Creation of a Birth Defects Biorepository

Major structural birth defects occur in approximately one in 30 live births. Birth defects are associated with a significant risk of mortality, morbidity and long-term disability in the survivors, resulting in an enormous impact on the lives of these children, their parents and families. There is a lifelong need for surveillance, multiple medical procedures, treatments and visits to specialists. This creates a substantial healthcare burden on the individual, the family and society as a whole.

The etiology of the majority of birth defects is unknown and likely to be multifactorial, involving a complex interplay of genetic and nongenetic factors, such as environmental exposures, medication use, maternal illness or nutritional imbalances. This information can be used for prognostication of neonatal and childhood outcomes. However, the long-term outcomes of therapy may not be as expected based on prenatal diagnosis for different cohorts of congenital defects, as the genetic basis remains unknown for many.

We lack the large study populations with genetic data, detailed phenotypes and longitudinal follow-up needed to address these questions. Many existing biobank and biorepository efforts dedicated to collecting samples during pregnancy are focused on maternal health and adverse pregnancy outcomes, not birth defects.

Exploring the relationship between characteristics of biological tissue at molecular, cellular and organ system levels to clinical course and outcome is critical in developing preventive measures and more individualized therapeutic strategies.

Creation of a Birth Defects Biorepository

The Center for Fetal Diagnosis and Treatment’s Birth Defects Biorepository (BDB) is a coordinated effort that involves identification and enrollment of a unique patient population of women carrying a fetus with a birth defect, employing high-throughput sequencing capacity, creation of a bioinformatics infrastructure, and information technology to integrate genetic data and patient medical records with detailed phenotypes and longitudinal follow-up.

The purpose of the BDB is to create a platform for discovery of patient-specific variables (in utero, genetic and environmental), as well as disease-specific variables, that underlie congenital defects and influence outcomes for patients, beginning during prenatal life and continuing across the lifespan.

The advent of high-throughput next-generation sequencing greatly improves our ability to dissect the contributions of genetic variation to complex traits like birth defects. The CFDT is a unique resource that provides the opportunity to enroll a large population of mothers carrying a fetus with a birth defect. Since its inception, the CFDT has cared for more than 24,000 expectant women from all 50 states and more than 70 countries.

Approximately one-third of women evaluated through the CFDT are offered the opportunity to continue their obstetric care and deliver at CHOP’s Garbose Family Special Delivery Unit (SDU), the world’s first birth facility in a pediatric hospital specifically designed for healthy mothers carrying babies with known birth defects. Each year, 450 to 500 babies with prenatally diagnosed birth defects are born in the SDU, providing a unique resource and allowing for enrollment of a large population of infants with birth defects.

Collecting detailed, long-term outcome data

Parents and families are our partners in this collaborative effort. Their willingness to participate and help others is critical. The overarching goal is to create a large cohort of patients and their families with detailed genetic and long-term outcome data. Very little is required for participation; a blood or saliva sample and permission to collect data from the medical record are the major requirements.

The data will be used to investigate factors that may cause birth defects and that may modify the long-term outcomes. In addition to searching for causative genetic variants related to developmental defects, the BDB will help us better understand interindividual variation in the response to therapeutic interventions.

Unique patient characteristics can impact disease manifestation and response to therapy, supporting the development of precision medicine approaches and individualized therapeutic strategies for at-risk patients. In addition, the well documented heterogeneity of drug response between individuals suggests that examining drug-gene interactions may help explain interindividual differences in outcomes, yet there are few pharmacogenetic studies in children.

Carefully-designed prospective investigations using our large cohort of patients with detailed genetic data, well characterized phenotypes, and longitudinal data will enable us to examine the importance of individual variation on the response to medications, as well as outcomes after surgery and other therapeutic interventions.