Necrotizing Enterocolitis (NEC) & Infant Formula

Nutrition is vital to growth - particularly for preterm infants. Infants born prematurely (before the 37th week of gestation) and even some full-term infants vary in their ability to drink from a breast or bottle. When infants cannot suckle, they are fed formula through a catheter.¹

One common type of infant formula is based on cows’ milk. Cows’-milk based formula is a staple of many infants’ diets for the first six months of life. However, this type of formula has recently come under scrutiny for its connection to cases of necrotizing enterocolitis (NEC).

Necrotizing enterocolitis (NEC) is a widespread gastrointestinal infection that can cause intestinal perforation if left untreated. Intestinal perforation results in the contents of the bowel invading the body. Systemic infection and death can result.²

Studies from the 1990s to the present reveal that when infants were fed exclusively with cows’-milk formula, NEC was 6 to 10 times more likely to occur.⁴ The average death rate for infants with NEC is approximately 20 percent.³

Recently, several brands of cows’-milk formula have been linked to the development of NEC. These include Similac and Enfamil, manufactured by Mead Johnson and Abbott Laboratories.⁵

Currently, research indicates that NEC has multifactorial causes: Several independent events related to a premature birth all contribute to the development of NEC.³

Several factors are linked to the development of NEC in infants. They include:

• Premature birth itself
• An abnormal or underdeveloped intestinal microbiome
• Formula feeding

Other potential factors include:

• Abnormal gut vascular regulation
• Red blood cell (RBC) transfusions
• Anemia³

One well-understood risk factor for NEC in preterm infants is enteral (tube) feeding with cows’-milk based infant formula.⁶ Preterm infants often have underdeveloped immune systems, which respond poorly to certain molecules introduced through the diet. The immune system’s response, in turn, may change the intestinal lining, making it more permeable.⁶

Enteral feeding of breastmilk alone appears to reduce the risk of NEC. A breast-milk diet that is even partially supplemented with cows’-milk based formula, however, appears to increase the risk again.

In a 2020 study, Lucas et al. observed a “4.2-fold increased risk of NEC and a 5.1-fold increased risk of NEC surgery or death” among preterm infants who received cows’-milk based formula.⁷

Clinical best practices currently recognize the following classical symptoms associated with NEC:

• Feeding intolerance
• Traces of blood in the stool
• Abdominal distension
• Intractable vomiting
• Temperature instability
• Lethargy⁸

Early detection of NEC and prompt treatment with appropriate antibiotics may avert the severest outcomes of the illness.

The symptoms of NEC may overlap with a more benign condition called food protein-induced enterocolitis (FPIES).⁹ Both NEC and FPIES have been documented in preterm infants. While antibiotics are the preferred course of treatment for NEC, treatment for FPIES typically involves removing allergy-provoking substances from the infant’s diet. However, the two conditions can be difficult to tell apart on an initial evaluation.

In 2017, an article published in the Journal of Perinatology proposed diagnosing NEC by examining the calprotectin levels in the stool of preterm infants. Calprotectin is a protein present in higher amounts in preterm neonates receiving cows’-milk based formula. The authors suggest that calprotectin levels can aid diagnosticians in confirming whether an infant’s symptoms are due to NEC.¹⁰

Recent studies of cows’-milk based formulas suggest multiple potential causes for the link between the use of these formulas and NEC in premature infants. Recent research also connects gut issues and neurological imbalances in infants.

Milk Proteins

Cows’-milk based formulas typically contain two proteins, whey protein and casein, which are hypothesized to trigger “the gut lesions and proinflammatory immune responses that precede NEC.”¹¹ Limited evidence currently supports this hypothesis, however.

Allergens

Both whey proteins (α-lactalbumin, β-lactoglobulin, bovine serum albumin, and bovine immunoglobulins) and casein proteins (α-s1, α-s2, β-casein, κ-casein) are known, common allergens. Both are present in cows’-milk based formulas.¹²

Neurological Outcomes

Recently-published studies also suggest a connection between intestinal issues and neurological imbalances in infants. In a 2019 study, researchers found that intestinal cells may release a protein known as TLR4, which can cause toxic reactive oxygen species (ROS) to accumulate in the brain. ROS may damage brain cells, impairing the brain’s functioning.¹³

Another study indicates the damage may accumulate in the hippocampus, the area of the brain that manages memory retention and recall.¹⁴

A timeline of lawsuits and filings related to the connection between Similac and Enfamil cows’-milk based formulas and NEC:

• December 2023: Four bellwether cases had been selected, but the start dates for the trials weren't confirmed. Lawyers expected the first trials might happen in 2024.
• April 2023: Lawyers continue to negotiate how discovery is to be conducted.
• March 2023: The judge scheduled science day proceedings for May 3, 2023. Science day allows the parties to present an overview of general medical and scientific issues to the court.
• December 2022: Defendants selected four cases for bellwether test trials: Clarke, Cresap, Inman and Mar.
• October 2022: Plaintiffs selected four bellwether test trials: Brown, Diggs, Lopez and Koeth. Randomly selected bellwether cases are: McCarthy, Jacobs, Kelton and Donaldson.

Multidistrict Litigation

MDL3026, In re: Abbott Laboratories, et al., Preterm Infant Nutrition Products Liability Litigation. Established in an April 8, 2022 transfer order from the MDL Panel.¹⁵

Early Cases

Hunte v. Abbott Labs, 556 F. Supp. 3d 70 (D. Conn. 2021). Plaintiff Annika Hunte alleged that feeding with three of Abbott’s cows’-milk based infant formulas resulted in her son’s developing NEC, which eventually proved fatal, and that Abbott knew or should have known the formulas were unreasonably dangerous.

The court granted Abbott’s motion to dismiss in part and denied it in part. Specifically, the court preserved plaintiffs’ claim under the Connecticut Products Liability Act (CPLA), seeking state supreme court clarification. The court also denied Abbott’s motion to dismiss negligence and related claims. The court granted Abbott’s motion to dismiss the plaintiff’s breach of express warranty claim.

A related case, Ferry v. Mead Johnson & Co, LCC, et al., was voluntarily dismissed a few months prior to the decision in Hunte.

J.B. v. Heltzer, 2021 N.Y. Slip Op. 30920 (N.Y. Sup.Ct. 2021). Defendants Dr. Paul Heltzer, Staten Island University Hospital, et al. sought summary judgment of plaintiffs’ claims, which the court granted in part and denied in part. Plaintiff J.B. was born unable to move or to cry. The infant suffered brain damage, NEC, and other injuries, which his parents allege were caused by the negligence of the defendants. Based on evidence from expert witnesses, the court dismissed the plaintiffs’ claims as to several defendants but allowed the claims against Dr. Heltzer and Staten Island University Hospital to proceed.

Regulatory Responses

In February 2022, the FDA launched an investigation of suspected contamination of Similac, Alimentum, and EleCare powdered infant formulas produced at Abbott Nutrition’s Sturgis, Michigan facility.¹⁶

In October 2022, Abbott announced a recall of several lots of liquid infant formulas in the US, Canada, Puerto Rico, and other Caribbean and South American nations. The recall was issued because some bottles may not have sealed, risking spoilage.¹⁷

In December 2023, the FDA announced a recall issued by Reckitt/Mead Johnson Nutrition of Enfamil Nutramigen Powder infant formula due to a suspected Cronobacter contamination.¹⁸ Cronobacter sakazakii has been connected to severe, life-threatening infections and cases of NEC in preterm infants.