The number of pre-term and very low birth weight infant births is rising.
This rise increases the risk of a critical disease in these infants, known as Necrotizing Enterocolitis, or NEC. This disease attacks the infant’s developing intestinal tract, causes severe infection, and has a very high mortality rate.
The cause of NEC is poorly understood. This is complicated by the presence multiple “imposter” diseases that mimic the symptoms of NEC.
While the biggest risk for NEC is attributed to premature birth, in recent years some studies have observed an increased number of cases of NEC in infants fed cow’s milk-based formula specifically made to meet the needs of preterm and low birthweight infants.
Over 1, 000 lawsuits against the makers of formula for premature infants, Abbott Laboratories and Mead Johnson, are in the US court system. The suits claim the manufacturers should have warned parents and healthcare providers about the increased risk in those infants who were fed the cow’s milk formulas. More than 500 are included in a consolidated set of cases to be tried in Illinois.
Two suits that have been completed awarded 10’s to 100’s of millions of dollars to plaintiffs. The companies have vowed to appeal in both instances.
Important groups, including the American Academy of Pediatrics, feel that the science underlying this issue is not fully developed or understood, and the companies are not at fault.
What is Necrotizing Enterocolitis?
As defined by the NIH, necrotizing enterocolitis (NEC) is a life-threatening illness almost exclusively affecting neonates. NEC has a mortality rate as high as 50%. Necrotizing enterocolitis affects 2-5% of all premature infants and is responsible for nearly 8% of all NICU (Neonatal Intensive Care) admissions.
The National Child Health Institute (NICHD) at the National Institutes of Health (NIH) defines NEC as “the most common, serious gastrointestinal disease affecting newborn infants.” Healthcare providers consider this disease as a medical and surgical emergency. The condition typically affects infants who are born preterm or who are already sick, and it usually occurs before the newborn leaves the hospital. NEC usually begins within the first 2 or 3 weeks after birth in preterm infants who otherwise appear to be getting healthier.
According to the Centers for Disease Control and Prevention’s (CDC) National Center for Health Statistics (NCHS), NEC is one of the 10 leading causes of infant mortality. An extensive review by Lin et al. shows that the population most at risk for NEC is increasing because technological advances make it possible for a growing number of very low birth weight (VLBW) infants to survive.
However, the overall percentage of cases of NEC has stayed at about 7%, NICHD reports on their website (updated 9/3/2024). Still, the smaller the infant or the more premature the delivery, the greater the risk.
What causes Necrotizing Enterocolitis?
The cause or causes of NEC are extremely complicated, multifaceted, and still poorly understood, even after decades of research.
In premature infants, the cause may be related to the immaturity of the child’s digestive system. NEC involves infection and inflammation in the child’s gut, which may stem from the growth of dangerous bacteria or the growth of bacteria in parts of the intestine where they do not usually live.
Other possible causes include:
- Inability to digest food and pass it through, allowing a buildup of toxic substances.
- Inadequate blood circulation to the gut.
- Inability of the infant’s digestive system to keep out dangerous bacteria.
- Inadequate ability of the immature intestine to provide an adequate structural barrier to bacteria. This barrier usually matures in the unborn infant starting about week 26 (11 to 12 weeks before a full-term birth).
- The inability of the immature gut to secrete its normal biochemical defenses.
A recent NICHD-supported study found that H2 blockers, sometimes given to infants for acid reflux, were associated with a slight increase in the risk of NEC in preterm infants.
The origin and etiology of this disease in premature infants is likely even more complex than described above, according to a 2021medical textbook, Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines, 2nd Edition:
In this updated edition, leading experts from all over the world present the most recent evidence of nutrient requirements and nutritional care (with a focus on very low birth weight infants) to provide guidance for clinicians:
- Necrotizing enterocolitis is ill-defined as a disease and likely includes several different diseases such as ischemic intestinal necrosis, spontaneous intestinal perforation, food protein intolerance enterocolitis syndrome, and congenital anomalies of the bowel. Progress in prevention and treatment of this disease has, therefore, been slow.
- The pathophysiology of necrotizing enterocolitis is not understood and therefore not well defined.
- Currently many theories on how necrotizing enterocolitis might be prevented; can be found; however, few are backed up with robust randomized controlled trials.
As was reported by researchers in 2017, some of the cases and deaths from Necrotizing Enterocolitis in premature infants have been associated with feeding of specialized baby formulas made from cow’s milk, specifically developed for premature, low, and very low birth weight infants. The causes of NEC, however, are not very well understood, and most premature and very low birthweight infants fed cow’s milk formula do not get the disease. There are also cases and deaths from NEC in infants fed mother’s own milk.
The feeding of preterm and VLBW infants can be challenging. Biological mother’s milk is considered the best source of nutrition with the least number of adverse effects. Some research shows that those infants fed breastmilk from their own mothers have better neurodevelopmental outcomes than those fed infant formula.
However, there are many reasons a mother may not to be able to nurse or express milk after birth, especially in the case of infants born prematurely. In these instances, pasteurized human donor milk fortified with essential nutrients is often given to extremely preterm infants, but only a few studies have been conducted on whether it is better than formula for infants’ growth and neurodevelopment. Human donor milk is also extremely expensive and has limited availability, as was reported by researchers in 2019.
A very recent study (2024) funded by NICHD found there were no differences in neurological development between infants fed donated human milk and those fed formula. Infants who received formula also grew slightly faster than those receiving donor milk. The authors noted, however, that those fed human donor milk had half the rate of necrotizing enterocolitis (4.2%) as those fed cow’s milk formula (9%). This finding, they wrote, suggests that donor human milk, like maternal milk, may reduce the risk of necrotizing enterocolitis compared to formula.
This finding is in agreement with trials in an updated review published by the Cochrane Collaboration this year. However, these have acknowledged limitations that decrease their accuracy, as well as problems with bias. There is also a problem with heterogeneity in the trials, as a number used infant formula developed for term infants while others used formula especially made for preterm and VLBW babies. Finally, a significant number of the trials used in the review are more than 30 years old.
In fact, the American Academy of Pediatrics President Benjamin Hoffmann, MD, said in an interview this past July, “Part of what is so challenging about NEC is that the causes are multifaceted and not completely understood. Our science does not tell us exactly how to prevent it.”
Looking into the mechanistic science of this result, it appears that there is nothing in the formula that was toxic or carried bacteria that causes NEC. A problem is that we currently do not know what an effective prevention would be, and experts agree that we are a long way from knowing this for a number of reasons, including not having enough understanding of pathogenesis, and the fact that a large number of “imposter diseases” are often mistaken for NEC. It is important to remember that the majority of preterm infants who are fend cow’s milk formula, do not develop NEC.
Lawsuits
There are currently about one thousand individual legal cases against the two major manufacturers of pre-term infant formula – Abbot Laboratories and Mead Johnson, and 571 of these are being included in a class action lawsuit. The plaintiffs claim that the manufacturers should have issued warnings for parents and healthcare professionals about the increased risk for NEC in babies fed the formula.
The first and second bell weather (test) cases have been tried and did not go well for the defense. The first verdict, in March 2024 in Illinois, instructed Mead Johnson to pay $60 million to the plaintiff. The second, which took place in Missouri, instructed Abbott Laboratories to pay $495 million to the plaintiff in that case. Both companies have stated their intention to appeal. As the individual and class action lawsuits move forward, more complications are developing. One case involves suing the hospital where the infant was fed, for damages from cases of NEC after feeding specialized preterm formula.
The American Academy of Pediatrics stated unequivocally in a response to these lawsuits: “Courtrooms are not the best place to determine clinical recommendations for the care of infants.” The organization emphasized that special formulas for preterm infants are an essential source of nutrition, prescribed by doctors in neonatal intensive care units. Dr. Hoffmann: “Providing special formula is a routine and necessary part of care of these preterm infants. Recent court cases, however, may jeopardize the availability of these formulas.”
Even the Cochrane Collaboration believes the science is not currently settled as there are limited data from RCTs on the comparison of feeding with formula milk versus nutrient‐fortified human milk. The author of the 2024 Cochrane Review and Meta-analysis states in the conclusion “Further RCTs of feeding with formula versus donor breast milk in situations where the expressed breast milk of the preterm or LBW infant’s mother is not consistently available are needed. Several such trials are in progress, and these propose to recruit more than 1200 infants in total. Incorporating the data from these trials in meta‐analyses should generate more precise estimates of effect sizes and strengthen the applicability of the trial evidence‐base to current practice.”
Other scientific limitations of the current studies include the limited information that exists regarding any mechanism for why an increased risk for NEC is observed in some (but not all) preterm infants fed specialized formula. Current animal models are lacking as animals do not mimic human disease outcomes from exposure. To move from observation of association to causation, much more needs to be understood about this disease, as well as its multifaceted pathophysiology. It is interesting to note that in the Cochrane Review, no difference in mortality rate was found between the groups of infants.
Moving Forward
Concern about reduced nutritional supply for preterm infants must be taken seriously, along with data from well executed studies, as we go through what may be an extended period of learning about the best methods to understand and prevent NEC.
Awarding hundreds of millions of dollars to plaintiffs in these cases where the science is incomplete and has not been justified. The Center agrees with both the American Academy of Pediatrics and the Cochrane Collaboration that there are too many unanswered questions, and the current science has too many limitations to determine whether preterm infant formula should be considered a cause of NEC. We support the idea of better studies, beginning with a state of the science systematic review that includes randomized controlled clinical trials, observational studies, animal studies, and mechanistic laboratory studies. This would help point research in the best direction.
Most infants are introduced to the cow’s milk formula while still in the NICU. The nutrition needs are addressed by doctors and nurses who specialize in neonatology and should be aware of any risk to the infant. Studies showing a higher rate of incidence of NEC in formula fed infants have been in the literature for more than ten years. However, the quality of these studies has been called into question.