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Congenital Diaphragmatic Hernia Physicians and Researchers Improve the Odds Prenatally Postnatally and Beyond

Congenital diaphragmatic hernia (CDH) remains an unsolved problem and a frustrating clinical disease for physicians, surgeons and scientists despite decades of research. Although it is a surgically correctable defect, the arrest in development of the lungs prenatally results in unacceptably high rates of neonatal mortality and long-term morbidity for the surviving child.

CDH with LabelsAttempts to improve outcomes in CDH-affected babies through prenatal interventions have been under way for more than 25 years. “In the late 1980s fetal surgeons demonstrated a high survival rate with open maternal-fetal surgery to repair the diaphragmatic defect when the liver was not herniated into the chest. In these cases outcomes were no better than what was seen with treatment after the baby was born,” says Anthony Johnson, D.O., professor in the division of Maternal-Fetal Medicine and the department of Pediatric Surgery at the John P. and Kathrine G. McGovern Medical School at UTHealth, co-director of The Fetal Center, and the immediate past president of North American Fetal Therapy Network (NAFTNet). “In the more severe cases, when the liver was herniated into the fetal chest, returning the liver to the abdomen and repairing the defect led to fetal death in many cases due to occlusion of blood flow from the umbilical vein. Prenatal intervention through open maternal-fetal surgery for CDH was subsequently abandoned. Later, research in animal models gave us a fortuitous finding: if the trachea is plugged, the fluid produced in the lungs will build up, with the increased airway pressure causing the lungs to expand and mature. Additionally, the increased growth of the lungs will gradually return the herniated organs back to the abdomen, thereby reducing the risk of pulmonary hypoplasia. Various attempts were made to use mechanical devices to close the trachea.”

Among these devices was a detachable balloon that could be placed using a telescope (fetoscope) through a small incision in the maternal abdomen, to reduce risk to the mother. In a randomized, controlled trial conducted at the University of California, San Francisco, from April 1999 to July 2001, researchers compared tracheal occlusion using the balloon with standard care. The results, which were published in the New England Journal of Medicine in 2003, showed that tracheal occlusion did not improve survival or morbidity rates in the chosen cohort of fetuses.1 Secondary analysis of this study found that the majority of prenatally treated patients would not have been considered severe or lethal CDH cases based on prenatal ultrasound findings. The trial was not conclusive for fetuses that would be considered at greatest risk.

In a later report from European studies using a similar tracheal balloon but with smaller fetoscopes to further reduce maternal complications, fetal tracheal occlusion (FETO) doubled the survival rate – from 25 to 50 percent – in severe cases of CDH and reduced morbidity as well.2

When the study found that FETO might improve neonatal survival in cases with isolated severe CDH, NAFTNet led the charge to extend the trial to the United States. Seven fetal centers, including The Fetal Center at Children’s Memorial Hermann Hospital, qualified to participate in the clinical trial, called Tracheal Occlusion to Accelerate Lung Growth (TOTAL) for Severe Pulmonary Hypoplasia. The Fetal Center is now accepting patients for evaluation as study participants.

“With improved prenatal detection through ultrasound and MRI imaging and the use of smaller devices, the appropriate cases can be selected to study the benefits of tracheal occlusion in more severe cases with minimal risk to the mother,” Dr. Johnson says. “Fetuses with a lung-to-head ratio (LHR) of less than 1 and liver herniation have a survival rate of only 10 to 20 percent. The TOTAL Trial looks at this group and examines whether we can improve the outcome with tracheal occlusion.”

Randomization to the study arm is done prior to 27 weeks. The balloon is placed at 27 weeks 0 days to 29 weeks 6 days and removed between 34 weeks 0 days and 34 weeks 6 days due to the risk of rupture and premature labor. Inclusion criteria are mothers ages 18 to 50 years with a singleton pregnancy, isolated left-sided diaphragmatic hernia with an LHR of less than 1 with liver up, normal chromosomes and willingness to live within 30 minutes of Children’s Memorial Hermann Hospital.

Because of the relatively low frequency at which CDH occurs, there have been few randomized, controlled trials involving infants or fetuses with the defect. One in every 2,500 infants is born with CDH independent of race, quality of prenatal care and socioeconomic factors. Its cause remains unknown, and because each case is different, there is no normal recovery time and no standard plan of postnatal care. Thanks to more accurate prenatal diagnosis and the work of the International Congenital Diaphragmatic Hernia Registry, which resides at Children’s Memorial Hermann Hospital and McGovern Medical School, the global survival rate of infants born with CDH is on the rise.

“We continue to make progress in the management of diaphragmatic hernia with mechanical ventilation, pharmacotherapy and other therapeutic modalities, including extracorporeal membrane oxygenation (ECMO),” says Kevin P. Lally, M.D., M.S., FACS, professor and chair of the department of Pediatric Surgery at McGovern Medical School, who has published more than 70 peer-reviewed articles about basic science and clinical research on CDH. “Overall, worldwide survival of infants born with diaphragmatic hernia has increased from about 55 percent to close to 70 percent in the last 20 years. Unfortunately, we still have a significant problem in the short- and long-term management of the most high-risk babies.”

In the 20 years since Dr. Lally helped found the CDH Study Group and the CDH Registry, the voluntary collaborative has gathered data on more than 9,000 babies with diaphragmatic hernia. The registry now represents centers in 14 countries. Advances in prenatal imaging have enhanced visualization of the anatomy of the fetus, providing specialists with more information for treatment decision-making, and about 20 CDH Study Group projects are using the registry’s data to evaluate diagnostic and prognostic variables such as preductal oxygen saturation, defect size/anomaly association and pulmonary hypertension.

“The mortality rate associated with CDH varies widely among fetal centers and still remains relatively high despite the availability of new therapeutic modalities,” Dr. Lally says. “It’s also important to note that many of the new therapies have been implemented without properly controlled studies.”

Most infants with CDH become symptomatic in the first few hours after birth and require endotracheal intubation and mechanical ventilation. In more complicated cases, other therapeutic modalities such as high-frequency oscillatory ventilation, inhaled nitric oxide and ECMO may provide significant benefits for selected infants.

“Some of these kids are so ill that many centers deem them unsalvageable,” Dr. Lally says. “We don’t do that. We take a very aggressive approach to the management of diaphragmatic hernia, and are one of two centers in the country that operate on 93 percent of all patients. Based on risk-adjusted data our outcomes are in the top 10 percent or higher. Except for a few obvious cases, we don’t make the call that a baby is too high risk to save. If blood gas values are really unfavorable early on, we’ll put the baby on ECMO. Our entire team works together to save the baby’s life.”

Once respiratory stability has been established, which may take days or weeks, surgical repair of the hole in the diaphragm is possible in most cases. “Surgery returns the abdominal organs to the abdominal cavity and makes room in the chest for the hypoplastic lung to grow,” says KuoJen Tsao, M.D., co-director of The Fetal Center at Children’s Memorial Hermann Hospital, secretary/treasurer of NAFTNet and an associate professor in the department of Pediatric Surgery at McGovern Medical School. “But diaphragmatic hernia is not just a hole in the diaphragm. It’s an embryonic defect with many facets. Along with the underdevelopment of lung tissue itself, the lung vasculature is compromised. When these kids die, they die of pulmonary hypertension as well as pulmonary hypoplasia. If they survive, both can cause long-term problems. From the prenatal period on, that’s our biggest challenge. We can assess how much pulmonary hypoplasia they’re likely to have when babies are born, but there’s a critical aspect of patient survival related to the vasculature that we as a specialty have difficulty measuring and predicting. We need a greater understanding of their challenges as they grow. The CDH Registry provides excellent information but we also rely on the physicians who see the patients long term to conduct research on outcomes and publish it.”

To that end, Matthew Harting, M.D., is creating a Congenital Diaphragmatic Hernia Clinic through UT Physicians to track children over the long haul. “We’re saving more and more of these kids but they’re living with a host of medical issues. At the clinic they’ll be able to see a team of specialists in one location, which will allow us to optimize their care, collect data and understand their challenges in ways that were previously impossible.”

Dr. Harting is also engaged in promising research using exosomes, small membrane particles released from mesenchymal stem cells, to help manage pulmonary hypertension. “Because we still have a 30 percent mortality rate, we’re trying to push the envelope in basic science and translational research to move the care of these critically ill babies to the next level,” says Dr. Harting, who is director of the pediatric ECMO program at Children’s Memorial Hermann Hospital and an assistant professor in the division of General and Thoracic Pediatric Surgery. “There is some evidence that stem cells can halt the progression of pulmonary hypertension but no evidence yet on how that effect applies to diaphragmatic hernia. This is still very early work but if we find that it’s as efficacious as we hope it will be, we can translate it to the clinical setting to mitigate some of the pulmonary hypertension we see in CDH.

“Over the last 20 years, Dr. Lally has put his heart and soul into getting physicians to collaborate internationally on this rare health issue,” Dr. Harting says. “That effort has paid off in lives saved but we also need new therapies, which is why the research we’re doing at The Fetal Center is important. We are state-of-the-art and expert at providing the full continuum of care for diaphragmatic hernia. Prenatally we can offer patients FETO, postnatally we have excellent clinical outcomes and we’re engaged in basic science research to develop new ways to take care of patients.”

See more info about how CDH is treated at Children's Memorial Hermann Hospital »

1 Harrison MR, Keller RL, Hawgood SB, Kitterman JA, Sandberg PL, Farmer DL, Lee H, Filly RA, Farrell JA, Albanese CT. A Randomized Trial of Fetal Endoscopic Tracheal Occlusion for Severe Fetal Congenital Diaphragmatic Hernia. New England Journal of Medicine. 2003 Nov 13;349:1916-24.

2 Jani JC, Nicolaides KH, Gratacos E, Valencia CM, Done E, Martinez JM, Deprest J. Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound in Obstetrics and Gynecology. 2009 Sept;34(3)3:304-10.

Patient Referrals to the TOTAL Trial

Inclusion Criteria

  • Consenting subjects
  • Fetus with isolated left-sided congenital diaphragmatic hernia
  • Severe pulmonary hypoplasia defined as O/E LHR <25 percent
  • Liver up
  • Willingness to live within 30 minutes of Children’s Memorial Hermann Hospital

Exclusion Criteria

  • Maternal contraindication to fetal intervention
  • Technical or maternal limitation to fetoscopy
  • Preterm labor or cervix <15 millimeters
  • Refusal to return to The Fetal Center during the time period airways are occluded

To refer a patient for evaluation for fetal endoscopic tracheal occlusion as part of the TOTAL trial, call832.325.7288.

More info about this research »