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Prenatal surgical prep

Fixing an arterial defect in newborns is generally successful but neurological side-effects can persist. Children's Hospital researchers are testing whether a hormone boost improves outcomes.

Graziella Nobile, 30, of Brick, N.J., undergoes a fetal echocardiogram at Children's Hospital of Philadelphia. Her fetus has a heart defect in which the great arteries are transposed and which will be corrected surgically within a few days of birth.
Graziella Nobile, 30, of Brick, N.J., undergoes a fetal echocardiogram at Children's Hospital of Philadelphia. Her fetus has a heart defect in which the great arteries are transposed and which will be corrected surgically within a few days of birth.Read moreCLEM MURRAY / Staff Photographer

In a few days, surgeons at Children's Hospital of Philadelphia are scheduled to operate on the heart of Graziella Nobile's newborn baby, fixing a grave arterial defect that, if left unrepaired, would be fatal.

The hospital lately has a stellar record on that type of operation, in the sense of getting patients home alive. From 2009 to 2012, the most recent data available, 60 infants had this surgery, called an arterial switch, and all survived.

The part that doctors have yet to figure out completely is the brain.

At least half of children with surgically repaired heart defects go on to experience a learning disability or other neurodevelopmental delay. These deficits begin well before the surgery, largely as the result of the fetus' receiving inadequate oxygen during pregnancy.

So now, doctors at Children's Hospital are undertaking a series of studies aimed at addressing the problem in the womb.

"In order to make these babies better," said cardiac surgeon J. William Gaynor, director of the research program, "we have to start treating them before they are born."

Nobile gave birth to a boy Friday night. She and her husband, Anthony, who live in Brick, N.J., are enrolled in one of the studies, in which pregnant mothers give themselves doses of progesterone. The hormone already is approved for extending pregnancy in women at risk of preterm birth, and several lines of evidence suggest it may also protect the developing brain, Gaynor said.

Another study will measure levels of lead, mercury, pesticides, and other environmental contaminants in the mother's body to see whether any are associated with delayed maturation of the fetal brain.

Still another will look at giving mothers supplemental oxygen, some of which would presumably make its way to the fetus. Several weeks ago, the hospital hosted a discussion of that approach with physicians visiting from Europe, Canada, and across the United States.

Often, the neurological delays in veterans of pediatric heart surgery are subtle, and a casual observer would not pick out these children as being any different on the playground, Gaynor said.

Still, the Nobiles, upon learning of the increased risk that their child would have a learning disability, were concerned.

The young couple first were told of a heart problem during an ultrasound at Riverview Medical Center in Red Bank, 20 weeks into the pregnancy. Such defects often are missed, but alert medical staff referred them to a cardiologist, who sent them to Children's Hospital.

There, pediatric cardiologist Jack Rychik told them of the progesterone study, which seeks to enroll 80 mothers.

"We thought about it a bit," said Nobile, 30, a lawyer. "We did some research. We felt comfortable doing it because progesterone, it's not a new drug. It's a drug that has been used for years."

Half of the women in the study are randomly chosen to give themselves the hormone twice a day, using a vaginal suppository. The other half administer a placebo; neither group knows which they are getting.

The Nobiles' baby has a condition called transposition of the great arteries, meaning the aorta and pulmonary artery are reversed.

Instead of pumping "blue" blood to the lungs, the heart sends that unoxygenated blood out to the body. Oxygenated blood, on the other hand, is pumped to the lungs instead of going out to the brain and other tissues.

Despite this faulty plumbing, in the womb the fetus still is able to receive some oxygen via the placenta, because the developing heart has holes that allow some mixing of the red and blue blood. But those holes close after birth. Without the arterial-switch surgery, developed decades ago, such babies would die within days.

In late February, the Nobiles went for a fetal echocardiogram, an ultrasound that measures blood flow in the developing heart. After hearing the heart's "whoosh-whoosh" amplified in the examination room, the couple got a progress report from Rychik, director of the hospital's fetal heart program.

"You're doing all right," the doctor said.

Though a developing fetus receives progesterone naturally from the placenta, there are several reasons additional doses might help the brain.

One is simply because it prolongs pregnancy. A second is that, in animal studies, the hormone appears to help the brain recover from oxygen deprivation. Other studies suggest it stimulates development of the brain's white matter, which carries signals between different cerebral regions.

In a December study in the New England Journal of Medicine, doctors found progesterone did not appear to help adults recover from traumatic brain injury.

Gaynor, who was not involved with the study, said those results were disappointing, but he cautioned that the hormone was given after the injury. The Children's Hospital researcher remains optimistic progesterone can help the developing fetal brain.

Amy P. Murtha, professor of obstetrics and gynecology at Duke University School of Medicine, agreed it was reasonable to try progesterone, because it was known to be safe for the baby.

It has long been given to pregnant mothers who have had a previous preterm birth. Injections of the hormone are associated with a 30 percent reduction in the risk of a second preterm delivery, Murtha said.

And in women who have a short cervix, vaginal administration of progesterone appears to reduce the risk of preterm birth by about 40 percent.

"It doesn't fix everything," Murtha said, "but it does help."

The Children's Hospital progesterone study includes babies with several kinds of heart defects that require surgery in the first month of life.

In MRI scans, the brains of fetuses with these heart conditions are a little smaller and their white matter looks "immature," Gaynor said. At birth, their brains are typically about a month behind, likely making them less able to withstand the rigors of surgery, he said.

Though first-time parents, the Nobiles seem fairly calm about the whole process.

Even if the new mother turns out to have gotten a placebo, she likes the fact that by participating in the study, her baby is getting additional MRIs and other tests.

"It can only help," she said.

And if Gaynor is right, it will benefit babies such as theirs for years down the road.

215-854-2430 @TomAvril1