UPMC research shows promise in treating disease that afflicts premature babies

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It's one of the unsolved mysteries in modern medicine: a stomach condition that strikes the tiniest of babies with potentially devastating consequences.

For years, doctors have known that necrotizing enterocolitis occurs much less frequently in babies who are fed exclusively breast milk instead of formula. Researchers at the University of Pittsburgh and Children's Hospital of Pittsburgh of UPMC now think they understand why -- and they have found promising results in treating mice.

"It's one of the last few enigmas," said David Hackam, co-director of the Fetal Diagnosis and Treatment Center at Children's Hospital and senior author of the study. "It's so frustrating. You have these babies, they seem to be doing well, and it happens out of the blue."

The study was published online Monday in the Proceedings of the National Academy of Sciences.

It found that premature babies have higher amounts of an immune protein called TLR4 than full-term babies. That surplus leads to a reduction in nitric oxide, which narrows blood vessels and decreases blood flow, leading to tissue death.

By adding sodium nitrate to formula that was fed to premature mice, the researchers were able to correct the blood flow, leading to dramatically lower incidences of necrotizing enterocolitis, or NEC, in the mice. Sodium nitrate naturally occurs in high levels in breast milk but is not a component in infant formula, Dr. Hackam said, in part because of concerns about a link between nitrate consumption and gastrointestinal cancer.

The findings in the study are "important and plausible," said Ardythe Morrow, director of the Center for Interdisciplinary Research in Human Milk & Lactation at Cincinnati Children's Hospital Medical Center, noting that more research in humans and other animal models is necessary.

NEC occurs in 10 to 15 percent of babies born before 36 weeks of gestation and in as many as 40 percent of babies born at 24 or 25 weeks. The mortality rate from the disease is nearly 30 percent.

The typical patient appears to be doing well for the first two weeks of life. Then, all of a sudden, the baby stops being able to digest food and his stomach swells.

"It becomes clear that the child has developed a major problem in his or her tummy, and an X-ray will usually confirm the diagnosis of necrotizing enterocolitis, in which the intestinal tissue is dying," Dr. Hackam said. "We have no choice but to remove the dead parts of the intestine."

That was the case with Georgia Cullen of Erie, who in early March was flown by helicopter to Children's Hospital here after she contracted NEC while at UPMC Hamot.

Georgia was conceived as a rare type of identical twin -- she shared both a placenta and an amniotic sac with her sister. After her sister died in utero, Georgia went into distress two weeks later and had to be delivered at a little more than 26 weeks gestation. She weighed 1 pound, 9 ounces, and her father's wedding ring fit around her wrist.

Despite her early birth -- her due date wasn't until June 6 -- all indications were good after her birth and her ventilator was removed in less than 12 hours. Two weeks later, however, Georgia contracted an infection and was diagnosed with NEC, despite being fed a breast milk diet. She flew to Pittsburgh, where she had her first of multiple surgeries.

The past month has been scary, said her father, Jim Cullen, as Georgia has struggled with problems with her stomach and her lungs. As of Sunday, however, she is tolerating breast milk again.

"She's made a turnaround of just epic proportions -- I don't know how to describe it," he said. "A week and a half ago, it was terrifying."

Like many other parents, the Cullens were not aware of NEC. "We had known the possibility of her lungs being in poor shape or something, but her gut being an issue wasn't something we were really prepared for," he said.

Georgia still has a long way to go before she can be released from the hospital -- including another surgery on her intestine.

And Dr. Hackam still has quite a while before his research moves from mice to humans. In his favor is that the compound of sodium nitrate that was added to mouse formula is already approved by the FDA for other uses.

Parents who are not able to provide breast milk and whose babies contract NEC often feel incredibly guilty, Dr. Hackam said, which is another reason why the possibility of adding sodium nitrate to formula is so promising. He believes that concerns about nitrates causing cancer are not applicable in this case because the levels added to formula would be so low.

"If there's something that we can do to give the parents a little bit of hope," he said, "we've done our job."

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Anya Sostek: asostek@post-gazette.com or 412-263-1308.


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