Hydrolyzed Formula May Not Protect Infants Against Allergies

Nicola M. Parry, DVM

March 10, 2016

The findings of a new study do not support current international guidelines that recommend the use of hydrolyzed milk formula to prevent allergic disease in high-risk infants.

"Our analyses suggest that current recommendations to use hydrolysed formula in place of standard cows' milk formula to prevent allergy in infants at high risk should be revised," write Robert J. Boyle, MBChB, PhD, from Imperial College London, United Kingdom, and colleagues. "We found no consistent evidence to support the current recommendations and found evidence of publication bias, methodological biases, and conflict of interest in those studies reporting allergic outcomes."

The authors published the results of their systematic review and meta-analysis online March 8 in the BMJ.

Prior studies suggested that early exposure to allergenic cow's milk proteins in baby formula plays an important role in the development of allergic or autoimmune disease in childhood. Conversely, hydrolyzed formulas, which are produced by using enzymatic processes to break proteins down into smaller fragments, are thought to reduce the risk for the development of allergic diseases in childhood. Therefore, current international guidelines, supported by the US Food and Drug Administration and by a Cochrane systematic review, recommend the use of hydrolyzed formula in the first 4 to 6 months of life in high-risk children who are not breast-fed.

As part of a series of systematic reviews commissioned by the UK Food Standards Agency to inform guidelines on infant feeding, Dr Boyle and colleagues performed a systematic review and meta-analysis of trials that evaluated the use of hydrolyzed formula for preventing allergic sensitization, allergic disease, or autoimmune disease.

They included studies undertaken between 1946 and 2015 in which hydrolyzed formula of cows' milk origin was compared with any nonhydrolyzed cows' milk formula, human milk, or another type of hydrolyzed cows' milk formula. They excluded studies that involved hydrolyzed formula of milk other than cows' milk.

However, among the 37 eligible intervention trials involving more than 19,000 participants, they found no consistent evidence to support a protective role for the use of partially or extensively hydrolyzed milk formula in infants at high preexisting risk of developing allergic or autoimmune disease.

Pooled data from 27 studies demonstrated no significant difference between extensively hydrolyzed formula and standard cows' milk formula in reducing the risk for eczema in children aged 0 to 4 years (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.67 - 1.07; I2 = 30%) or 5 to 14 years (OR, 0.86; 95% CI, 0.72 - 1.02; I2 = 0%).

The authors also analyzed data from 21 studies that investigated the outcome of wheeze or recurrent wheeze. Although analysis of the outcome "wheeze" was inconclusive, analysis of "recurrent wheeze" demonstrated no significant difference between the use of partially hydrolyzed formula and standard cows' milk formula and the risk for recurrent wheeze in children aged 0 to 4 years (OR, 0.82; 95% CI, 0.48 - 1.41; I2 = 15%) or aged 5 to 14 years (OR, 0.99; 95% CI, 0.65 - 1.51; I2 = 43%).

Although pooled data from 12 studies showed that the use of partially hydrolyzed formula (but not extensively hydrolyzed formula) was associated with significantly reduced risk for allergic rhinitis in children aged 0 to 4 years, a multifaceted intervention study in which uptake of the intervention was low dominated this evaluation. Moreover, neither partially (OR, 1.03, 95% CI, 0.82 - 1.30; I2 = 0%) nor extensively (casein [OR, 0.87; 95% CI, 0.66 - 1.15; I2 = 0%] or whey [OR, 0.93; 95% CI, 0.69 - 1.26; single study]) hydrolyzed formula significantly reduced the risk for allergic rhinitis in children aged 5 to 14 years.

Similarly, the authors found that the use of hydrolyzed formula did not protect against development of food allergy (13 studies) or allergic sensitization (19 studies). In particular, the data showed that compared with using standard formula, using partially (risk ratio [RR], 1.73; 95% CI, 0.79 - 3.80; I2 = 42%) or extensively (RR, 0.86; 95% CI, 0.26 - 2.82; I2 = 42%) hydrolyzed formula did not significantly reduce the risk for development of "any food allergy" in children aged 0 to 4 years. Use of extensively hydrolyzed formula also did not affect this risk in those aged 5 to 14 years.

Six studies also reported that compared with using standard formula, using extensively hydrolyzed formula in infancy did not significantly affect the risk of developing type 1 diabetes mellitus (RR, 1.12; 95% CI, 0.62 - 2.02; I2 = 25%).

Overall, the study found no evidence to support either the health claim approved by the US Food and Drug Administration that a partially hydrolyzed formula could reduce the risk for eczema or the conclusion of the Cochrane review that hydrolyzed formula could prevent allergy to cows' milk.

Perhaps more concerning, however, was that the review demonstrated evidence of conflict of interest, often because of support of a particular study or investigators from manufacturers of hydrolyzed formula. Dr Boyle and colleagues found high or unclear risk for bias in most studies investigating allergic outcomes and evidence of publication bias in those investigating eczema and wheeze, which, "suggests that these systematic reviews might still overestimate the possibility that hydrolysed formula has beneficial effects."

"Our findings conflict with current international guidelines, in which hydrolysed formula is widely recommended for young formula fed infants with a family history of allergic disease. Such recommendations might therefore need revision," they write.

"We suggest that any future trials on hydrolysed formula should be prospectively registered, independently funded, and include adequate oversight to ensure that they do not negatively impact on breastfeeding in study participants," the authors conclude.

In an accompanying editorial, Caroline J. Lodge, MBBS, Adrian J. Lowe, MPH, PhD, and Shyamali C. Dharmage, MBBS, MD, PhD, from the University of Melbourne, Victoria, Australia, note that a major strength of this study "is its assessment of all included studies for quality, along with an overall assessment of the quality of evidence from each meta-analysis by using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) criteria."

However, they also note that when the authors were able to assess the effect of conflict, they did not find evidence that these conflicts influenced the reported associations for individual outcomes.

"With increasing and necessary involvement of industry in medical science it is imperative that we take steps to ensure transparency and prevent commercial priorities from influencing published results," they emphasize.

However, according to the editorialists, the most undesirable consequence of recommending the use of hydrolyzed formulas for prevention of allergic disease is that it thwarts efforts to promote breast-feeding: "We know that formula feeding, whether the formula is hydrolysed or not, cannot replicate the complex and adaptive constituents of breast milk and the benefits of breast feeding for mothers or babies," they write.

They also stress the need to use this this evidence to update and clarify current recommendations and guidelines, concluding: "Furthermore, we encourage industry to pursue development of effective allergy reducing infant formulas and call for further transparent and well conducted studies in this area."

This study was funded by the Food Standards Agency and supported by the National Institute for Health Research Biomedical Research Centre. The Food Standards Agency commissioned both the study and external peer review of the study protocol, statistical methods, and study report. Dr Boyle and three coauthors received support from the UK Food Standards Agency for this study. Dr Boyle was a coinvestigator and author of one of the trials included in this systematic review. The authors have disclosed no relevant financial relationships. Dr Lodge, Dr Lowe, and Dr Dharmage received commission for their editorial commentary.

BMJ. Published online March 8, 2016. Article full text, Editorial full text

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