Predicting Congenital Diaphragmatic Hernia with Precision

How is miRNA helping doctors better predict the severity of congenital diaphragmatic hernia before a baby is born to create the best possible care plan for survival post-delivery?

Congenital diaphragmatic hernia (CDH) is a rare condition in which the diaphragm doesn’t completely develop before birth. It impacts 1 out of 3,000 live births. Even though the Colorado Fetal Care Center at Children’s Hospital Colorado achieves better-than-average outcomes for babies with severe cases of CDH, treating these babies remains difficult. In fact, about 50% of babies with severe cases will die from pulmonary hypertension, pulmonary hypoplasia or cardiac dysfunction as a result of their condition. Accurate prognostication for this population is essential, offering an opportunity for in-utero interventions and a tailored care plan post-delivery. Right now, diagnostic tools don’t always offer the clarity providers need. Children’s Colorado’s fetal and pediatric surgeon Chris Derderian, MD, is exploring new ways to predict CDH severity with more accuracy, ultimately offering babies the best chance for survival.

Understanding the severity of CDH in utero is very important for two main reasons. One, it allows the team to better counsel families on what to expect when their baby is born, so they understand survival likelihoods and what a hospital stay might look like after birth. Second, it helps the care team with delivery planning. Some of the most severe CDH cases require a Cesarean section and immediate extracorporeal membrane oxygenation (ECMO) support for the baby. The baby must then have CDH surgery to repair the diaphragm. If the condition is identified early enough, doctors may also offer fetoscopic endoluminal tracheal occlusion (FETO) — an experimental surgery performed in-utero that can help with fetal lung growth for the most severe cases. Currently, doctors diagnose the severity of CDH through ultrasound and MRI scans, which are limited in their ability to diagnose and understand these complex cases.

“Neither of these modalities are particularly accurate for predicting the need for ECMO or for survival,” Dr. Derderian says. “There are opportunities for more accurate prediction.”

Three years ago, Dr. Derderian and his team started to explore new approaches to enhance their predictions. For this study, they collected maternal serum samples from pregnant patients, amniotic fluid, cord blood, and infant blood samples to analyze microRNA, which help regulate gene expression. Data points also included prenatal imaging predictors through ultrasound and MRI, such as lung volumes, whether the baby needed ECMO post-delivery, and how many babies survived and ultimately were discharged from the hospital. This study involved 11 control patients and 10 patients with CDH, and the team collaborated with the University of Colorado to obtain control samples.

First, the team analyzed the microRNA to identify which had the highest level of gene expression. Then they compared the CDH patients with the control patients using pathway analysis to identify differences that might relate to pulmonary hypertension and pulmonary hypoplasia, pointing at a possible therapeutic intervention opportunity.

Next, the team looked specifically at the microRNA for just the patients with a CDH diagnosis to conduct a biomarker analysis to identify any differences between CDH survivors and nonsurvivors. The researchers found there were a number of microRNAs that were expressed differently between those two groups. Using machine learning random forest analysis, which uses multiple decision trees to reach a single result, they measured the levels of expression for those microRNAs, compared survivors to nonsurvivors and found that they could predict which babies would survive with 100% accuracy. This gives the team a reliable biomarker to use to predict survival for these babies, providing families with a more clear and targeted care plan.

“These findings are promising,” Dr. Derderian says. “Because this study was conducted on a relatively small sample size and at a single institution, we now need to validate with larger cohorts and across multiple institutions.”

Dr. Derderian and his team are also exploring similar research using second trimester serum, rather than third trimester serum, to see if they can replicate this success with the same high degree of accuracy. Those findings would be significant, because they would allow doctors to predict survival at an even earlier point in pregnancy, giving patients access to lifesaving fetal interventions, such as FETO, in hopes of impacting chances of survival.

The team will continue to explore and validate these findings to offer more detailed counseling for babies facing a CDH diagnosis.