Age at First Introduction of Cow Milk Products and Other Food Products in Relation to Infant Atopic Manifestations in the First 2 Years of Life: The KOALA Birth Cohort Study

METHODS

RESULTS

Of the 2834 infants enrolled at birth, we included 2558 infants in this study (after excluding infants with Down syndrome [n = 3]) and participants with missing information of the main determinants (age of introduction of cow milk products and/or other food products [n = 273]). The response rate of the questionnaire at age 2 years was high (n = 2434 of 2558 [95%]). Mothers in the alternative cohort showed more delay in the age of introduction of cow milk products (Table 1). Also, they had a higher rate and a longer duration of breastfeeding compared with the conventional cohort (Table 1). Other characteristics that differed between both groups were maternal age, maternal smoking during pregnancy, environmental tobacco smoking, and maternal education (Table 1).

More delay in introduction of both cow milk products and other food products was associated with a higher risk for eczema (P = .01 and .02 for trend, respectively; Table 2). No associations were found between the introduction of cow milk products and AD according to UK-WP criteria; however, more delay in other food products was associated with a higher risk for AD according to UK-WP criteria (P = .00 trend; Table 2).

A delayed introduction of other food products showed a higher risk for recurrent wheeze (P = .01 for trend; Table 3), whereas this was not found for a delayed introduction of cow milk products (after adjustment for confounding factors). The results for breastfeeding duration (confounder) between 7 and 9 months showed a reduced risk for recurrent wheeze (aOR: 0.31 [95% CI: 0.14–0.70]).

Delaying the introduction of cow milk products tended to be associated with a lower risk for atopic sensitization but did not reach statistical significance (P = .26 for trend; Table 3). Unexpected, a delayed introduction of other food products was positively associated with atopic sensitization at 2 years (P = .01 for trend; Table 3).

In addition, besides “any sensitization,” we assessed whether the introduction of cow milk or other food products was associated with sensitization against the introduction of separate food allergens (cow milk, hen egg, peanut). A delay in introduction of cow milk products tended to be associated with a lower risk for sensitization against cow milk, but this trend was not statistically significant (P = .10 for trend; Table 4). Also, we studied the associations for sensitization against ≥1 inhalant allergens (birch, grass pollen, cat, dog, or house dust mite), showing that delayed introduction of other food products led to a higher risk for inhalant allergen sensitization (P = .00 for trend; Table 4). To control for reverse causation (early symptoms urging the parents to delay the introduction of foods in the hope of diminishing the symptoms), we excluded infants with early symptoms in several so-called risk-period–specific analyses.

DISCUSSION

In this study, a delayed introduction of cow milk products was associated with an increased risk for eczema and recurrent wheeze. Also, our data demonstrated that a delayed introduction of other food products was associated with an increased risk for eczema, similar to our findings with AD according to UK-WP criteria. Furthermore, a delayed introduction of other food products was associated with an increased risk for recurrent wheeze, atopic sensitization, and, in particular, inhalant allergen sensitization. We also demonstrated that longer breastfeeding duration (7–9 months) showed a reduced risk for recurrent wheeze. The risk for recurrent wheeze for breastfeeding >9 months tended in the same direction. Overall, we found a statistically significant trend toward a reduced risk for recurrent wheeze with longer duration of breastfeeding. Previously, we speculated that these results may be explained by a protection of breastfeeding against respiratory infections.¹³

It has been suggested that early introduction of solid foods may result in allergic sensitization against (food) allergens because the infant's gut-mucosal barrier is immature and early exposure to (food) allergens may trigger an allergic response of the immune system.¹⁴ In a study of children with an immature gastrointestinal tract or immune response, no increased risk for the development of food allergies was found¹⁵; however, there is only scarce scientific evidence to support this hypothesis. Most studies have focused on the duration of breastfeeding as a preventive measure to avoid the development of asthma and allergy. In 1999, Oddy et al¹⁶ found that it was the later age at which cow milk was introduced rather than the duration of breastfeeding that was more closely associated with lower risk for asthma or atopy at 6 years of age. They found that the introduction of milk other than breast milk was a significant risk factor for asthma, wheeze, and a positive skin prick test reaction against at least 1 common aeroallergen. These results favor “exclusion mechanisms”; however, it was noted that studies that attempt to separate the effects of breastfeeding duration and the age of introduction of cow milk or food products face problems of high correlation between these variables. Therefore, the possibility that it may be breastfeeding itself that may confer protection cannot be rejected.¹⁶

Several other studies previously focused on the introduction of first exposure of milk or food products. The results of our study tended toward the same direction as several previous studies. Zutavern et al⁹ showed an increased risk for eczema in relation to late introduction of egg and milk in a prospective birth cohort study in the United Kingdom. Late introduction of egg was furthermore associated with a nonsignificantly increased risk for preschool wheezing. Our results confirm that also wheeze may be implicated as an atopic outcome, because we found that age of introduction of food products other than cow milk products was associated with higher risk not only for eczema but also for wheeze and sensitization for inhalant allergens. Mihrshahi et al¹⁷ showed that breastfeeding for ≥6 months (yes versus no) and introduction of solid foods after 3 months (yes versus no) both were associated with an increased risk for atopy (defined as the presence of any allergen weal ≥2 mm and larger than the negative control) at 5 years of age. It is interesting that Poole et al¹⁸ showed that children who were first exposed to cereals after 6 months of age had an increased risk for wheat allergy compared with children who were first exposed to cereals before 6 months of age. In contrast with these studies, Morgan and colleagues¹⁹ showed that the introduction of ≥4 solids before 17 weeks' postterm (compared with <4 foods at 17 weeks' postterm) was associated with a higher risk for eczema in infants with and without a family history of allergy, suggesting that a delay of the introduction of solids reduced the development of eczema; however it should be noted that this study was done in preterm infants, which may possibly confound⁸ their results because prematurity has been shown to reduce the long-term risk for atopy.²⁰ Andreasyan et al²¹ showed recently that there was no association between introduction of nonmilk fluids in infancy and childhood atopic disease. The results of a follow-up analysis of a double-blind, placebo-controlled, randomized feeding intervention trial showed that brief neonatal exposure to cow milk (quantity was regarded sufficient to induce sensitization) in breastfed children was not associated with atopic disease or allergic symptoms up to age 5.^22,23

Most studies that addressed the relationship between timing of solid introduction and atopy development were prospective birth cohort studies instead of randomized, controlled trials. A major disadvantage of cohort studies has been the phenomenon of reverse causation when interpreting the results.^8,9 Zutavern et al²⁴ investigated whether a delayed introduction of solids (after 4 or 6 months) is protective against the development of AD and atopic sensitization when taking into account reverse causation in a German prospective birth cohort study. Their results provided evidence (ie, their results changed) for reverse causation between the introduction of solids and early skin or allergic symptoms. In this study, we indeed thought of the idea that parents of infants with early symptoms of eczema or wheeze may delay the introduction of cow milk products or other food products, which would make our results susceptible to reverse causation. We have attempted to avoid reverse causation in our analysis as follows: first, we excluded all infants with reported symptoms of eczema between 0 and 7 months, resulting in cases that were “at risk” for developing eczema between 7 and 24 months. Second, in the same way, we excluded all infants with reported symptoms in the first year of life (0–12 months), resulting in infants who were at risk in the second year of life (12–24 months). The same was done for the outcome “recurrent wheeze.” We noted that the results (ORs and 95% CIs) of our so-called risk-period–specific analysis did slightly change, which suggests that the presence of reverse causation as a potential bias cannot be fully excluded; however, in our opinion, the interpretation of our main findings were minimally affected by reverse causation. Unfortunately, we were not able to assess whether our results of AD according to UK-WP criteria and allergic sensitization were prone to reverse causation, because the data were available only at the age of 2 years; therefore, we could not exclude infants who developed early symptoms.

Another explanation that has been put forward to explain the results of an increased risk for atopy by a delayed introduction of cow milk or food allergens is the induction of “oral tolerance” (ie, the induction of systemic immunologic hyporesponsiveness, a usual response to soluble dietary proteins). Although the biological mechanism of this is largely unexplained, the induction of oral tolerance affects a broad spectrum of immunologic functions, locally and systemically, to a varying degree.²⁵ Previously, it was also put forward that late introduction of food products is associated with allergy, because introducing food products to older infants tends to be in greater amounts.²⁶ Hence, it has been speculated that a larger antigen dosage may result in T-cell activation instead of anergy or tolerance.¹⁸ Indeed, it may be anticipated that our results can be explained by the induction of oral tolerance that will be induced by larger amounts of cow milk and other food products, leading to an increased exposure to (food) antigens in older infants (>7 vs 0–3 months) in this study.

CONCLUSIONS

We have shown that a delayed introduction of cow milk products is associated with a higher risk for eczema. In addition, a delayed introduction of other food products is associated with an increased risk for atopy development in the first 2 years of life (eczema, AD according to UK-WP criteria, recurrent wheeze, any sensitization and inhalant allergen sensitization). Although breastfeeding remains definitely favorable for the infant's health (ie, protection against infections), it may be questioned whether delaying the introduction of cow milk or other food products may have a substantial additional advantage as a possible preventive measure to avoid the development of atopic manifestations. On the basis of the current knowledge, it may be too early to change the current guidelines on the introduction of cow milk (eg, World Health Organization), although these guidelines may be discussed in light of the “induction ” of oral tolerance. Future research may focus on separating formula products from “other cow milk products,” because the current guidelines suggest that introduction of cow milk products should wait but are not meant to suggest that milk-based formulas cannot be used.