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Breast milk compound may prevent deadly preemie infection

Picasa / Jim Cullen

Georgia Cullen was born four months early and developed a potentially deadly condition called necrotizing enterocolitis. Now doctors think they found a way to prevent it - in breast milk.

When little Georgia Cullen was born four months early last February, she weighed less than two pounds. Her doctors supplemented her mother Julie’s breast milk with formula to help her grow, and she did. But last March, Georgia developed a dangerous and potentially deadly intestinal infection.

“Her stomach started to swell up,” says her father, Jim Cullen, of Erie, Pa. She was flown by helicopter to Children’s Hospital of Pittsburgh. “To have your daughter born early is scary. She was doing so well up to that point, so it was even scarier.”

Georgia pulled through, but lost much of her intestine to the infection. Now the surgeon who operated on her thinks he’s helped find a compound in human breast milk that may prevent that complication.

Her condition, called necrotizing enterocolitis, is an immune system overreaction that kills thousands of premature babies every year. “Breast milk for many years has been known to protect against this disease,” says Dr. David Hackam, who treated Georgia.

Necrotizing enterocolitis (NEC for short) affects about 25,000 babies a year in the United States, according to the American Pediatric Surgical Association. The risk goes way up for babies born weighing less than three pounds, 1,500 grams. Anywhere between 20 percent and 30 percent of them die, according to a 2009 study in the Journal of Pediatric Surgery.

Doctors suspect it happens because these tiny babies don’t have fully developed digestive systems. Partly digested food may sit for too long, allowing harmful bacteria to thrive. Some experts believe formula may contribute to the problem because it’s so rich, feeding the bacteria.

“They don’t have a specific infection,” says Hackam. An allergic reaction might be involved. Their intestinal linings are destroyed. The inflammation lets bacteria leak into the blood and the immune system goes into overdrive.

“This is one of the last few diseases that is truly still an enigma to clinicians,” he said in a telephone interview.

In the worst cases, surgeons like Hackam have to take out the affected parts of the intestine. “When we operate on their intestines, they’re just black,” Hackam said. If the babies survive, they often have problems well into adulthood.

Doctors also know that breast milk seems to protect babies, although it’s not 100 percent effective. “About 10 percent of cases occur in babies that are breast-fed,” Hackam says. And in any case, many mothers of premature infants are not producing breast milk yet. While there are breast milk banks, the milk must be pasteurized and that could affect its qualities.

So it’s simply not an option to never use formula to feed preemies, Hackam says.

Jim Cullen

Julie Cullen holds Georgia, who was born weighing less than 2 pounds and who developed a devastating condition called necrotizing enterocolitis.

“What we seek to do is harness the effects of breast milk,” he said. His team followed up on a theory that the same over-reaction seen in sepsis is at work in NEC.

“The secret may be in an important compound. One of the things that happens in sepsis is blood flow to the various organs can be shut down,” Hackam says. This happens in NEC, too -- the intestinal tissue dies because the blood flow stops coming. And, like with sepsis, a compound called TLR4 is involved, Hackam’s team reports in this week’s issue of the Proceedings of the National Academy of Sciences.

Mice bred to lack TLR4 don’t develop NEC. And premature babies seem to make extra amounts of it in the gut, for reasons that are not yet clear.

"Abundant TLR4 triggers a shutdown of the blood supply to the intestine, leading to tissue death or necrosis,” Hackam said.

Hackam’s team discovered that breast milk contains sodium nitrate, which the body converts to nitric oxide, or NO. NO is a well-known vasodilator -- it helps encourage blood flow. Stimulating NO is the basis for Viagra and other erectile dysfunction drugs, and when Hackam’s group gave mice sildenafil, the generic form of Viagra, it helped counteract TLR4 and reduce the severity of NEC.

Even more intriguing: Formula does not contain nitrates. “Look at the label -- formula proudly states that it is nitrate-free,” says Hackam. Nitrates in cured meat have been linked with cancer risk -- thus the fear. But this is a different situation, and for the preemies, a little bit of nitrate might be a good thing.

There’s a drug in development that Hackam’s team thinks is better than sildenafil for babies with NEC and his team would like to test it in newborn preemies. It stimulates NO production. Adding such a drug to formula might reduce the risk of NEC, he believes.

In the meantime, Georgia is still in the hospital, and is likely to stay there until her actual due date, in June.

“Dr. Hackam explained that right now her intestines are the consistency of wet tissue paper,” Cullen says. “So in order to reverse the surgery, she has to have more surgery to put her back together. She has to be a little bit older.”

Georgia was delivered early because her twin died in utero. But the family is coping with the tragedy and hardship, Cullen says. He, his wife Julie, a 5-year-old daughter and 3-year-old son are living in special housing at the University of Pittsburgh Medical Center, and just celebrated the 3-year-old’s birthday Monday.

“He woke up to lots of balloons and streamers all over the apartment,” Cullen says. “We feel like we are a stronger family because of this.”

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