Maternal and Infant Dietary Patterns Are Not Related to Food Allergy Risk in Singapore Children: GUSTO Cohort Study

Abstract

Background

We previously reported that delayed allergenic food introduction in infancy did not increase food allergy risk until age 4 y within our prospective cohort. However, it remains unclear whether other aspects of maternal or infant diet play roles in the development of childhood food allergy.

Objectives

We examined the relationship between maternal pregnancy and infant dietary patterns and the development of food allergies until age 8 y.

Methods

Among 1152 Singapore Growing Up in Singapore Towards healthy Outcomes study mother–infant dyads, the infant’s diet was ascertained using food frequency questionnaires at 18 mo. Maternal dietary patterns during pregnancy were derived from 24-h diet recalls. Food allergy was determined through interviewer-administered questionnaires at regular time points from infancy to age 8 y and defined as a positive history of allergic reactions, alongside skin prick tests at 18 mo, 3, 5, and 8 y.

Results

Food allergy prevalence was 2.5% (22/883) at 12 mo and generally decreased over time by 8 y (1.9%; 14/736). Higher maternal dietary quality was associated with increased risk of food allergy (P ≤ 0.016); however, odds ratios were modest. Offspring food allergy risk ≤8 y showed no associations with measures of infant diet including timing of solids/food introduction (adjusted odds ratio [aOR]: 0.90; 95% confidence interval [CI]: 0.42, 1.92), infant’s diet quality (aOR: 0.93; 95% CI: 0.88, 0.99) or diet diversity (aOR: 0.84; 95% CI: 0.6, 1.19). Most infants (89%) were first introduced to cow milk protein within the first month of life, while egg and peanut introduction were delayed (58.3% introduced by mean age 8.8 mo and 59.8% by mean age 18.1 mo, respectively).

Conclusions

Apart from maternal diet quality showing a modest association, infant’s allergenic food introduction, diet quality, and dietary diversity were not associated with food allergy development in this Asian pediatric population. Interventional studies are needed to evaluate the efficacy of these approaches to food allergy prevention across different populations.

Introduction

Various infant and maternal dietary intervention strategies have been explored as a means of food allergy prevention. Recent evidence suggests that in areas with high peanut allergy prevalence, early peanut introduction may reduce the burden of peanut allergy in high-risk patients with pre-existing severe eczema or food allergy [1,2]. The timing of allergenic food introduction has been shown to reduce the risk of peanut and egg allergies [3,4]. However, as indicated by a recent meta-analysis of randomized controlled trials (RCTs), rates of noncompliance to such interventions are relatively high [5]. Although several of the included studies were carried out in Japan, the meta-analysis did not make comparisons between timing of introduction in different populations, and there is currently no data from other Asian populations, with only 1 ongoing RCT in China (ChiCTR2100053552) and 2 in Japan (UMIN000030214 and jRCTs041190089). Some studies have shown that maternal avoidance of allergenic foods during pregnancy does not prevent and may in fact increase the risk of food allergy in the offspring [6,7]. Recent studies also suggest that mothers’ consumption of peanuts or milk during pregnancy and lactation might reduce specific food sensitization or allergy in their offspring [8].

Alongside this key factor, overall nutrition and diet of mothers and infants have also been shown to potentially play a role. Systematic reviews by de Silva et al. [9] and Garcia-Larsen et al. [10] reported no major effect of maternal avoidance of allergenic food during pregnancy or breastfeeding on food allergy in children [9,10]. Meta-analyses of vitamin supplementation, including vitamin D, showed no association with any allergic outcomes [10]. de Silva et al. [9] also consolidated various interventions to prevent food allergy in children. They found that prebiotics, vitamin supplementations, and breastfeeding had little to no effect on food allergy in early childhood. However, there is some evidence of fish oil supplementation during pregnancy and continuing during breastfeeding having a slightly protective effect on child’s food allergy risk.

Additionally, research assessing holistic markers of diet such as diet diversity, diet variety, and diet indices in both mothers and infants are gaining traction [11]. Their role in food allergy prevention is postulated given that nutrients and food are often not taken in isolation. It has been posited that a diverse diet increases the intake of essential nutrients, modulating the gut microbiome positively and thereby allergic outcomes as well [12]. However, insufficient studies on maternal diet are available to conclusively determine their role in food allergy prevention [13].

As studies from various parts of the world have demonstrated variability in the patterns of prevalence and allergen triggers for food allergy and anaphylaxis across different populations [14], risk factors and the effectiveness of prevention strategies for food allergy may differ between populations. We previously found that delayed allergenic food introduction in infancy was not associated with an increased risk of food allergy development (particularly peanut allergy) up to age 4 y in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort [15]. However, as peanut and egg introduction were delayed, there remains the question of whether food allergy onset may manifest much later in this cohort. This study aimed to analyze associations between maternal and infant diet quality, diet diversity, and allergenic food exposure and food allergy development up to age 8 y.

Methods

Study population

The GUSTO study is a longitudinal birth cohort study in Singapore. Pregnant women aged 18 to 50 y (n = 1247), with spouses of homogenous ethnicity from the main ethnic groups in Singapore—Chinese, Malay, or Indian—were recruited from 2 major public maternity hospitals in Singapore, namely KK Women’s and Children’s Hospital and National University Hospital, Singapore, between June 2009 and September 2010. Mother–infant dyads were followed up antenatally and throughout childhood at multiple time points. The detailed methodology of the GUSTO study has been described previously [16].

The study received ethics approval from the Domain Specific Review Board of Singapore National Healthcare Group (D/2009/021; 26/02/2009) and the Centralised Institutional Review Board of SingHealth (2018/2767; 02/03/2009). Written informed consent was collected from all mothers.

Maternal data collection and identification

A total of 1152 women with singleton, naturally conceived pregnancies were included in this study. Parental sociodemographic characteristics such as age, ethnicity, educational level, smoking status, and family history of atopy were collected upon recruitment (<14 wk gestation) via questionnaires. Several maternal dietary measures were collected during pregnancy. These included maternal plasma vitamin D concentrations measured at 26 to 28 wk gestation and maternal consumption of allergenic food, namely peanut, egg, milk and shellfish.

Maternal dietary patterns

Maternal consumption of allergenic food was captured using 3-d food diaries administered during mid-late trimester. Maternal dietary patterns during pregnancy were derived from interviewer-administered 24-h recall diets using exploratory factor analysis resulting in 3 dietary patterns, namely vegetable–fruit–rice pattern; seafood–noodle pattern; and pasta–cheese– meat pattern. Trained clinical staff conducted the 24-h recalls using a 5-stage, multiple-pass interviewing technique. To ensure better accuracy of data collection, visual aids such as food photos and portion sizes were incorporated during the interviews [17]. Detailed methods on the dietary patterns derivation [18] have been described previously.

Maternal Healthy Eating Index

Additionally, to evaluate diet quality, a maternal Healthy Eating Index for Pregnant Women in Singapore (HEI-SGP) was calculated using dietary intake collected using 24-h recalls and validated using 3-d food diaries. A detailed description of the HEI-SGP and its scoring has been described previously [19]. The HEI-SGP was developed to assess diet quality of pregnant women in the GUSTO cohort. It is an adaptation of the Healthy Eating Index (HEI) and Alternate HEI for Pregnancy (AHEI-P), modified to be aligned with recommendations from the Singapore dietary guidelines for pregnant women. A detailed comparison of included components in the HEI-SGP compared to the HEI and AHEI-P can be found in Han et al. [19]. The HEI-SGP is made up of 11 components (total fruit, whole fruit, total vegetables, dark green leafy and orange vegetables, total rice and alternatives, whole grains, dairy, total protein foods, antenatal supplements, total fat, saturated fat) reflecting dietary adequacy, quality of food groups, nutrients intake, and adherence to antenatal supplementation. With a total possible score of 90, the raw HEI-SGP was then converted to a scale of 0 to 100. The nutrient analyses for 24-h recalls were conducted using a nutrient software (Dietplan, Forestfield Software). The software comprises a database of locally available foods. For foods not available in the database, nutrient information was obtained from food labels or the USDA national nutrient database. The individual food components in each 24-h recall were assigned to 1 of 68 food groups, which were grouped according to nutrient composition.

Infant data collection and identification

Information on birth and delivery, child health, pet ownership, feeding practices such as breastfeeding, timing of introduction of solids and formula, allergenic food, and infant supplementation in first year of life as well as allergic outcomes were collected from interviewer-administered questionnaires at multiple time points from birth up to age 8 y. Breastfeeding pattern was characterized from type of infant feeding from 3 wk to 12 mo of age.

Data on breastfeeding patterns and infant formula feeding were captured from interviewer-administered questionnaires from 3 wk to 12 mo postnatally [20]. Full breastfeeding was defined as a combination of exclusive and predominantly breastfeeding, the latter comprising breastmilk alongside other liquids such as water or water-based drinks [21]. Any breastfeeding was defined as any reported breastfeeding alongside liquid (including infant formula) and solid foods. WHO guidelines promote exclusive breastfeeding for the first 6 mo of life and complementary solid food introduction at ∼6 mo [22]. Using this guidance, breastfeeding status was categorized as full breastfeeding >6 mo, any breastfeeding <6 mo, and any breastfeeding >1 y.

Data on the infant’s age of weaning to solids was obtained at 9 and 12 mo postpartum. Timing of introduction of solids was categorized into <4 mo, 4 to <6 mo, and ≥6 mo. Timing of introduction of specific allergenic foods (milk, egg, peanut, prawn) was grouped into ≤9 mo or >9 mo, suggesting appropriate and delayed introduction, respectively.

Food allergy and eczema

Skin prick tests (SPTs) to food allergens (egg, peanut, cow milk, and shellfish) and house dust mite allergens (Dermatophagoides pterynossinus, Dermatophagoides farinae, and Blomia tropicalis) were offered to all children at age 18 mo and 3, 5, and 8 y, while food allergy data was obtained via questionnaires at ages 12, 15, and 18 mo and thereafter yearly from 2 y up to 8 y. Food allergy was defined by a convincing history of an IgE-mediated reaction (hives, angioedema, vomiting, diarrhea, etc.) within 4 h of ingestion of the specific allergenic food (namely, the major allergens milk, egg, peanut, tree nuts, fish, wheat, soy, and crustaceans). For time points at which SPT was carried out, the definition of food allergy also included a positive SPT with an average wheal size of 3 mm or larger. Prevalence of any food allergies and specific food allergies (cow milk, egg, peanut, and seafood) were categorized cumulatively by 18 mo and 3, 5, and 8 y. For each of these cumulative time points, ≥60% of the time points would need to have complete food allergy data in order to be classified as a control or food-allergic. Participants were otherwise classified as having a missing food allergy status (by 18 mo, both time points with complete data required; by 3 y, 3 of 4 time points completed; by 5 y, 4 of 6 time points completed; by 8 y, 6 of 9 time points completed).

Early-onset eczema was defined as parent-reported doctor’s diagnosis of eczema at any time in the first 6 mo of life.

Infant supplementation

Data on supplementation feeding practices were collected via interviewer-administered questionnaires at the 6-, 9- and 12-mo postnatal visits. Dietary supplements were categorized into probiotics (probiotic drops/powder or probiotic-enriched foods) and vitamins and mineral supplements (multivitamins, such as iron or calcium, fish oil, and individual vitamins [A, B-12, C, and D]) [23].

Infant Diet Quality Index (DQI) and diet diversity score

A DQI was previously developed by the GUSTO cohort [24] to assess the overall diet quality in Asian toddlers. Development of the DQI is primarily based on Singapore’s dietary guidelines for children from 1 to 2 y of age, while also taking into consideration guidelines from other Asian and Western countries. The detailed methodology pertaining to the derivation of the DQI has been previously explained [24]. In summary, the DQI comprises 7 components: total rice, bread, and alternatives; total fruit; total vegetables; total meat and alternatives; total milk and dairy products; whole grains; and foods high in sugar. Participants were scored for each component, and a raw DQI score was eventually derived by adding the individual scores. The score was then adjusted by standardizing to an energy intake of 845 kcal/d, based on average daily energy requirements for 1-y olds in Singapore [25]. A higher DQI score correlates with better diet quality, which is associated with higher consumption of several nutrients and food groups, but no standard cutoffs exist in literature (theoretical range: 0–65).

On the other hand, the diet diversity score was defined as per the Infant and Young Children Feeding Practices [22], which is the total count of different food groups consumed by the infant at 18 mo over an average of 28 d 24-h period (irrespective of amount consumed). Maximum score possible is 8 based on the following food groups: breastmilk; grains, roots and tubers; legumes, nuts and seeds; dairy products (milk, yogurt, cheese); flesh foods (meat, fish, poultry, liver or other organs); eggs; vitamin A-rich fruits and vegetables; and other fruits and vegetables.

Statistical analyses

All data were analyzed with SPSS Version 26 (IBM Corp) and/or STATA I/C 16. Results with P values <0.05 were considered statistically significant. The prevalence of food allergy by 8 y was estimated as the observed proportion with 95% confidence intervals (CIs) generated using the normal approximation to the binomial distribution. We adjusted for differences in demographics and other potential risk factors between participants included in the analyses and those who were excluded due to missing food allergy status as a result of loss to follow-up/uncertain food allergy status. Reweighting was performed using the inverse probability weighting method described by Little and Rubin [26].

Chi-squared and Fisher’s exact tests were used to assess the significance between food allergy by 8 y and sociodemographic characteristics, infant characteristics, maternal and infant dietary patterns, and feeding practices.

Associations between maternal and infant exposures and food allergy were analyzed using both univariate and adjusted logistic regressions. To assess potential confounding factors, directed acyclic graphs (DAGs) were developed using a browser-based interface environment, DAGitty (version 3.0) [27] based on confounders chosen a priori [28,29]. Logistic regression models were then adjusted for a minimum set of confounders reflected by the curated DAGs (see Supplemental Figures 1–5). Potential confounders considered in the DAGs were collected from an interviewer-administered questionnaire at every time point; these comprised maternal highest education (primary and secondary/pre-tertiary/tertiary), maternal ethnicity (Chinese/Malay/Indian/Mixed), siblings (binary), breastfeeding, mode of birth (vaginal/cesarean), childcare attendance in first year of life (binary), maternal history of atopy which included asthma, rhinitis, eczema (binary), infant’s early-onset eczema (binary), pet ownership in first year of life (binary), sex (male/female), maternal smoking during pregnancy (nonsmoker/ex-smoker/current smoker), household smoking exposure (binary), maternal BMI during pregnancy (continuous), and maternal age at delivery (continuous).

Results

Characteristics of study participants

Of the 1152 singleton, naturally conceived infants in the cohort, food allergy outcome data was available for 822 (18 mo), 826 (3 y), 794 (5 y), and 728 (8 y) children, who were included in the final analysis. The cumulative prevalence of any food allergy by age 8 y was 8.1% (95% CI: 6.3, 10.3%); namely, milk 0.4% (3/700); egg 4.2% (30/710); shellfish 3.5% (25/716); and peanut 1.1% (8/704). An initial peak food allergy prevalence of 2.5% (22/883) was observed at age 12 mo, and this generally decreased over time, with a prevalence of 1.9% (14/736) at 8 y. Another peak in prevalence of 2.9% (23/790) was recorded at 4 y, primarily due to shellfish and peanut allergies.

Comparison between participants who were included in analysis and those with missing data showed significant differences in maternal education, ethnicity, and breastfeeding duration of <6 mo (Supplemental Table 1). A sensitivity analysis that included sampling weights to adjust for these differences found no change in cumulative food allergy prevalence: 8.2% (95% CI: 6.4, 10.5%).

The demographic factors of the study population at 8 y are shown in Table 1 [30]. Notably, children with food allergies tended to have early-onset eczema (before 6 mo of age) and a maternal history of atopy. Early-onset eczema and maternal history of atopy were also associated with an increased risk of food allergy in the univariate analyses (Supplemental Table 2). Of those with eczema by 6 mo (8.5%, n = 61/716), 29.5% developed food allergy by 8 y.

TABLE 1.

Demographic variables of children included in analyses stratified by food allergy status by 8 y (N = 728)¹

	Nonfood allergic by 8 y (%) n = 669	Food allergic by 8 y (%) n = 59 (8.1% of total population N = 728)	P2
Maternal demographics
Ethnicity
Chinese	378 (56.5)	37 (62.7)
Malay	177 (26.5)	17 (28.8)
Indian	113 (16.9)	5 (8.5)
Others	1 (0.2)	0 (0.0)	0.30
Maternal highest education
Primary and secondary	195 (29.4)	18 (30.5)
Pre-tertiary	241 (36.3)	15 (25.4)
Tertiary	228 (34.3)	26 (44.1)	0.19
Maternal history of atopy (eczema, rhinitis, wheeze)	185 (28.5)	28 (50.0)	0.001
Smoking exposure at pregnancy 26 wk
Nonsmoker	572 (86.5)	53 (91.4)
Ex-smoker	72 (10.9)	5 (8.6)
Current smoker	17 (2.6)	0 (0.0)	0.53
Children’s demographics
Male	336 (50.2)	36 (61)	0.11
Having siblings	352 (56.0)	28 (48.3)	0.26
Mode of delivery
Vaginal	471 (70.4)	42 (71.2)
Cesarean	198 (29.6)	17 (28.8)	0.90
Childcare attendance	49 (8.8)	6 (13.6)	0.29
Early-onset eczema (<6 mo)	43 (6.5)	18 (31.6)	<0.001
Pet ownership in first year of life	56 (13.9)	5 (14.7)	0.90
Smoking exposure in first year of life	215 (47.4)	13 (37.1)	0.24
Children’s dietary variables
Solid food introduction <4 mo	15 (2.7)	2 (4.1)	0.64
Solid food introduction 4–5 mo	193 (34.3)	17 (34.7)	0.95
Solid food introduction ≥6 mo	355 (63.1)	30 (61.2)	0.80
Full breastfeeding >6 mo3	49 (7.6)	4 (7.3)	1.00
Any breastfeeding <6 mo	386 (59.8)	33 (61.1)	0.86
Any breastfeeding >1 y	138 (21.4)	14 (25.9)	0.44
Dietary supplements—vitamins and minerals consumption ≤3 mo4	30 (8.4)	2 (6.7)	1.00
Dietary supplements—vitamins and minerals consumptions from 6–12 mo4	110 (19.5)	13 (26.5)	0.24
Probiotics consumption ≤3 mo	13 (2.1)	2 (3.9)	0.34
Probiotics consumption from 6–12 mo	22 (3.9)	6 (12.2)	0.007
DQI score at 18 mo5, median (IQR)	44.39 (11.58)	41.6 (11.84)
Diet diversity score at 18 mo (binary)6
≥5 items7	194 (50)	15 (45.5)	0.63

Abbreviations: DQI, Diet Quality Index; IQR, interquartile range; IYCF, Infant and Young Children Feeding Practices.

Percentage in parentheses are column percentages with the number of cases (n = 59) or controls (n = 669) respectively being the denominator.

¹424 participants were classified as missing because they had missing food allergy status for ≥1 of the time points in the first 8 y of life.

²P values were obtained from chi-square test except in cells with sample sizes <5, in which P values from Fisher’s exact test are quoted.

³Full breastfeeding: exclusive and predominant breastfeeding without solids introduction but may be alongside other liquids such as water or water-based drinks.

⁴Vitamins and minerals included the consumption of multivitamins, vitamins A, B-12, C, and D, fish oils, and other minerals from 6–12 mo.

⁵Diet Quality Index (DQI) reflects overall diet quality in Asian children based on scoring of 7 components. Total score was then adjusted by standardizing to energy intake of 845 kcal/d. A higher DQI score correlates with better diet quality.

⁶Diet diversity score defined as per IYCF [45], based on the total count of different food groups consumed by the infant at 18 mo over “an average of 28 days.” Possible maximum score of 8.

⁷WHO IYCF recommended minimum dietary diversity score ≥5 [45].

Maternal diet during pregnancy

The majority of mothers consumed egg and milk (75.8% and 91.1%, respectively) during pregnancy, but fewer than half consumed peanut (27.7%) and shellfish/crustaceans (41.4%). Of the 405 mothers who avoided ≥1 allergenic food during pregnancy, only 37 (9.1%) had offspring with food allergy. Of the mothers, 33/628 consumed all 4 allergenic foods, and of these, 4/33 (12.1%) had children with food allergy.

Although the mothers of the 3 children with peanut allergy had not consumed peanuts during pregnancy, the majority of peanut-avoiding mothers (99%) nevertheless had healthy children. Similarly, only 3.2% of egg-avoiding mothers had egg-allergic children, compared to 5.4% in infants of egg-consuming mothers. However, none of these reached statistical significance, likely due to very small numbers (Supplemental Table 3).

Maternal dietary patterns and vitamin D status also did not impact infant’s food allergy risk (Supplemental Table 4). Although a statistically significant association (P ≤ 0.016) was reported between higher maternal dietary quality (HEI-SGP score) and higher risk of infant food allergy at every cumulative time point, the odds ratios were small and clinical significance is uncertain (Supplemental Table 4). Results were similar when models were adjusted for maternal food allergy status. Mean HEI-SGP scores also did not differ significantly by maternal food allergy status (54.1 and 52.6 in mothers with, and without, food allergy respectively).

Breastfeeding and vitamin and probiotics supplementation in the first year of life

More than half of the infants were breastfed for <6 mo, and this proportion was similar in both allergic (61.1%) and nonfood-allergic (59.8%) infants (Table 1). Generally, no associations were observed between breastfeeding duration and food allergy until 8 y of age in both univariate (Supplemental Table 2) and adjusted analyses (Table 2). Although statistically significant in the univariate model, probiotics consumption between 6 and 12 mo of life was no longer associated with food allergy status after adjusting for confounders (Table 2).

TABLE 2.

Adjusted analyses of the association between infant risk factors and food allergy at various time points (by 18 mo and 3, 5, and 8 y)

	Any food allergy
	By 18 mo		By 3 y		By 5 y		By 8 y
	aOR (95% CI)	P	aOR (95% CI)	P	aOR (95% CI)	P	aOR (95% CI)	P
Any breastfeeding <6 mo1	0.62 (026, 1.52)	0.301	1.01 (0.46, 2.21)	0.988	1.01 (0.51, 2.37)	0.809	1.00 (0.49, 2.05)	0.995
Any breastfeeding >1 y1	2.15 (0.89, 5.22)	0.09	1.55 (0.70, 3.48)	0.283	1.52 (0.69, 3.36)	0.299	1.39 (0.65, 2.96)	0.394
Full breastfeeding >6 mo1	1.65 (0.50, 5.47)	0.412	1.17 (0.37, 3.70)	0.793	1.17 (0.37, 3.69)	0.790	1.06 (0.34, 3.31)	0.913
Weaning <4 mo2	—	—	—	—	—	—	1.34 (0.16, 11.38)	0.787
Weaning 4–5 mo2	1.05 (0.39, 2.82)	0.917	1.13 (0.47, 2.69)	0.790	0.94 (0.40, 2.22)	0.895	1.08 (0.50, 2.31)	0.848
Weaning ≥6 mo2	1.04 (0.39, 2.80)	0.934	1.02 (0.43, 2.44)	0.963	1.22 (0.52, 2.86)	0.650	0.90 (0.42, 1.92)	0.782
Vitamins and mineralsconsumption ≤3 mo3,4	—	—	—	—	—	—	—	—
Vitamins and mineralsconsumption 6–12 mo3,4	0.82 (0.23, 2.85)	0.750	0.89 (0.30, 2.65)	0.839	1.09 (0.40, 3.00)	0.865	0.76 (0.29, 2.02)	0.589
Total probioticsconsumption ≤3 mo3,4	1.71 (0.18, 16.10)	0.640	1.26 (0.14, 11.08)	0.838	2.88 (0.55, 15.01)	0.211	2.33 (0.46, 11.88)	0.309
Total probioticsconsumption 6–12 mM3,4	3.14 (0.68, 14.46)	0.142	3.11 (0.83, 11.66)	0.093	2.61 (0.72, 9.46)	0.145	2.32 (0.65, 8.26)	0.192
DQI score at 18 mo5	0.91 (0.84, 0.98)	0.013	0.94 (0.88, 1.00)	0.066	0.94 (0.88, 1.00)	0.058	0.93 (0.88, 0.99)	0.016
Diet diversity score at 18 mo5	0.83 (0.54, 1.28)	0.394	0.94 (0.64, 1.37)	0.751	0.90 (0.62, 1.31)	0.587	0.84 (0.6, 1.19)	0.333
	Specific foodallergy6
By 18 mo7		By 3 y8		By 5 y9		By 8 y10
Milk introduction2
≤9 mo	—	—	—	—	—	—	—	—
>9 mo	REF
Egg introduction2
≤9 mo	0.53 (0.15, 1.94)	0.338	0.78 (0.26, 2.30)	0.648	0.70 (0.24, 2.10)	0.526	0.83 (0.28, 2.42)	0.734
>9 mo	REF
Peanut introduction2
≤9 mo	—	—	—	—	—	—	—	—
>9 mo	REF
Prawn introduction2
≤9 mo	17.98 (0.64, 501.61)	0.089	2.05 (0.21, 20.02)	0.538	1.15 (0.13, 9.98)	0.900	1.63 (0.33, 8.03)	0.548
>9 mo	REF

Abbreviations: aOR, adjusted odds ratios; CI, confidence interval; DQI, diet quality index; REF, reference.

Confounders were included based on directed acyclic graphs provided in the Supplementary Material. Cells with no data had small sample sizes after adjusting for confounders.

¹Adjusted for childcare attendance in first year of life, maternal education, mode of delivery, maternal ethnicity, siblings, and maternal history of atopy.

²Adjusted for childcare attendance in first year of life, maternal history of atopy, infant’s early-onset eczema, maternal education, maternal ethnicity, presence of siblings, breastfeeding duration, and mode of delivery.

³Adjusted for childcare attendance in first year of life, infant’s early-onset eczema, maternal education, maternal ethnicity, breastfeeding duration, maternal history of atopy, and mode of delivery.

⁴Vitamins and minerals supplementation included multivitamins, vitamins A, B-12, C, and D, fish oils, and other minerals.

⁵Adjusted for childcare attendance in first year of life, child’s sex, maternal education, maternal ethnicity, siblings, breastfeeding duration, mode of delivery, and maternal history of atopy.

⁶As respective outcomes at each time point, milk introduction was analyzed with milk allergy, egg introduction with egg allergy, peanut introduction with peanut allergy, and prawn introduction with shellfish allergy.

⁷By 18 mo: milk (n = 14); egg (n = 513); peanut (n = 3); prawn (n = 78).

⁸By 3 y: milk (n = 13); egg (n = 505); peanut (n = 45); prawn (n = 421).

⁹By 5 y: milk (n = 12); egg (n = 483); peanut (n = 46); prawn (n = 405).

¹⁰By 8 y: milk (n = 12); egg (n = 448); peanut (n = 42); prawn (n = 476).

Timing of introduction of solids and allergenic food

Figure 1 depicts patterns in the timing of introduction of allergenic foods into the infants’ diet. The weaning age (age at first solid introduction) ranged from 0.75 to 9 mo (mean age of introduction 5.7 ± 1.1 mo) (Figure 1A). The majority of infants were introduced to cow milk protein within the first month of life (median 0 mo, IQR 0.25 mo, range 0–16 mo) (Figure 1B). However, the introduction of other allergenic foods such as eggs (mean age 8.8 ± 3.7 mo) and particularly peanut (18.1 ± 7.0 mo) was delayed. The mean age of prawn introduction could not be calculated because the data for age at prawn introduction was only collected up to age 1 y. However, data from the first 12 mo of life showed that only 8.9% of infants had been introduced to prawn by this age.

FIGURE 1.

Timing of introduction of (A) solids, (B) egg, peanut, cow milk protein, and prawn over 3 y. Among the 4 main allergens, cow milk protein was introduced into the infant’s diet the earliest (beginning from birth), while peanut and egg introduction into the infant’s diet occurred later in life, at around 18 mo and 8 mo, respectively. Although data on egg, peanut and cow milk protein was collected ≤3 y follow-up, data on timing of prawn introduction was only collected ≤1 y. // indicates the time point when data collection for timing of prawn introduction stopped. Those who had yet to introduce prawn by 12 mo were classified as 0 mo to not exclude these participants from the total sample size in the graph.

The timing of introduction of specific cow milk products such as milk formula and dairy products and milk allergy outcomes was assessed further. The majority of infants were introduced to cow milk protein in the form of infant formula within the first month of life (86.7%; n = 880/1015) with only 2.6% introduced to cow milk protein (infant formula) beyond 9 mo (n = 26/1015). By 9 mo of age, 99.4% of infants had already been introduced to cow milk protein (n = 1015/1021) in various forms such as dairy, formula, cheese, or yogurt.

We next assessed patterns of cow milk protein consumption over the first year of life, in particular, whether this was continued or ceased after initial introduction in early life, because cessation of cow milk protein consumption after an initial exposure has been reported to increase the risk of milk allergy development [30]. Similar proportions of infants were introduced to cow milk formula early in life (≤1 mo) followed by continuation, as opposed to cessation of cow milk formula consumption until dairy-containing solid foods were introduced during weaning (217/898 [24.2%] compared with 232/844 [27.5%], respectively). Only 15.3% (137/898) of infants were not introduced to cow milk protein (exclusively breastfed) until the time of dairy solid food introduction.

No associations were observed between food allergy and timing of introduction of any of the allergenic foods in both univariate (Supplemental Table 5) and adjusted analyses (Table 2). There were also no differences when stratified by eczema status (data not shown).

DQI and diet diversity score at 18 mo of age

The energy-adjusted DQI and diet diversity score were available for 514 children. The DQI scores did not differ significantly at each individual time point or by food allergy status: median DQI score was 44.4 (IQR: 11.5) in nonfood-allergic subjects compared with 41.6 (IQR: 11.8) in food-allergic subjects (Table 1). ≥45% had a diet diversity score of 5 regardless of food allergy status (Table 1). Higher DQI scores were associated with a reduced risk of food allergy by 18 mo and by 8 y, although odds ratios crossed the null (Table 2). No associations were observed between diet diversity score and food allergy at any time point (Table 2).

Discussion

In a high-income tropical Asian country, we examined potential exposures proposed to affect food allergy risk in children up to age 8 y. As a follow-up to our previous work [15], we analyzed the impact of maternal and infant diet quality, diversity, and allergenic food exposure on food allergy development up to age 8 y. Contrary to studies in mainly Western populations showing that timing of allergenic food introduction [1,3,31,32], dietary diversity [11,33], and maternal allergenic food consumption [34] impact food allergy risk in children, these factors showed no clinically important associations with food allergy development in this Asian child population.

Maternal diet

Our findings suggest that maternal dietary patterns do not significantly impact food allergy risk in populations in which food allergy prevalence is low. A systematic review by Venter et al. [35] similarly found no consistent evidence for the role of maternal dietary factors on offspring food allergy, although there were only a small number of studies on food allergy and there was high heterogeneity among the included studies. Additionally, the Nutrition Evidence Systematic Review in the United States [36] concluded that there is currently insufficient evidence to determine associations between dietary patterns during pregnancy and lactation on offspring food allergy risk. Nevertheless, some individual studies that showed positive associations reported so only among mothers with high levels of consumption of the relevant allergenic foods (highest quartile of milk consumption and peanut/tree nut consumption of ≥5 times/mo) [37,38]. As data on levels of allergenic food consumed in pregnancy were not collected in our study, we were not able to conduct subgroup analyses to examine the impact of this particular factor on infant food allergy risk, which is an area for future research. Although we observed that higher maternal diet quality was associated with a small increased risk of food allergy in their offspring, it is not certain if this is mediated through specific nutrients instead of overall dietary quality or if unmeasured confounders might be responsible. It is also currently unclear if the small effect sizes reported bear meaningful clinical implications, and further research is required to elucidate the specific pathways through which this might occur.

Infant diet

Results from RCTs such as Learning Early About Peanut Allergy [1], Enquiring About Tolerance [2], and Prevention of Egg Allergy in Tiny Amount Intake [3] collectively showed a reduction in risk of allergy with early introduction of allergenic food. Here, we found that peanut allergy rates remained very low even up to age 8 y, further strengthening the hypothesis that timing of allergenic food introduction plays a small role in food allergy inception in this low-risk population. Our results are further corroborated by recent findings from an Australian study that showed reduced risk of peanut allergy with early peanut introduction in infants of Australian ancestry but not among those of East Asian ancestry [39].

We found that although a quarter of infants were introduced to cow milk formula within the first month of life followed by a period of cessation (due to exclusive breastfeeding), this did not translate to an increased risk of cow milk allergy, with cow milk allergy prevalence remaining very low, ranging from just 0.1% to 0.44% across the cohort. This is despite recent studies suggesting an increased risk of cow milk allergy with irregular consumption or discontinuation of formula within the first year of life. An RCT performed in Japan illustrated the introduction of cow milk formula daily between 1 and 2 mo of life for prevention of cow milk allergy [40]. Further analyses indicated that early discontinuation of cow milk formula in the first month of life increased the risk of cow milk allergy at age 6 mo [41], suggesting that cow milk formula supplementation as a bridge to breastfeeding in the first few days of life should be avoided if possible and donor breastmilk may be a viable alternative, although no studies have been performed on the latter.

Previous studies reported that a higher diet diversity score in the first year of life was linked to a reduced risk of food sensitization ≤2 y [42], parental report of food allergy ≤6 y [43] and food allergy outcomes over the first 10 y of life [33]. Our study, however, did not find any associations with diet diversity score but reported similar associations between DQI and food allergy at 2 time points: by 18 mo and by 8 y. Effect sizes, though, were small and included the null. Differences in reported findings may be due to the lack of power in this study or a result of varied definitions used to curate diet diversity scores or indices.

Collectively, our findings are aligned with current guidelines by the European Academy of Allergy and Clinical Immunology task force, which makes no recommendation for early peanut introduction in countries with a low prevalence of peanut allergy [44]. The Asia Pacific Academy of Pediatric Allergy, Respirology & Immunology consensus statement on timing of allergenic food introduction suggested that in low-risk populations, allergenic foods are recommended to be introduced as per family preferences and cultural practices and there should be no delay in introduction [15]. In high-risk infants with moderate to severe eczema and/or pre-existing food allergy, early introduction of peanut and/or egg under allergist supervision may still be beneficial at an individual level. There remains little guidance on the ideal timing of cow milk protein introduction and continuation in a low-risk population.

Strengths and limitations

One limitation of this study was the lack of confirmatory food challenges for the diagnosis of food allergy. However, data was collected at close intervals (3–6 monthly), and reported symptomatology were also examined in detail to ensure they fulfilled a convincing history of an IgE-mediated reaction to a food trigger; the addition of corroborative SPTs further mitigated this bias. This study has also been designed to focus on IgE-mediated food allergy, and the findings are not applicable to non-IgE-mediated food allergy. Another limitation of this study was that infant DQI and diet diversity data was only obtained after the first year of life and not during weaning because solid food diversity is expected to be low in the first few months of weaning and earlier data collection would likely not be meaningful.

Nonetheless, one of the strengths of this study is its extensive longitudinal follow-up, which allows analyses for temporality and reverse causality to be performed. The standardized International Study of Asthma and Allergies in Childhood questionnaire used in the study for the evaluation of food allergy is a well-established instrument that has been internationally validated for the assessment of allergenic outcomes and associated risk factors.

In conclusion, approaches to allergy prevention strategies are complex and multilayered, lacking a universally recommended approach. Differences in infant and maternal dietary patterns such as delayed introduction of allergenic foods, dietary quality, or maternal allergenic food avoidance did not appear to confer any significant additional risks for food allergy in this population. To affirm our findings, there is a pressing need for comparative studies on the efficacy of allergy prevention strategies on food allergy risk across different populations. It may be plausible that dietary guidelines for infants be tailored according to food allergy risk factors and burden, and interventions should be customized at an individual patient level rather than across the whole population [15].

Acknowledgments

We acknowledge the contribution of the rest of the GUSTO study group, which includes Airu Chia, Allan Sheppard, Amutha Chinnadurai, Anna Magdalena Fogel, Anne Eng Neo Goh, Anne Hin Yee Chu, Anne Rifkin-Graboi, Anqi Qiu, Arijit Biswas, Birit Froukje Philipp Broekman , Bobby Kyungbeom Cheon, Boon Long Quah, Candida Vaz, Chai Kiat Chng, Cheryl Shufen Ngo, Choon Looi Bong, Christiani Jeyakumar Henry, Ciaran Gerard Forde, Claudia Chi, Daniel Yam Thiam Goh, Dawn Xin Ping Koh, Desiree Y. Phua, Doris Ngiuk Lan Loh, E Shyong Tai, Elaine Kwang Hsia Tham, Elaine Phaik Ling Quah, , Evelyn Chung Ning Law, Fabian Kok Peng Yap, Faidon Magkos, Falk Müller-Riemenschneider, George Seow Heong Yeo, Hannah Ee Juen Yong, Helen Yu Chen, Heng Hao Tan, Hong Pan, Hui Min Tan, Iliana Magiati, Inez Bik Yun Wong, Ives Yubin Lim, Ivy Yee-Man Lau, Izzuddin Bin Mohd Aris, Jeannie Tay, Jeevesh Kapur, Jenny L. Richmond, Jerry Kok Yen Chan, Jia Xu, Joanna Dawn Holbrook, Joanne Su-Yin Yoong, Joao Nuno Andrade Requicha Ferreira, Johan Gunnar Eriksson, Jonathan Tze Liang Choo, Jonathan Y. Bernard, Jonathan Yinhao Huang, Joshua J. Gooley, Jun Shi Lai, Karen Mei Ling Tan, Kenneth Yung Chiang Kwek, Keri McCrickerd, Kok Hian Tan, Kothandaraman Narasimhan, Krishnamoorthy Naiduvaje, Kuan Jin Lee, Leher Singh, Li Chen, Lieng Hsi Ling, Lin Lin Su, Ling-Wei Chen, Lourdes Mary Daniel, Marielle V. Fortier, Mark Hanson, Mary Rauff, Mei Chien Chua, Melvin Khee-Shing Leow, Michael J. Meaney, Michelle Zhi Ling Kee, Min Gong, Mya Thway Tint, Navin Michael, Neerja Karnani, Ngee Lek, Oon Hoe Teoh, P. C. Wong, Paulin Tay Straughan, Peter David Gluckman, Pratibha Keshav Agarwal, Priti Mishra, Queenie Ling Jun Li, Rob Martinus van Dam, Salome A. Rebello, Sambasivam Sendhil Velan, Seang Mei Saw, See Ling Loy, Seng Bin Ang, Shang Chee Chong, Sharon Ng, Shiao-Yng Chan, Shirong Cai, Shu-E Soh, Sok Bee Lim, Stella Tsotsi, Stephen Chin-Ying Hsu , Sue-Anne Ee Shiow Toh, Suresh Anand Sadananthan, Swee Chye Quek, Varsha Gupta, Victor Samuel Rajadurai, Walter Stunkel, Wayne Cutfield, Wee Meng Han, Wei Wei Pang, Wen Lun Yuan, Yanan Zhu, Yap Seng Chong, Yin Bun Cheung, Yiong Huak Chan, Yung Seng Lee. For the purpose of Open Access, the author has applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising from this submission.

Author contributions

The authors’ responsibilities were as follows – NHAS, MFFC, EHT, ELXL, HPVB, SPCL, AENG, OHT, TKH, LBW, KMG: designed research; NHAS, MFFC, TJY, MTC, PWW: provided essential databases necessary for the research; NHAS, KQY, MSF, VXS: analyzed data or performed statistical analysis; NHAS, KQY, MFFC, EHT: wrote the article. TJY, VXS, MTC, CR, MSF, PWW, ELXL, HPVB, SPCL, AENG, OHT, TKH, LBW, KMG: reviewed and edited the manuscript; EHT: had primary responsibility for final content; and all authors: read and approved the final manuscript.

Conflict of interest

KMG has received reimbursement for speaking at conferences sponsored by Nestle. SPCL has received reimbursement for speaking at conferences sponsored by Danone and Nestle and consulting for Mead Johnson and Nestle. KMG is part of an academic consortium that has received research funding from Abbott Nutrition, Nestle and Danone. SPCL has received research funding from Danone. All other authors report no conflicts of interest.

Funding

The study is supported by the National Research Foundation (NRF) under the Open Fund-Large Collaborative Grant (OF-LCG; MOH-000504) administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC) and the Agency for Science, Technology and Research (A∗STAR). In RIE2025, GUSTO is supported by funding from the NRF’s Human Health and Potential (HHP) Domain, under the Human Potential Programme. EHT is supported by the National Medical Research Council (NMRC) Transition Award grant [MOH-TA18nov-003] and the Clinician-Scientist Award grant [MOH-001415] from NMRC, Singapore. KMG is supported by the UK Medical Research Council [MC_UU_12011/4], the National Institute for Health Research (NIHR Senior Investigator [NF-SI-0515-10042] and the NIHR Southampton Biomedical Research Center) and by the European Union’s Erasmus+ Programme [ImpENSA 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP].

Data availability

Data described in the manuscript, code book, and analytic code will be made available upon request pending.

Appendix A. Supplementary data

The following is the Supplementary data to this article: