Main findings

This updated meta-analysis of RCTs and quasi-RCTs confirmed that use of pHF compared to CMF reduced the risks of eczema and all allergic diseases among children at high risk for allergy. Both ITT analyses and per-protocol analyses showed that the reduction was statistically significant only at some, albeit not all, time points. Some results were of borderline statistical significance in favor of pHF, i.e., the upper limit of the 95% CI for RR was 1.01 or 1.02. As the 95% CI for RR included 1, there was no significant difference between treatments in these cases. However, we cannot conclude that these results are not clinically important. For example, 95% CIs ranging from 0.75 to 1.02 included both RRs of clinical importance and RRs of no importance. It is possible that the sample size was too small to allow confidence about where the true result lies.

Interestingly, two studies that contributed the most to the pooled results showed opposite findings, adding to the current discussion on the role of pHF. One of them is the GINI study, a large, well-designed and conducted, randomized, double-blind (until 3 years of age) trial, with a 15-year follow-up period [22–24]. Second, also a large, but single-blinded study is the MACS study [17]. A number of issues related to these two trials have been discussed by the authors themselves elsewhere [28–30].

We present the results of both the ITT (more precisely, available case analysis) and the per-protocol analyses, as they complement each other. In the two largest studies (i.e., the GINI and the MACS), the rate of breastfeeding was high (approximately 40%). Thus, the ITT analyses included infants who were exclusively breastfed, including infants who were never exposed to pHF. The per-protocol analysis included all participants who adhered adequately to the assigned regimen. While not ideal from a methodological point of view, the per-protocol analysis is important for understanding the role of pHF in allergy prevention, and hence, our decision to include both. Clearly, the promotion of exclusive feeding with pHF from birth would be unethical.

We focused only on a single formula. This decision was in line with the opinion of the European Food Safety Authority [31], which has clearly stated that it is necessary to demonstrate if, and to what extent, a particular formula reduces the risk of developing short- and long-term clinical manifestations of allergy in at-risk infants who are not breastfed.

Strengths and limitations

The review question and inclusion criteria were clearly defined. Various major databases were accessed. No language restrictions were applied. The corresponding authors were contacted to clarify reported data in the case of questions. Experts in the field were contacted. Unpublished data from the manufacturer of pHF were available. Thus, the risk that relevant studies were missed was minimized. Additionally, efforts were made to minimize reviewers’ errors and bias. Two reviewers independently identified, selected, and assessed the risk of bias using accepted criteria in the included trials. Another strength is the use of the GRADE profile to rate the overall quality of evidence, which can be useful for future guideline development.

However, this review has some limitations. As this review represents an update of our previously reported meta-analysis [7], the analyses were defined a priori. However, the protocol of the review has not been registered. This was because the review was carried out according to the same methodology as used in our original review. Not all included trials were free of the risk of bias. Only the GINI study seemed methodologically sound. One concern with studies involving hydrolyzed formulas is the lack of true blinding. The latter is challenging, as hydrolyzed formulas have a specific taste and smell, and study personnel and caregivers may have suspected the intervention. Assessment of selective reporting was challenging, as with one exception, the trial protocols were not registered. Only the MACS was registered, but retrospectively. However, registration on a public trial registration database prior to the start of the study with sufficient protocol information has become the standard only recently.

The majority of included studies were industry supported. A 2012 Cochrane Review provided evidence that there is bias associated with study funding sources [32]. Compared with non–industry-sponsored studies, drug and medical device studies sponsored by the manufacturers tended to have more favorable effectiveness and harm findings and more favorable conclusions. Funding of research by manufacturers of infant formulas may be considered an even more complex and controversial topic because of the need for protection and promotion of breastfeeding. However, in the case of studies involving infant formulas, industry involvement is unavoidable, as investigators lack the means to manufacture quality infant products. Thus, industry sponsorship will likely continue to be a major source of funding for research on infant formulas, although collaborative clinical research between academia and industry is in both the mutual and public interest. Of note, in the largest GINI study, even if the study formulas were provided by the manufacturers (for the first 3 years), the study was financed from public resources.

Ideally, the diagnosis of allergic diseases should be based on widely agreed-upon criteria. However, in most of the included studies, heterogeneous definitions made direct comparisons between the studies difficult. Caution is needed when interpreting ‘all allergic diseases’ [33]. In the included trials, this composite outcome was defined differently by the authors of the original trials. It is also important to consider how the outcomes were assessed. For example, in one of the studies, the primary outcome measures, including eczema and any allergic manifestation, were assessed during telephone interviews with parents [17]. This contrasts with the assessment in another trial, at least during the first 3 years of the study, made by one investigator according to predefined diagnostic criteria and confirmation by a second, specially trained allergist [22].

With two exceptions [17, 22], the included trials had small sample sizes and lacked sample size calculations. However, to increase power is one of the reasons why a meta-analysis is performed within a systematic review [34].

While not formally assessed due to the limited number of eligible trials for any given outcome, publication bias, i.e., bias due to the publication or non-publication of research findings depending on the nature and direction of the results, cannot be excluded.

Finally, one of the limitations of our review is that we did not systematically assess the safety of pHF. All formulas intended for infants must be safe and suitable to meet their nutritional requirements; they must promote the growth and development of infants born at term when used as the sole source of nutrition during the first months of life, as well as when used as the principal liquid element in a progressively diversified diet after the introduction of appropriate complementary feeding [31]. However, available data do not indicate that pHFs are potentially harmful for healthy, term infants. Based on limited available data, summarized elsewhere, the use of pHF in healthy infants is safe with regard to growth [35].

Agreement and disagreement with other studies or reviews

Compared with a 2016 meta-analysis by Boyle et al. [6], our review focuses on one type of hydrolyzed formula (pHF), as not all hydrolyzed formulas are equal. Moreover, our review included only RCTs, and it excluded observational studies. Compared with the analysis by Boyle et al., we included only studies carried out in a high-risk population. We report outcomes at time intervals reported by the authors of the original studies. In contrast, Boyle et al. grouped participants who were aged at assessment 0–4, 5–14, and ≥15 years. As the reviewers subjectively chose these time intervals, a number of decisions were made as to which data should be used for their analyses, which may have introduced bias. Both reviews presented the intention-to-treat analyses without imputation. However, Boyle et al. presented the results of systematic reviews as odds ratios (ORs), mainly because the GINI study used generalized estimating equations (GEE) (to generate odds ratios in some of their publications). Consequently, ORs were calculated by the authors for all data pooled with GINI GEE data. In our review, we present the RR, which is recommended by the Cochrane Handbook for Systematic Reviews of Interventions as the summary statistic that is easier to understand and apply in practice. We contacted the study authors to obtain additional information if it was not available from the published report or reports from studies. Furthermore, Boyle et al. included studies in which in the intervention group, but not in the control group, additional interventions were applied such as house dust mite control measures and a smoke-free environment. In our analysis, we excluded such studies. Moreover, Boyle et al. pooled data on cumulative incidence and prevalence. In our analysis, we report these data separately. Of note, in the Food Standards Agency report, post hoc, Boyle et al. evaluated the effect of using pHF, as in our review, compared with cow’s milk-based formula on the risk of eczema in children aged 0–4 years (https://www.food.gov.uk/science/research/allergy-research/fs305005hf). No difference between the groups was found. However, it remains unclear which studies were included in the pooled analysis. Taken together, in our view, our results more precisely define the effects of pHF on allergy outcomes.