respect to their family history of allergic disease when this history is only assessed at baseline [27].
Clinical trials have demonstrated that the risk of developing atopic dermatitis is reduced when using HF to feed infants with a documented risk of atopy when breastfeeding is not practiced [1, 2, 16, 26-30]. In 2006, a Cochrane review, based on 14 randomized controlled trials (RCTs) or quasi-RCTs, concluded that there is no evidence to support feeding with HF for the prevention of allergy compared to exclusive breastfeeding. In high-risk infants who are not breastfed, there is limited evidence that prolonged feeding with HF compared to CM standard formula (SF) reduces infant allergy and infant CMA [26]. As the potential benefit of these formulas has only been documented in infants at genetic risk of developing atopic disease, additional studies are needed particularly among unselected infants or infants at low risk [2, 31].
Partially Hydrolyzed Formulas
Compared to eHFs, pHFs offer economical and taste advantages, and a theoretical benefit in inducing oral tolerance to the CMP as they still have a higher residual allergenicity.
A meta-analysis showed that a specific whey-based pHF (pHF-W) significantly reduces the incidence of atopic dermatitis approximately 44% [11 trials; summary relative risk (RR) estimate 0.56, 95% CI 0.4-0.77] up to 3 years of life in at-risk infants compared to CM-SF [28]. Another meta-analysis based on the use of the same pHF involving 3,284 participants (1,027 in pHF and 2,257 in control groups) reported reductions in all allergic diseases of 52% (5 RCTs: RR 0.48, 95% CI 0.23-1.00) at 3 and 6 months of age, 38% at 12 months (4 RCTs: RR 0.62, 95% CI 0.45-0.85; number needed to treat 12) and 58% at 30-36 months (1 RCT: RR 0.42, 95% CI 0.19-0.90) compared to SF [29]. For atopic dermatitis or atopic eczema (8 RCT), using a random effect model, the use of pHF compared with SF statistically significantly reduced the incidence of eczema at 1 year (4 RCTs: RR 0.68, 95% CI 0.48-0.98), but not at 4-6 months (5 RCTs), 2 years (3 RCTs) or 30-36 months (2 RCTs) [29]. However, many trials included in the analysis presented a lack of methodological rigor in sequence generation, allocation, blindness, definition of atopic manifestations, outcome data, intention-to-treat analysis, calculation of the sample size, selective reporting and other biases [29, 31].
A single-blind RCT, published after these meta-analyses, enrolling 620 high-risk infants before birth, found a higher incidence of allergic symptoms at 2 years in the ones fed with soy formula (44%) compared to a similar rate (37.7 vs. 37.3%) in pHF- and CM formula-fed participants. There was no difference in skin prick test reactivity or, at 6 and 7 years, in the rates of eczema, asthma or allergic rhinitis among the three groups [32]. However, different methodological issues have been raised that call for caution, including the unclear reason for publishing the results 15 years after collecting the data, outcome assessment through telephone interviews with parents and changing definitions of outcome indicators compared with previous publications on this cohort [33]. Moreover, the formulas were introduced after discontinuation of breastfeeding, determining a possibly delayed intervention and reduced clinical efficacy.
Partially versus Extensively Hydrolyzed Formulas
Only few studies compared the effect of pHFs and eHFs [29, 31]. Differences in the study design, definition of atopic manifestations, selection of formulas (not all commercially available), presence of concomitant intervention and small sample sizes limited the comparative analysis [31].
In a prospective comparative Danish study, 595 high-risk infants were randomized at birth to one of three different blinded formulas. Of 478 infants who completed the study, 232 were exclusively breastfed, 79 received eHF-C, 82 eHF-W and 85 pHF-W during the first 4 months of life. The three formula groups were identical in regard to the atopic predisposition, cord blood IgE, birthplace, tobacco smoke exposure, gender, duration of breastfeeding, and age at introduction of the formula and solid foods. No significant differences were found in the three groups regarding the cumulative incidence of atopic dermatitis or respiratory symptoms. pHF was found to be less effective than eHF in preventing CMA (0.6 vs. 4.7%; p = 0.05) [34].
GINI, the largest German study, prospectively analyzed 2,252 at-risk infants, of which 945 represented the intervention arm and were randomly assigned to receive one of three HFs (n = 689) or CM-SF (n = 256). The 3 HFs were pHF-W, eHF-W and eHF-C [35]. The authors reported a significant reduction in eczema at all study points (1, 3, 6 and 10 years) when using the pHF (odds ratio, OR, 0.56; 95% CI 0.32-0.99) or the eHF-C (OR 0.42, 95% CI 0.22-0.79) but not with eHF-W or CM-SF. The RRs for the cumulative incidence of atopic dermatitis in the intention-to-treat analysis (n = 2,252) were 0.82 (95% CI 0.68-1.00) for pHF-W, 0.91 (95% CI 0.76-1.10) for eHF-W and 0.72 (95% CI 0.58-0.88) for eHF-C compared with the infant SF. The cumulative incidence of atopic manifestations was better reduced with the eHF-C compared to the other HFs. No effect was found regarding rhinitis, asthma and urticaria [30, 35]. Thus, this study highlights that different hydrolysates may have different effects on atopic disease [17].
Economic analyses in 5 European countries (Denmark, France, Germany, Spain and Switzerland) have evaluated the costs and cost-effectiveness of a specific brand of 100% pHF-W (NAN-HA®) compared with a CM-SF in the prevention of atopic dermatitis in at-risk children [36, 37]. Outcomes were considered from the perspective of the public health care system (e.g. the Ministry of Health; MOH), family and society. The cost-effective analysis per avoided case of atopic dermatitis showed the following results: pHF-W versus SF EUR 982-1,343 (MOH perspective), EUR -2,202 to -624 (family perspective) indicating savings, and EUR -1,220 to 719 from the societal perspective. The main costs are related to formula (MOH and society) and time loss (family). In the cost-minimization analysis, pHF-W yielded savings of EUR 4.3-120 million compared with eHF-W when the latter was used in disease prevention. In conclusion, pHF-W was cost-effective versus SF in the prevention of atopic dermatitis and cost savings compared with eHF when used in disease prevention [36, 37]. However, it should be noted that Nestlé employees are involved as coauthors in these papers, what may have induced a bias.
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