Survival improves in clinical trial for severe birth defect, with or without fetal surgery

Endoscopic fetal treatment increases survival to 73 percent for a severe defect that hampers lung growth — comparison group in a randomized trial increases survival to 77 percent with standard care in an expert neonatal intensive care unit

Newborns with a severe birth defect that hampers lung growth have an equal chance of survival whether they are treated with maternal/fetal surgery or receive their first operation after birth — if the infant receives life support from the moment of birth from a highly experienced neonatal intensive care team.

Both treatments achieved far better survival rates than earlier standard therapy, according to an NIH-sponsored randomized clinical trial. Results are reported in the November 13, 2003 New England Journal of Medicine.

Pediatric surgeon Michael Harrison, MD, and his colleagues at the Fetal Treatment Center at UCSF Children’s Hospital called an early halt to the trial, which evaluated treatment for congenital diaphragmatic hernia (CDH). The trial compared patients who received maternal/fetal surgery with a control group of patients given an advanced form of standard postnatal care. In both groups, fetuses were diagnosed with a severe form of CDH that causes fetal lungs to be dangerously undersized at birth. The control subjects fared surprisingly well — and that result underscores the need for randomized studies of surgical innovations, the researchers say.

The CDH fetal treatment technique in the trial was developed by UCSF pediatric surgeons. They used a small endoscopic tube, dubbed a fetoscope, to inflate a balloon inside the trachea of a fetus floating in its mother’s womb, and stimulate growth of the fetal lungs. At delivery, the newborn’s trachea was unblocked and the lungs cleared before the umbilical cord was cut. In this fetal treatment group, 73 percent of infants with severe CDH survived. The control group of newborns with comparably severe CDH were delivered at UCSF and treated from the moment of birth. UCSF neonatologists employed advances in life support for all infants in both groups. In the group given this advanced form of standard postnatal care, the survival rate was 77 percent.

Both results are a dramatic change from previous research that showed survival rates of less than 40 percent for newborns treated after birth for this severity of CDH.

Mothers and babies from both groups received care from the same group of experts in prenatal diagnosis, high-risk pregnancy care, surgery, and neonatal intensive care. Mothers in the fetal treatment group did not suffer lasting health problems, and those hoping for more children have been able to carry subsequent pregnancies to term. Newborns in the fetal treatment group were born on average six weeks younger in gestational age, yet survival and preliminary health outcomes were similar in both groups. The strongest predictor was the size of the fetus’ lungs at diagnosis – those with the smallest lungs were least likely to survive.

“This study shows how far we’ve come in trying to save babies affected with congenital diaphragmatic hernia – and how far we have to go,” said Harrison, who is the study’s lead author. He is director and co-founder of the UCSF Fetal Treatment Center at UCSF Children’s Hospital, part of UCSF Medical Center, and professor of surgery, pediatrics, and obstetrics/gynecology at UCSF.

“We stopped the trial as soon as an interim data review showed that advanced neonatal care from the moment of birth will give fetuses with one type of severe CDH a similar chance of survival as fetal intervention, without the need for surgery to the mother,” Harrison said. “Although survival in both groups is encouraging, long-term follow-up of survivors shows that, as they grow up, some children from both treatment groups continue to have significant health problems.”

Although very intensive treatment either before or after birth allowed most babies to survive, half the babies needed supplemental oxygen as they left the hospital; most babies went home with gastrointestinal difficulties and trouble with feeding. The study continues, following the long-term outcome for the survivors.

Harrison said that both treatment approaches present dilemmas for physicians and patients. Intervention before birth helps increase lung size, but so far, fetal intervention also causes prematurity, which can cause problems of its own. Improved intensive care for newborns now has improved survival, but for the most at-risk CDH patients, it also has long-term side effects.

The study shows the importance and feasibility of randomized clinical trials to test the value of promising surgical procedures against advances in standard care, according to Sam Hawgood, MD, chief of neonatology at UCSF Children’s Hospital and interim chair of the department of pediatrics at UCSF.

“When a patient’s condition is very complex, as in the case of congenital diaphragmatic hernia, care at every level improves over time,” Hawgood said. “This study was designed to compare the best available current care for each group, and to minimize confounding variables by treating the patients at the same institution for most stages of care.” In other research – including a 1994 NIH study at UCSF – fetal surgery mothers and infants got all their care from one highly-experienced medical team, while comparable standard-care infants received this expertise only after they were transported to a number of different tertiary care hospitals.

Hawgood said that the study shows that to improve the chances of survival for fetuses with severe CDH, it may be important for the mother to deliver her baby at the same hospital where neonatal intensive care experts will care for the newborn, to ensure experienced care from the moment of birth.

Harrison said that one very positive result was that the trial could be done at all. “We found that a very novel intervention for a life-threatening fetal disease in the highly charged circumstances of pregnancy could be put to the test of a sound randomized clinical trial, ” he said. Many physicians believe that such trials cannot be done because patients are not willing to accept a randomization that may assign them to standard care rather than an innovative new treatment. In this trial, with cooperation from other U.S. fetal treatment centers, UCSF was the only center offering this treatment for CDH, and offered it only within the context of the trial.

He credits the courage of mothers and families who came to UCSF seeking fetal surgery. “Our patients learned that we had developed a promising new therapy, but we did not know whether fetal intervention, which includes risks to the healthy mother, would be the right choice for them. If the CDH proved severe enough to warrant fetal intervention, the family then had to choose whether to accept randomization. Surprisingly, almost all chose to join the study. Each of these mothers offered a gift of knowledge to CDH mothers in the future,” he said.

During the clinical trial, UCSF offered randomization to either maternal/fetal surgery or postnatal care for 28 mothers. Four decided not to participate.

The standard treatment for all babies with CDH at UCSF (whether treated before birth or not) is for neonatologists to put the baby on breathing support from the moment of birth. Both standard-care and fetal-surgery babies need advanced breathing support to allow their underdeveloped lungs to grow; neonatologists use a wide range of techniques including surfactant, nitrous oxide, high-frequency ventilation and ECMO (extra-corporeal membrane oxygenation). Later, pediatric surgeons repair the hole in the baby’s diaphragm and return the organs to their proper places.

Co-authors with Harrison and Hawgood in the NEJM study are: Roberta L. Keller, MD, Joseph A. Kitterman, MD, Per L. Sandberg, MD, Diana L. Farmer, MD, Hanmin Lee, MD, Roy A. Filly, MD, Jody A. Farrell, MSN, PNP and Craig T. Albanese, MD.