Participant Population

The median age of the participants at enrollment was 3.4 months. The two groups were balanced, except for a significantly higher rate of birth by cesarean section in the early-introduction group than in the standard-introduction group (Table S4 in the Supplementary Appendix). A total of 91.3% of the participants attended the final clinic visit, 90.0% of whom attended within the visit window (by 4 years of age). A total of 94.0% of the participants’ families completed the 3-year questionnaire.

Food Allergy

A food allergy developed in 74 participants. In 70 of these participants (39 in the standard-introduction group and 31 in the early-introduction group), diagnoses were made on the basis of double-blind, placebo-controlled food challenges (primary-outcome categories 1A and 1B), and in 4 (3 in the standard-introduction group and 1 in early-introduction group), diagnoses were made on the basis of an allergic reaction that resulted in a wheal size of 5 mm or more in diameter on skin-prick testing (primary-outcome category 3). A diagnosis of any food allergy was significantly associated with the presence of eczema at enrollment, nonwhite race, and having siblings. In the post hoc dominance analysis, these three factors accounted for 92.6% of the variation in the fit statistic of the overall logistic model (Table S5 in the Supplementary Appendix).

Food Consumption and Allergy in the Intention-to-Treat Analyses

Figure 1. Figure 1. Primary Outcome of Allergy to One or More Foods and Secondary Outcomes of Allergy to Peanut and to Egg. The prevalence of IgE-mediated food allergy is shown with respect to one or more of the six early-intervention foods (peanut, cooked egg, cow’s milk, sesame, whitefish, and wheat; Panel A), to peanut (Panel B), and to egg (Panel C). The results regarding IgE-mediated food allergy to the other early-introduction foods are shown in Figure S5 in the Supplementary Appendix. The first column shows the intention-to-treat analysis, the second column the per-protocol analysis, and the third column an adjusted per-protocol analysis. The intention-to-treat analysis included all the participants who had data that could be evaluated; the per-protocol population included all participants who adhered adequately to the assigned regimen. The adjusted per-protocol analysis was a conservative per-protocol analysis that adjusted the prevalence of food allergy in the standard-introduction group by subtracting the number of participants in the early-introduction group who had a positive result on the challenge at enrollment and who completed the trial with a confirmed food allergy from both the numerator (the number of participants with allergy in the standard-introduction group) and the denominator (the number of participants in the standard-introduction group who adhered to the protocol). P values are based on chi-square analyses or Fisher’s exact test, as appropriate. The relative risks with 95% confidence intervals are shown in Table S6 (intention-to-treat analysis) and Table S10A (per-protocol analysis) in the Supplementary Appendix.

For the primary outcome, 595 of 651 enrolled participants (91.4%) in the standard-introduction group and 567 of 652 (87.0%) in the early-introduction group were included in the intention-to-treat analysis (Fig. S1 in the Supplementary Appendix). The rate of the primary outcome was nonsignificantly lower in the early-introduction group than in the standard-introduction group (5.6% [32 of 567 participants] and 7.1% [42 of 595], respectively), which represented a relative risk of 0.80 (95% confidence interval [CI], 0.51 to 1.25; P=0.32), with the point estimate representing a 20% lower prevalence in the early-introduction group (Figure 1, and Table S6 in the Supplementary Appendix). The prevalence of allergy to more than one food was nonsignificantly lower in the early-introduction group than in the standard-introduction group (P=0.17) (Table S7 in the Supplementary Appendix).

Peanut allergy occurred in 1.2% of the participants in the early-introduction group and in 2.5% of those in the standard-introduction group, representing a nonsignificant 51% lower relative risk in the early-introduction group (P=0.11). Egg allergy occurred in 3.7% of the participants in the early-introduction group and in 5.4% of those in the standard-introduction group, representing a nonsignificant 31% lower relative risk in the early-introduction group (P=0.17) (Figure 1).

For other early-introduction foods, the prevalence of food allergy was 0.7% or less in each group (Fig. S5 in the Supplementary Appendix). Non–IgE-mediated allergy-type symptoms are discussed in Tables S8 and S9 and the Results section in the Supplementary Appendix.

Food Consumption and Allergy in the Per-Protocol Analysis

In the per-protocol analysis, the rate of the primary outcome was significantly lower in the early-introduction group than in the standard-introduction group (2.4% [5 of 208 participants] vs. 7.3% [38 of 524]). The relative risk in the early-introduction group was 0.33 (95% CI, 0.13 to 0.83; P=0.01), representing a prevalence that was 67% lower than that in the standard-introduction group (Figure 1).

With regard to food-specific per-protocol consumption, the protective effects with respect to egg and peanut were larger in the early-introduction group than in the standard-introduction group. In the per-protocol analysis of peanut consumption, there were no cases of peanut allergy among the 310 participants in the early-introduction group, as compared with 13 cases among 525 participants (2.5%) in the standard-introduction group (P=0.003) (Figure 1). The prevalence of egg allergy among participants who adhered to the protocol with respect to egg consumption was 1.4% in the early-introduction group versus 5.5% in the standard-introduction group, representing a 75% lower relative risk (P=0.009) (Figure 1). The rates of food allergy in the per-protocol analysis were lower, but not significantly so, in the early-introduction group than in the standard-introduction group for milk (P=0.63) and sesame (P=0.56). There were no cases of wheat allergy in either group in the per-protocol analysis. The rate of fish allergy was nonsignificantly higher in the early-introduction group than in the standard-introduction group (P=1.00) (Fig. S5 in the Supplementary Appendix).

Although adjustment for multiple testing was not part of the statistical analysis plan, if these six component food tests were adjusted for multiple testing with the use of a Bonferroni correction, the critical value for statistical significance would be 0.0085 (i.e., 1−0.951/6). Under this constraint, in the per-protocol analysis the effect on peanut allergy would remain significant, and the results for egg would remain borderline significant (see the Discussion section in the Supplementary Appendix).

Protective effects with respect to the primary outcome and with respect to peanut allergy and egg allergy remained significant in the conservative adjusted per-protocol analysis. This analysis was not adjusted for multiple comparisons (Figure 1, and the Results section in the Supplementary Appendix).

Participants in the two trial groups who did not adhere to the protocol or whose adherence could not be evaluated had rates of allergy that were similar to the rate among the participants in the standard-introduction group who adhered to the protocol. Statistical comparisons between the participants in the standard-introduction group who adhered to the protocol and the participants in the early-introduction group who did not adhere to the protocol or whose adherence could not be evaluated were all nonsignificant (Table S10B in the Supplementary Appendix).

Results of Skin-Prick Testing

Figure 2. Figure 2. Secondary Outcome of Results on Skin-Prick Testing. The prevalence of a positive skin-prick test (wheal of any size) is shown for one or more of the six early-intervention foods (Panel A), peanut (Panel B), egg (Panel C), and raw egg white (Panel D; this test was performed only at the 36-month visit). Results of skin-prick testing for the other early-introduction foods are shown in Figure S6 in the Supplementary Appendix. The first column shows the intention-to-treat analysis, and the second column the per-protocol analysis. P values are based on chi-square analyses. The group-specific denominators and relative risks with 95% confidence intervals are shown in Table S11 in the Supplementary Appendix.

A similar pattern was seen for the results of skin-prick testing (Figure 2). In the intention-to-treat analyses, the risk of a positive skin-prick test to any food was 22% lower in the early-introduction group than in the standard-introduction group at 12 months of age (P=0.07) and 12% lower at 36 months of age (P=0.47); both differences were nonsignificant. Positive skin-prick tests to wheat occurred significantly less frequently in the early-introduction group than in the standard-introduction group at 12 months (1.3% vs. 3.2%, P=0.03) and at 36 months of age (1.4% vs. 3.2%, P=0.04). The prevalence of positive skin-prick tests at 12 months and 36 months of age was nonsignificantly lower in the early-introduction group than in the standard-introduction group for every other food, with the exception of fish at 12 months of age, which had a higher prevalence in the early-introduction group (Figure 2, and Fig. S6 and Table S11 in the Supplementary Appendix).

In the per-protocol analyses, the early-introduction group had a significant 42% lower rate of positive skin-prick tests to any food than the standard-introduction group at 12 months of age (P=0.01) and a significant 67% lower rate at 36 months of age (P=0.002). On food-specific testing, the relative risk of a positive result on skin-prick testing at 12 months of age was consistently lower, by approximately 50%, in the early-introduction group than in the standard-introduction group for every food with the exception of fish; the difference was significant with respect to egg (P=0.009) and peanut (P=0.04). At 36 months of age, the effect was greater; the relative risk of a positive result on skin-prick testing was 67% lower in the early-introduction group than in the standard-introduction group with respect to peanut (P=0.007), 48% lower with respect to egg (P=0.10), 88% lower with respect to milk (P=0.02), 100% lower with respect to both sesame (P=0.04) and fish (P=0.17), and 69% lower with respect to wheat (P=0.12). The rate of a positive skin-prick test to raw egg white was also lower in the early-introduction group than in the standard-introduction group at 36 months of age; the 49% lower relative risk (P=0.07) was similar to that observed with commercial egg extract (Figure 2, and Table S11 in the Supplementary Appendix).

Adherence to the Protocol

A total of 92.9% of the participants in the standard-introduction group whose primary-outcome status could be determined (524 of 564 participants) adhered to the protocol (Fig. S1 in the Supplementary Appendix). In the dominance analysis, shorter duration of maternal education and maternal smoking accounted for the majority of the variation in the fit statistic of the overall model (Tables S12 and S13 in the Supplementary Appendix). A total of 85.6% of the participants in the standard-introduction group consumed no cow’s milk formula before 6 months of age.

A total of 42.8% of the participants in the early-introduction group whose primary-outcome status could be determined (208 of 486 participants) adhered to the protocol (representing 31.9% of the total number of participants enrolled in the early-introduction group) (Fig. S1 in the Supplementary Appendix). Four factors accounted for 78% of the nonadherence in the dominance analysis: nonwhite race (odds ratio, 2.21; 95% CI, 1.18 to 4.14), parentally perceived symptoms in the child related to any of the early-introduction foods (odds ratio, 1.70; 95% CI, 1.02 to 2.86), reduced maternal quality of life (psychological domain) (odds ratio, 0.69; 95% CI, 0.47 to 1.00), and the presence of eczema in the child at enrollment (odds ratio, 1.38; 95% CI, 0.87 to 2.19) (Tables S12 and S14 in the Supplementary Appendix).

The rate of adherence to the protocol with respect to individual foods in the early-introduction group varied. The rates were as follows: 43.1% for egg (215 of 499 participants), 50.7% for sesame (266 of 505), 60.0% for fish (297 of 495), 61.9% for peanut (310 of 501), and 85.2% for milk (415 of 487).

The levels of peanut protein in bed dust were similar at baseline in the early-introduction group and the standard-introduction group (median, 7.6 μg of peanut protein per gram of dust and 9.7 μg per gram, respectively). However, by 1 year of age, the levels were significantly higher in the early-introduction group than in the standard-introduction group (387.9 μg of peanut protein per gram of dust vs. 77.0 μg per gram, P<0.001). At 1 year of age, participants in the early-introduction group who adhered to the protocol had higher levels of peanut protein in bed dust than did those in the same trial group who did not adhere to the protocol (P=0.04) (Fig. S7 in the Supplementary Appendix). Further details on adherence to the protocol are provided in the Results section in the Supplementary Appendix.

Dose–Response Analysis

Variations in the number of foods consumed, the weekly dose of each food consumed, and the number of weeks during which this dose was consumed resulted in a rate of adherence in the early-introduction group that ranged from 6% to 81%. The prevalence of food allergy overall and the prevalence of allergy to specific foods were reduced in concert with increases in any of these variables. At a consumption level of 2 g or more per week of allergenic protein for 4 or more weeks, peanut was consumed by 85.3% of the participants in the early-introduction group for whom adherence with peanut consumption could be determined (419 of 491 participants) and egg by 75.5% (370 of 490). The corresponding rates of allergy were 0.2% for peanut and 1.9% for egg. Details are provided in Tables S15A, S15B, and S16 in the Supplementary Appendix.

Figure 3. Figure 3. Dose–Response Analysis of the Relationship between Mean Weekly Dose of Peanut or Egg Protein Consumed and Allergy or Positive Result on Skin-Prick Testing to Peanut, Egg, and Raw Egg White. Shown are the predictive probability plots that were generated from statistical models of the prevalence of peanut allergy and egg allergy (Panel A) and of a positive result on skin-prick testing to peanut and egg at 12 months (Panel B) and to peanut, egg, and raw egg white at 36 months (Panel C), according to the mean weekly consumption of peanut and egg protein between enrollment and 6 months of age. The prevalence of both food allergy and positive skin-prick test diminishes with increasing levels of mean weekly consumption. Insets show the same data on an enlarged y axis. Plots of the raw data and the probability plots are shown in Figure S8 in the Supplementary Appendix.

The mean weekly consumption of egg and peanut protein between enrollment and 6 months of age was calculated and divided into quartiles. The prevalence of allergy to peanut and egg and the prevalence of positive responses on skin-prick testing to peanut, egg, and raw egg white diminished with increasing quartile levels of consumption (Fig. S8 in the Supplementary Appendix). The mean weekly consumption data were used to generate predictive probability plots that were based on logistic modeling; analysis showed that higher consumption was associated with a lower prevalence of allergy and sensitization to that food (Figure 3). The mean weekly consumption of 2 g of peanut protein and 4 g of egg protein (equivalent to 2 g of egg-white protein) was associated with the prevention of these two respective food allergies. The consumption of cooked egg was equally effective in inhibiting reactivity to raw egg-white protein and egg extract on skin-prick testing at 3 years of age.

Safety

No deaths occurred in the trial. There were three life-threatening events, all of which occurred in the standard-introduction group; none were related to allergic disease (heart-valve damage, prolonged febrile convulsion, and extensive burns). There were no significant between-group differences in the rates of hospitalization. There were no cases of anaphylaxis with the introduction of foods at home in the early-introduction group. The use of the epinephrine autoinjector is discussed in the Results section in the Supplementary Appendix.

The rate of visits to the emergency department was similar in the two groups. The early-introduction regimen did not affect the growth of the participants or the duration of breast-feeding.8 Details on safety outcomes are provided in Tables S17 through S28 and Figures S9 through S19 in the Supplementary Appendix.

Results According to Skin-Prick Testing and Allergy Status at Baseline

At enrollment, 33 of the 652 participants in the early-introduction group (5.1%) had a positive skin-prick test to an early-introduction food. All 33 participants were invited to undergo food challenges to the relevant foods: 7 participants had positive results (to one or more foods), 22 had negative results (to one or more foods), and 4 did not return for the challenges. Of the 7 participants who had a positive result on a challenge at baseline, 5 subsequently had a positive result with respect to the primary outcome, 1 had a negative result, and 1 withdrew from the trial. Of the 22 participants who had negative results on the challenge at baseline, 1 subsequently had a positive result with respect to the primary outcome, 3 could not be evaluated, and 18 had a negative result. Details are provided in Table S29A in the Supplementary Appendix.

All the reactions in the seven participants who had positive results on challenges at baseline were mild (Table S30 in the Supplementary Appendix). There were 10 positive challenges among these seven participants; 6 reactions required no treatment, and 4 were treated with antihistamines. There were no cases of anaphylaxis during the challenges, and no intramuscular epinephrine was administered.