the hope of reducing the condition’s long-term effects.”
Indeed, clinical trials run by a large consortium of researchers, including Moldenhauer and colleagues at CHOP, have generated evidence to suggest that fetal surgery improves long-term outcomes and lessens healthcare needs for children with myelomeningocele3,4,5. However, these interventions are not without risk — prenatal surgery may increase the odds of preterm birth and other complications. Nonetheless, the improvement of long-term outcomes for children is encouraging. And this is just the beginning: the team at CHOP is continuing follow-up with study participants in the MOMS3 clinical trial to learn more about their teenage and adult years.
“I’m really interested to know how this diagnosis might affect these kids as they face the challenges of teenage life,” says Moldenhauer. “Additionally, the impact on sexual function and reproduction for both affected men and women will be paramount to learning how best to educate and prepare these young adults.”
Sonographers and imaging technicians work closely with maternal-fetal medicine specialists who can thoroughly explain the diagnostic results to patients.Credit: Children's Hospital of Philadelphia
Recording outcomes
The extensive maternal-fetal care at CHOP also creates a unique opportunity to identify and act on specific research needs within the field. “It starts with seeing the problem in the clinic, and then trying to solve this real-world problem with clinical, translational or basic research,” says Hedrick, who is also director of CHOP’s Pulmonary Hypoplasia Program that follows many of these babies until adulthood. Both Moldenhauer and Hedrick are also studying the long-term outcomes of pre- and postnatal interventions, not only for the fetus and child, but for the childbearer as well. To facilitate this work, CHOP has developed the clinical outcomes data archive (CODA) which aggregates and provides accessible clinical data for every patient at the fetal centre. “Not only does CODA help us track clinical outcomes over a patient’s lifetime, but it catalyses improvement, making it easier for us to see how we can refine patient care to give each child the best possible outcome,” adds Hedrick. “For example, Emily Partridge, a paediatric and fetal surgeon, is exploring better ways to administer and even avoid extracorporeal membrane oxygenation for critically ill babies. This would be a significant innovation.”
As with any major research effort, collecting large repositories of data is critical to success. Moldenhauer’s team has therefore been building a large biobank of fetal DNA — typically collected from cord-blood and paired with DNA from family members — to facilitate genetic research. When combined with data from prenatal screening results, birth outcomes, and long-term follow-up visits, this fetal DNA bank enables Moldenhauer’s team to identify potential environmental and clinical factors that influence outcomes, ultimately with the goal of enabling patient-specific healthcare. “Discovering the best way to get the best possible outcome for the mother, baby, and the whole family, is really what we're trying to do.”
Genomic medicine
Although many fetal interventions now focus on structural birth defects, diseases resulting from mutations in single genes have the potential to cause significant health problems and even death before birth. Gene editing technologies, including CRISRP-Cas9, offer hope for a single treatment for these diseases. “Prenatal cell and gene therapies represent an exciting future for fetal intervention,” says William Peranteau, a paediatric and fetal surgeon, and researcher at CHOP.
“We focus on the application of gene editing before or shortly after birth,” Peranteau says, “specifically for diseases where the pathology begins before birth and is difficult to reverse.” Lysosomal storage diseases (LSDs), for example, are debilitating conditions that lead to multi-organ dysfunction with pathology, including in the central nervous system, beginning before birth6. In theory, correcting LSD-causing mutations may help prevent disease progression and morbidity.
What’s more, the developmental properties of the fetus, including the immature immune system and accessible cell populations, may prove these tiny patients to be more permissive for gene editing therapies. “Targeting gene editing therapies to the brain after birth is known to be very difficult,” explains Peranteau. “But, the blood-brain barrier in the fetus is not as robust as it is after birth. So, there are some normal developmental properties of the fetus that may make prenatal correction of LSDs and other diseases a little bit easier.”
For now, Peranteau’s team has considerable work to do before any such therapy can enter clinical trials. Nonetheless, Peranteau, Moldenhauer, Hedrick and their colleagues will continue their work to advance prenatal care, whether it’s through improved care in pregnancy, better genetic diagnoses, or gene editing technology. As Hedrick says, “it’s all about changing the trajectory of someone's life.”