Can Probiotics Prevent Deadly Infections in Preemies?
Humans need about 40 weeks in the womb to fully develop. MaKenzie Trice, however, took an early exit. Her mom’s water broke at 20 weeks, and by 27 weeks MaKenzie’s head was so far down in her mother’s pelvis, doctors struggled to get a good ultrasound image. When MaKenzie came bursting into the world at 28 weeks and four days, she was tiny—no bigger than an eggplant. Her skin was paper-thin, and she needed a ventilator to breathe.
Today, MaKenzie is nearly two months old. She still needs help breathing, and she still weighs far less than a typical newborn. Like other babies in the neonatal intensive care unit at the University of Iowa Stead Family Children’s Hospital, she receives a daily cocktail of helpful bacteria, or probiotics. MaKenzie, dressed in a striped sleeper with bright red feet designed to look like strawberries, is about to get today’s dose. A nurse hooks up a syringe full of milky liquid to MaKenzie’s feeding tube and pushes the plunger, jettisoning billions of live bacteria into her stomach.
MaKenzie is lucky, perhaps due to the hospital’s special probiotic protocol. So far she has avoided the worst complications of being born too soon, including an insidious intestinal illness called necrotizing enterocolitis, known as NEC. The disease, which primarily affects preemies, is relatively rare, but it can be devastating. In the U.S., about 5% of all babies who enter the neonatal intensive care unit (NICU) develop the disease and, of those, between a third and one half die. Others develop complications that persist into adulthood.
The practice of administering probiotics to preemies is, in some ways, a leap of faith. While more than 30 randomized controlled trials suggest that probiotics can protect preemies from NEC, the largest trial to date found no effect. What’s more, it’s not yet clear which strains of bacteria provide the best protection, what dose a baby needs to receive, or exactly how these microbes protect the gut from NEC. As a result, the debate over whether probiotics should be a standard of care for babies can be heated; only 14% of NICU’s in the U.S. have adopted the practice.
“Neonatology is a field where we’ve really had some mess-ups,” says Josef Neu, a neonatologist at the University of Florida. “I think we have to be extremely careful.” Giving babies probiotics isn’t like giving them a dose of penicillin, he adds. “These are live agents,” some of which can stick with babies long-term. Many others share Neu’s caution, arguing that the evidence of a benefit isn’t strong enough yet and that probiotics in the U.S. are subject to little regulatory oversight.
Yet some neonatologists see no reason to delay. “There’s now actually more evidence for the use of probiotics in neonatology than for just about everything else that we do,” says Keith Barrington, a neonatologist at Sainte Justine University Health Center, which offers probiotics in its NICU. “I’m really not sure what kind of evidence would convince someone like Dr. Neu.”
Phantom Menace
What makes NEC so tragic is that it often strikes weeks after birth, when many premature babies seem to be out of the woods. The peak seems to occur in babies who are between 29 and 33 weeks post conception. That means a baby born at 26 weeks will be at greatest risk three to six weeks after birth. “There’s something around that period of time developmentally in the babies that appears to predispose to the disease,” Neu says.
At that point, “everybody is starting to get a little optimistic that the baby is going to survive,” says Mark Underwood, head of pediatric neonatology at the University of California-Davis. Then, without warning, the baby’s belly swells, his stool becomes bloody, and he begins to vomit. In the most severe cases, surgeons must open the abdomen to remove dead bowel. “I’ve been taking care of little babies since 1990, and NEC has always been the worst possible complication,” Underwood says. “It’s just devastating.”
NEC isn’t a new disease. In 1823, French physician Charles Billard wrote up possibly the first case report, a nine-day-old infant with green diarrhea and a swollen abdomen who later died. But back then, the disease was exceedingly rare—NEC primarily affects preemies. As doctors have become better at keeping the tiniest babies alive, the number of patients at risk has grown.
Yet many parents of preemies don’t have any idea their babies are at risk until they receive a diagnosis. That was the case for Jennifer Canvasser, who gave birth to twin boys—Zachary and Micah—at 28 weeks. “By the time they were six weeks old, they both weighed about five pounds, and we thought we were on the easy road to recovery,” she says. Then Micah developed NEC. In a matter of hours, “Micah went from being this beautiful healthy five-pound baby to having wires and tubes and being intubated,” she says.
The doctors managed to keep Micah alive despite a daunting laundry list of complications. The surgeons had to remove portions of Micah’s bowel. The disease also damaged his kidneys, so he needed dialysis. When Micah was 11 months old, he came down with pneumonia and had to be readmitted to the hospital. The respiratory illness on top of all the other complications proved to be too much for Micah’s body, and he died.
The tragedy was devastating. “We were just at a complete loss as to how to go on,” Canvasser says. “We had to learn how to breathe and eat and just function again.”
An Ounce of Prevention
Scientists have yet to get a handle on the precise sequence of events that leads to NEC, but bacteria seem to play a key role. While babies born at full term tend to develop a diverse and robust microbiome, preemies have an odd, sparse assortment of bacteria including some pathogens that seem to come from the NICU itself. This already abnormal microbial profile seems to become even more unnatural in babies who develop the disease. “We see some differences in the microbial ecology,” Neu says, including more bacteria that contain molecules known to promote inflammation.
There is circumstantial evidence to suggest that bacteria are involved, too. Babies who receive antibiotics have an increased risk for developing NEC—whereas breastmilk, which is teeming with live bacteria, dramatically protects preemies from the disease. In fact, it’s the best preventative therapy available. Most NICUs encourage breastfeeding, and offer donated human milk if the baby’s mother can’t produce enough herself. But it’s not a panacea. Even breastfed babies sometimes develop the disease.
If bad bacteria in the gut bear some of the blame for NEC, then it makes some sense that the good bacteria found in probiotics might provide some protection. A probiotic could populate the gut with good bacteria and make it harder for the bad bugs to take hold. Or it might help regulate the baby’s immune response and prevent inflammation. Many probiotics also seem to help the baby’s gut mature. “There are tons of bacteria that are considered probiotics and they all have different mechanisms of action,” says Steven McElroy, a neonatologist at the University of Iowa.
The first compelling evidence that probiotics might work to curb NEC came from a public hospital in a poor neighborhood in Bogota, Colombia. Desperate to curb recurring outbreaks of the disease, doctors began administering probiotics to newborns in 1994. Each baby received a daily dose of 500 million bacteria—half Lactobacillus acidophilus and half Bifidobacterium infantis. Before the hospital offered probiotics, 6.6% of the babies admitted developed NEC. After doctors began dosing the babies, the NEC rate fell to 3%. Fewer babies died of the disease, too. The study wasn’t a randomized controlled trial, the gold standard in clinical research, but the results seemed promising.
Animal studies seemed to support the idea too. In 1999, Michael Caplan, now chair of pediatrics at NorthShore University HealthSystem in Illinois, and his colleagues showed that B. infantis reduced the risk of NEC in a rat model of the disease. The results were dramatic. Without probiotics, about 70% of the baby rats in the model developed NEC. With probiotics, that number dropped to just 30%. The research “received some interest, but people were still somewhat skeptical that probiotics could play a significant role,” Caplan says.
Over the next decade, however, researchers around the world tested various bacterial cocktails in the tiniest babies. As the evidence for an effect began to mount, the push for neonatologists to adopt probiotics grew. In 2010, Australian researchers combined data from all the trials published thus far and concluded that probiotics cut the risk of NEC by half. “Withholding probiotics from high-risk neonates is now almost unethical,” the authors argued.
Perhaps the most persuasive evidence that probiotics prevent NEC came from a large clinical trial conducted in Australia and New Zealand called ProPrems. Starting in 2007, the ProPrems team randomized 1,100 preemies weighing less than 1,500 grams (or 3.3 pounds) to receive either a placebo or a probiotic powder called ABC Dophilus, a mix of three different strains of bacteria manufactured in New Jersey. The team picked sepsis, a systemic infection, as their primary outcome, but they also examined NEC. They didn’t see any significant difference in sepsis between babies who received the probiotics and babies who didn’t, but probiotics more than halved the risk of NEC. The results, published in 2013, had the field buzzing with excitement.
Barrington, who writes a blog devoted to discussing issues in neonatology, found the data so convincing he penned a post titled, “Probiotics work, they really, really, work! (And they are safe).” Soon after, the Cochrane Collaboration, a network of independent researchers that analyze medical evidence, published a review of the research on probiotics and NEC. The authors found the evidence compelling and advised physicians to offer probiotics to preemies.
Less than a year later, however, a tragic death would call into question the safety of these supplements.
Hidden Danger
Calvin Jimmy Lee-White was born at Yale-New Haven hospital on October 11, 2014. In the NICU, he received four doses of ABC Dophilus Powder, the very same probiotic tested in the ProPrems trial. Eight days later, he was dead. An autopsy revealed an intestine teeming with fungus. Scientists at the Centers for Disease Control and Prevention determined that several bottles of the ABC Dophilus powder from the hospital’s pharmacy were contaminated with mold.
Roger Soll, a neonatologist at the University of Vermont, became an advocate for probiotics after the ProPrems study came out, but Calvin’s death gave him pause. “I was definitely humbled by what happened at Yale,” he says. “Part of our oath is ‘do no harm,’” he says.
Contamination is still a concern today. In the U.S., probiotics are generally considered dietary supplements, which means they aren’t subject to the same federal oversight as drugs and other therapeutics. Because these products are “generally recognized as safe,” the FDA isn’t required to verify their safety and efficacy. As long as probiotic manufacturers avoid claims that their product can treat or prevent a disease, they are allowed to police themselves.
That self-policing model has some serious drawbacks. Researchers have tested common probiotics and found that the capsules often contain far fewer live bacteria than the bottle claims. What’s more, many lack ingredients that are listed on the label and contain ingredients that aren’t listed. The lack of quality control worries Caplan. He points out that doctors will have to treat many, many babies to prevent just one case of NEC. “What if one out of a whole lot of babies dies because you have a contaminant that you cannot remove from the preparation?” he says. “You cannot be careful enough in my opinion.”
Some of the hospitals that offer probiotics have found workarounds. The NICU at the University of Iowa offers a product manufactured in Canada, where there is more regulatory oversight of probiotic supplements. “That’s the only one I’ll trust. That’s the only one that has any regulation over it,” says McElroy, who currently heads the division of neonatology there.
Knowing what bacteria a probiotic contains is important given that different strains of bacteria have different effects. Doctors at Emory University Hospital Midtown began giving preemies Culturelle, one of the most popular probiotics in the U.S., in 2014 because it was the only probiotic available through the hospital’s pharmacy. But rather than seeing a decrease in the rate of NEC, the incidence rose—from 10.2% to 16%. “It was the opposite of what we were expecting,” says Ravi Patel, a neonatologist at Emory University. Patel doesn’t think the product caused more NEC—other factors may be to blame for the rise. But the data does suggest that Culturelle didn’t provide a benefit. Patel is still convinced probiotics can reduce the risk of NEC, but the hospital no longer administers Culturelle. “We stopped and decided to look at other products,” he says.
Other probiotics have also failed to provide protection. In 2010, researchers in England launched trial involving more than 1300 babies—the largest study to date—to test whether a certain strain of Bifidobacterium breve could prevent sepsis and NEC. The team chose the microbe because it was the only probiotic that had been shown to have positive effects in newborns when the study was designed and because it seemed safe. But they saw no significant difference in the rate of NEC between babies that received the probiotic and those that received a placebo.
“This is the one thing that really bothers me,” Neu says. “People talk about the generic probiotic.” But, he adds, “we’ve got hundreds of probiotics,” and we don’t have a good sense of which ones work and which don’t.
From Bug to Drug
Soll anticipates that more NICUs will use probiotics once there is greater regulatory oversight. “Neonatology is a little bit of the wild west,” Soll says. “We use all sorts of drugs that are not FDA-approved” for use in babies. But all those drugs are approved by the FDA for some other use, which means the agency has deemed them safe and effective. Probiotics, on the other hand, don’t come with similar assurances.
Several companies have begun the arduous process of proving that their products are worthy of being classified as drugs. A Swedish company called Infant Bacterial Therapeutics (IBT) has gone the furthest. IBT launched in 2013, but it took three years and $80 million to develop the actual drug they hoped to test. “The difference between that and what you buy in Walmart is massive,” says Eamonn Connolly, the company’s chief scientific officer.
Later this year, IBT will launch its second trial, involving 2,000 babies, of its product. It will be a true test of whether probiotics can reduce the risk of NEC. Everybody thinks that probiotics are “God’s gift to mankind,” Connolly says, “but nobody has developed a drug and shown the drug is effective.”
Researchers are looking at additional uses for probiotics, too. Evidence suggests that these beneficial microbes can prevent diarrhea in children taking antibiotics. And a large trial in India recently found that probiotics could stave off sepsis in full-term babies. Some scientists think babies who take certain probiotics may be less likely to develop health problems like allergies and asthma later in life. Still, many questions remain.
Any clarity future studies provide will be a boon not only to doctors, but also to parents. The fact that some NICUs offer probiotics and others don’t is “confusing and upsetting to families who have this range of outcomes with their babies,” says Canvasser, who in 2014 cofounded the NEC Society, a nonprofit focused on the understanding, prevention, and treatment of NEC.
Six years after her son Micah’s death, Canvasser still can’t let go of all the “what ifs”— what if Micah’s doctors hadn’t given him broad-spectrum antibiotics, what if they had listened when she first told them that Micah seemed “off,” what if they had offered him probiotics. “I do feel like Micah’s NEC was preventable,” she says. “I feel very strongly that we could have done things differently to allow Micah to live a healthy life.”
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