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Norris JM, Barriga K, Klingensmith G, et al. Timing of Initial Cereal Exposure in Infancy and Risk of Islet Autoimmunity. JAMA. 2003;290(13):1713–1720. doi:10.1001/jama.290.13.1713
Context Dietary exposures in infancy have been implicated, albeit inconsistently,
in the etiology of type 1 diabetes mellitus (DM).
Objective To examine the association between cereal exposures in the infant diet
and appearance of islet autoimmunity (IA).
Design Birth cohort study conducted from 1994 to 2002 with a mean follow-up
of 4 years.
Setting Newborn screening for HLA was done at St Joseph's Hospital in Denver,
Colo. First-degree relatives of type 1 DM individuals were recruited from
the Denver metropolitan area.
Participants We enrolled 1183 children at increased type 1 DM risk, defined as either
HLA genotype or having a first-degree relative with type 1 DM, at birth and
followed them prospectively. We obtained exposure and outcome measures for
76% of enrolled children. Participants had variable lengths of follow-up (9
months to 9 years).
Main Outcome Measures Blood draws for the detection of insulin autoantibody, glutamic acid
decarboxylase autoantibody, or IA-2 autoantibody were performed at 9, 15,
and 24 months and annually thereafter. Children with IA (n = 34) were defined
as those testing positive for at least 1 of the autoantibodies on 2 or more
consecutive visits and who tested positive or had diabetes on their most recent
Results Children initially exposed to cereals between ages 0 and 3 months (hazard
ratio [HR], 4.32; 95% confidence interval [CI], 2.0-9.35) and those who were
exposed at 7 months or older (HR, 5.36; 95% CI, 2.08-13.8) had increased hazard
of IA compared with those who were exposed during the fourth through sixth
month, after adjustment for HLA genotype, family history of type 1 DM, ethnicity,
and maternal age. In children who were positive for the HLA-DRB1*03/04,DQB8
genotype, adjusted HRs were 5.55 (95% CI, 1.92-16.03) and 12.53 (95% CI, 3.19-49.23)
for initial cereal exposure between ages 0 to 3 months and at 7 months or
Conclusion There may be a window of exposure to cereals in infancy outside which
initial exposure increases IA risk in susceptible children.
Type 1 diabetes mellitus (DM) results from the destruction of the insulin-producing
cells of the pancreas. Autoantibodies to the islet cells, or islet autoimmunity
(IA), which mark this destructive process, can be present for years prior
to the diagnosis of type 1 DM. Exposures in the infant diet have been implicated,
albeit inconsistently, in the etiology of type 1 DM.1 Of
4 cohort studies examining IA as the outcome, 3 showed no effect of the duration
of exclusive breastfeeding2,3 or
age at exposure to cow's milk2,4 on
the risk of IA, and 1 showed that short-term exclusive breastfeeding and early
exposure to cow's milk increased risk for IA.5 One
explanation for these discrepant findings is that exposure to cow's milk may
be correlated with the actual diabetogenic exposure in some populations but
not in others.
Studies of other foods in the infant diet also have been contradictory.
While 2 studies found that type 1 DM cases had been exposed to solid foods
earlier than controls,6,7 2 studies
found no association,8,9 and 1
study reported that type 1 DM cases had been exposed to solid foods later
than controls.10 Finally, exposure to cereals
before age 6 months was not associated with IA in a study of children with
a family history of type 1 DM.2
While the definition of solid foods differs from country to country,
cereal is one of the first solid foods to be introduced into the infant diet
in the United States.11 The purpose of this
prospective study was to examine the association between exposures to cereals
and cow's milk in the infant diet and appearance of islet autoantibodies in
a birth cohort of children at increased risk of type 1 DM based on HLA genotype
and family history of type 1 DM.
Since 1994, the Diabetes Autoimmunity Study in the Young (DAISY) has
been investigating the natural history of IA in infants and children who are
at moderate to high risk of developing type 1 DM.12 Newborns
at increased risk for type 1 DM were identified from those born at St Joseph's
Hospital in Denver, Colo, by screening umbilical cord blood samples for diabetes
susceptibility alleles in the HLA region. The St Joseph's Hospital newborn
population is representative of the general population of the Denver metropolitan
area. We did not recruit families in which parents had difficulties understanding
English, or whose newborn was in very poor health, due to either being extremely
premature or having severe congenital malformation or disease, as assessed
by hospital personnel. Of the families approached, 86% gave written informed
consent to the genetic screening. HLA screening has been completed on more
than 27 000 newborns; the details of the newborn screening have been
published elsewhere.12 Based on their HLA genotype,
newborns were categorized into 3 risk groups determined by the odds of developing
type 1 DM by the age of 20 years: high, odds of developing type 1 DM by the
age of 20 years, 1:16; moderate, 1:75 in non-Hispanic whites or 1:230 in Hispanics;
or low, less than 1:300. All newborns found to be at high risk and a sample
of those found to be at moderate risk were asked to participate in the follow-up.
In addition to the HLA-screened population, newborns were recruited
(January 1994 and ongoing) from families with type 1 DM using The Barbara
Davis Center for Childhood Diabetes in Denver, Colo, other diabetes care clinics,
the Colorado IDDM (insulin-dependent DM) Registry,13 and
newspaper publicity. We obtained prospective exposure and outcome data on
76% of the recruited infants. The study population consists of 841 HLA-screened
children without a family history of type 1 DM and 342 children with a first-degree
relative (parent or sibling) with type 1 DM. For the analysis herein, the
study dates were 1994 to 2002.
In the DAISY follow-up, all children were tested at 9, 15, and 24 months
of age and annually thereafter for antibodies to pancreatic islet antigens
(as described below). Children who are autoantibody positive were placed on
an accelerated schedule in which they returned for a blood draw every 3 to
6 months. Children in this cohort were followed up from birth to a mean of
4.0 years (range, 9 months to 9 years of age). Written informed consent was
obtained from the parents of each study participant at genetic screening (for
the HLA-screened population) and again at enrollment in the DAISY follow-up.
The Colorado multiple institutional review board approved all study protocols.
The majority of the cohort (71.0%, n = 837) was non-Hispanic white.
The remaining 346 children were divided between the following ethnic/racial
groups: Hispanic (n = 268, 77%), biracial (n = 41, 12%), African American
(n = 26, 8%), Asian (n = 5, 1%), Native American (n = 1, 0.3%), and not specified
(n = 5, 1%). One sibling from 989 families, 2 siblings from 91 families, and
3 siblings from 4 families comprised the birth cohort of 1183 children.
Insulin autoantibodies were measured by a micro-insulin autoantibody
(IAA) assay with sensitivity of 58%, specificity of 99%, and interassay coefficient
of variation of 11%.14 The combined glutamic
acid decarboxylase 65 (GAD65) and IA-2 autoantibody radioassay
was performed in duplicate using methods described previously.15 The
levels of both antibodies are expressed as an index = (sample cpm [counts
per minute] − negative control cpm)/(positive control cpm − negative
control cpm). In the 1995 Immunology of Diabetes Society Workshop, the GAD
autoantibody (GAA) assay showed an 82% sensitivity and 99% specificity using
sera from patients with new-onset DM who were younger than 30 years. The interassay
coefficient of variation was 6%. The IA-2 assay showed a 73% sensitivity and
100% specificity and the interassay coefficient of variation was 10%.15 Based on 198 controls without DM, aged 0.4 to 67.5
years, the 99th percentile for IAA (0.01) and GAA (0.032) and the 100th percentile
(single highest value) for IA-2 (0.07) were used as the cutoffs for positivity.
All serum samples that were positive for IAA, GAA, or IA-2 and a random 10%
of the remaining samples were retested in a blinded manner for confirmation.
Persistent IA confers a high risk of subsequent development of type
1 DM in relatives16 and the general population.17 Therefore, we defined a case of IA as a child who
had at least 1 autoantibody (IAA, GAA, or IA-2) above the 99th percentile
on 2 or more consecutive visits and who remained positive for the autoantibody
at their most recent visit (n = 34); that is, children who subsequently have
tested negative for the autoantibody were not included in this case definition.
This definition excluded positivity due to transplacental transmission of
autoantibodies, which we defined as positivity at the 9-month blood draw and
negative on all subsequent visits. As of July 3, 2003, 16 of the 34 children
who met this definition have converted to type 1 DM.
Data for infant diet were collected during telephone or face-to-face
interviews at 3, 6, 9, 12, and 15 months of age. At each interview, mothers
were asked to report the date of introduction and frequency of exposure (ie,
number of servings per day) of all milks, formulas, and foods that the infants
consumed during the previous 3 months. The type and brand name of infant formulas
and the types of cereal were recorded. In addition, juice, fruit, vegetables,
meat, breads, other dairy products, eggs, sweets, and snack foods were recorded
separately. Breastfeeding initiation and termination also were recorded.
The exposure to cow's milk was defined as intake of any formulas, milks,
or foods containing cow's milk, yogurt, cheese, or milk products of any kind.
The cereal definition included both gluten-containing and gluten-free (rice)
cereals. Gluten exposure was defined as an intake of foods containing oats,
wheat, barley, or rye, including infant cereals, zwieback, breads, crackers,
tortillas, teething biscuits, cookies, cakes, pretzels, and pasta. Rice exposure
was defined as an intake of foods containing rice, such as infant rice cereal,
boiled rice, rice milk, rice cakes, or rice noodles. We chose the age at initial
exposure of 4 to 6 months as the reference group for the current analyses
because US pediatricians generally recommend the introduction of solid foods,
and in particular cereals, between the ages of 4 and 6 months, although no
official American Academy of Pediatrics practice guideline exists regarding
this practice.11 The study was a purely observational
study. No dietary advice was given to the participating families.
All analyses were performed in SAS version 8 (SAS Institute Inc, Cary,
NC). Pearson correlation coefficients were used to examine the correlation
between the timing of infant diet exposures. Ongoing recruitment since 1994
and continuing follow-up have resulted in variable lengths of follow-up for
the children in DAISY, producing right-censored data. Some of the affected
children were positive for autoantibodies on their first blood draw (at approximately
9 months of age), producing left-censored data. Finally, we have interval-censored
data in that we know only the time of the last negative and first positive
autoantibody blood draw, rather than the actual time of conversion to autoantibody
positivity. Therefore, all unadjusted and adjusted hazard ratios (HRs) were
estimated using survival analysis (SAS Proc Lifereg) with the Weibull distribution,
and accounting for right, left, and interval censoring.18 Calculations
of follow-up time began at birth. The variables, HLA risk-group and family
history of type 1 DM, were included in our multivariate models to account
for the fact that our cohort was selected based on these risk characteristics.
To determine whether inclusion of multiple siblings per family in this
cohort affected our findings, we randomly selected 1 child per family, resulting
in the exclusion of 100 children, and performed the analyses again. The results
were the same as those from the full cohort; therefore, we are presenting
the data from the full cohort of 1183 children. The level of significance
was set at .05.
Of the 1183 children, 85% (n = 1001) were breastfed. We examined which
foods infants in our cohort first were exposed to after breast milk, if applicable.
After breast milk, milks and foods containing cow's milk and cereals were
the first exposures in the diet in 55% and 15% of the children, respectively,
and in another 6%, exposure to cow's milk and cereals occurred at the same
time. Soy-based infant formulas were the first exposure in 13% of the children,
with another 4% exposed to soy formula and cow's milk (formulas) at the same
time. In only 7% of the children did their first food not contain either cow's
milk, cereal, or soy formula. These other foods included hydrolyzed protein
formulas, fruit juices, and fruits.
Breastfeeding duration was correlated with age at first exposure to
cow's milk (r = 0.33; P<.001),
to all cereals (r = 0.27; P<.001),
to rice cereals (r = 0.25; P<.001),
and minimally, to gluten-containing cereals (r =
0.09; P = .003). In addition, the age at first exposure
to cow's milk was correlated with age at first exposure to all cereals (r = 0.22; P<.001), to rice
cereals (r = 0.20; P<.001),
and to a lesser extent to gluten-containing cereals (r =
0.14; P<.001). Finally, age at first exposure
to gluten-containing cereals was correlated with that of rice cereals (r = 0.26; P<.001).
The mean (SD) age at first visit with a positive autoantibody result
for the 34 affected children was 2.2 (1.5) years, and the mean (SD) age at
the last follow-up for the 1149 unaffected children in the cohort was 3.9
(2.1) years (Table 1). Affected
children compared with unaffected children were more likely to be non-Hispanic
white (91% vs 70%), positive for HLA-DRB1*03/04,DQB8 genotype (53% vs 26%),
and have a first-degree relative with type 1 DM (65% vs 28%).
In unadjusted survival analyses, children initially exposed to any cereals
before 4 months or after 6 months of age showed an increase in the hazard
of IA compared with those exposed to cereals between ages 4 and 6 months (1-3
months: unadjusted HR, 3.03; 95% confidence interval [CI], 1.42-6.44; ≥7
months: unadjusted HR, 3.86; 95% CI, 1.56-9.56) (Table 2). We examined whether this association was due to exposure
to a certain type of cereal by performing additional analyses using restricted
definitions of exposure based on whether the cereals contained gluten. Similar
associations between the hazard of IA and age at exposure to gluten-containing
cereals and age at exposure to rice cereals were observed (1-3 months: unadjusted
HR, 2.76; 95% CI, 0.88-8.66 vs unadjusted HR, 2.74; 95% CI, 1.28-5.85, respectively;
≥7 months: unadjusted HR, 1.95; 95% CI, 0.93-4.11 vs unadjusted HR, 2.31;
95% CI, 0.94-5.68, respectively). Neither age at initial exposure to cow's
milk (1-3 months: unadjusted HR, 0.77; 95% CI, 0.31-1.92; ≥7 months: unadjusted
HR, 0.89; 95% CI, 0.32-2.49) nor breastfeeding duration (unadjusted HR, 0.99;
95% CI, 0.94-1.04) was associated with risk of IA.
We initially explored the independent associations between IA and exposures
to gluten-containing cereals and rice cereals by placing both variables in
the model (Table 3, model 1).
Adjusting for HLA genotype, family history of type 1 DM, ethnicity, and maternal
age, children first exposed to rice cereals before age 4 months and those
who were first exposed at 7 months or older had increased hazard of IA compared
with those who were exposed between ages 4 and 6 months (1-3 months: adjusted
HR, 3.20; 95% CI, 1.40-7.34; ≥7 months: adjusted HR, 2.77; 95% CI, 1.07-7.20).
This result was independent of the association between IA risk and gluten-containing
cereals, which was increased but nonsignificant (1-3 months, adjusted HR,
2.65; 95% CI, 0.76-9.33 and ≥7 months: adjusted HR, 1.70; 95% CI, 0.79-3.66).
These analyses suggest that both rice and gluten-containing cereals
contribute to IA risk. We more efficiently examined the effect of cereal exposure
by performing all subsequent analyses using the combined "any cereal" definition.
Adjusting for covariates and confounders, children exposed to any cereals
before 4 months of age and those who were first exposed at 7 months or older
had increased hazard of IA compared with those who were exposed between ages
4 and 6 months (adjusted HR, 4.32; 95% CI, 2.00-9.35 and adjusted HR, 5.36;
95% CI, 2.08-13.77, respectively) (Table
3, model 2). Being breastfed when first exposed to cereals was associated
with a lower hazard of IA (adjusted HR, 0.50; 95% CI, 0.25-0.99). Adjusting
this model for age at exposure to cow's milk did not change the HRs for cereal
exposure (data not shown), suggesting that these 2 dietary variables showed
no confounding. We also examined other solid foods in the infant diet that
did not contain cereal or cow's milk (eg, fruit, vegetables, meat, and eggs).
The age at introduction of these foods did not differ by affected status,
nor did it alter the association between cereal introduction and IA (data
We stratified our cohort on whether the children had the HLA-DR3/4,DQ8
genotype (321 positive and 862 negative for the genotype) to examine whether
the association between IA risk and cereal exposure was consistent by genetic
risk status. The association between age at exposure to any cereal and IA
was stronger in children who were HLA-DRB1*03/04,DQB8 positive than in children
who were HLA-DRB*03/04,DQB8 negative, although the trend of the association
was similar in both (1-3 months: adjusted HR, 5.55; 95% CI, 1.92-16.03 vs
adjusted HR, 2.93; 95% CI, 0.95-9.07, respectively; >7 months: adjusted HR,
12.53; 95% CI, 3.19-49.23 vs adjusted HR, 2.42; 95% CI 0.62-9.44, respectively).
We examined whether HLA modified the effect of cereal exposure by including
2 interaction terms in the model (representing the interaction between the
dichotomous and trichotomous variables). The P values
for the interaction terms were .34 and .10, suggesting marginal evidence for
effect modification of cereal exposure by HLA status (Table 4). Figure 1 displays
the proportion of children who became IA-positive by age at exposure to cereals
overall, and in children who were HLA-DRB1*03/04,DQB8 positive and HLA-DRB1*03/04,DQB8
A previous study suggested that infant diet associations may only be
seen when the affected children in the analysis are positive for at least
the IA-2 autoantibody,5 presumably because
IA-2 is one of the last autoantibodies to appear before clinical onset of
type 1 DM and thus may be the most predictive of disease.19,20 We
therefore limited our affected population to only those who were positive
for at least the IA-2 autoantibody (n = 21 affected children) to address this
hypothesis. The HRs for age at exposure to cereals were very similar to those
found in the analysis of all children (Table 4).
Our study cohort consisted of children with and without a family history
of type 1 DM. We examined whether we would see different associations in these
2 groups (Table 4). Exposure to
cereals before 4 months of age or after 7 months of age was associated with
an increased risk of IA in both children with and without a family history
of type 1 DM (1-3 months: adjusted HR, 3.08; 95% CI, 1.11-8.51 vs adjusted
HR, 8.51; 95% CI, 2.14-33.83, respectively; ≥7 months: unadjusted HR, 4.21;
95% CI, 1.37-13.00 vs adjusted HR, 8.40; 95% CI, 1.35-52.37, respectively)
We also examined the association of cow's milk in these subgroups to
explore possible explanations as to why our findings regarding cow's milk
were negative and inconsistent with a similar cohort study.5 No
associations were observed between hazard of IA and age at first exposure
to cow's milk in any of these subgroups (Table 4).
Our finding of an association between age at exposure to cereals and
the development of IA has not been reported previously. We chose age at exposure
of 4 to 6 months as the reference group for the current analyses because US
pediatricians generally recommend the introduction of solid foods, and in
particular cereals, between the ages of 4 and 6 months, although no official
American Academy of Pediatrics practice guideline exists regarding this practice.11 Our data suggest that introducing cereals before
age 4 months may increase a child's risk of IA. Interestingly, waiting until
age 7 months or older to first introduce cereals also may increase the risk
for IA. This finding suggests a window of exposure to cereals outside which
an increase of IA risk exists in susceptible children.
The bimodal nature of this association would make it easy to miss with
conventional analyses that compare mean age at exposure or use just 1 age
cutoff for exposure. When we performed our analyses again using cutoffs used
in other studies (eg, exposed before vs after 6 months of age), we saw no
association between exposure to cereal or cow's milk and IA hazard (data not
shown). This finding may explain why we did not find this association in our
previous analysis of a separate DAISY cohort.2
The reason why IA risk is increased when cereal exposure occurs both
early or late is not entirely clear, and may be due to a combination of factors.
The risk associated with early exposure might suggest a mechanism involving
an aberrant immune response to cereal antigens in an immature gut immune system
in susceptible individuals. The risk associated with late exposure to cereals
may be related to the larger amount of exposure at initial introduction in
the older children. Ivarsson et al21 found
that children with celiac disease were exposed to a larger amount of gluten-containing
foods at first exposure than children without celiac disease, and that this
amount may increase the later in life gluten is introduced. In our cohort,
infants exposed to cereals at 7 months or older were more likely to be given
1 or more servings per day in the first month of exposure compared with children
who were exposed between 4 and 6 months or before 4 months (52%, 43%, and
31%, respectively), suggesting that the overall frequency of exposure at initial
introduction differs by age.
An argument may be made that individuals who follow pediatricians' guidelines
regarding the timing of cereal introduction may be different than those who
do not. Indeed, in our cohort, mothers who introduced cereals in their infant's
diet between ages 0 and 3 months were younger and less educated, and those
who introduced cereals at age 7 months or older were older and more educated
than mothers who introduced cereals during the 4- to 6-month period. However,
adjusting for these factors in the analyses did not change the estimate of
the HR for the cereal variable, suggesting that these differences were not
responsible for the observed associations.
We found that if cereals were introduced while the child was still breastfeeding,
the risk of IA was reduced, independent of the age at exposure to cereals.
This finding is similar to that of Ivarsson et al21 in
that children with celiac disease were less likely to have been breastfed
when gluten was introduced than controls (odds ratio, 0.59). Similarly, Scott
et al22 showed that the high rates of DM seen
in BBdp rats weaned onto a wheat gluten-based diet could be substantially
reduced by first exposing the rats to small amounts of gluten during the neonatal
period. The authors hypothesized that early exposure to cereal while the pup
was still breastfeeding had a modulating effect over the detrimental effect
of weaning onto cereals directly.
Because of the similarities between the epidemiological features of
celiac disease and type 1 DM and the coexistence of the 2 diseases in the
same individuals or families, gluten exposure is a strong candidate for a
risk factor for type 1 DM.23 Ventura et al24 found that at diagnosis patients with celiac disease
were positive for type 1 DM autoantibodies, which disappeared after the initiation
of a gluten-free diet, suggesting a potentially common etiology of these 2
diseases. However, elimination of dietary gluten for 12 months in 7 IA-positive
relatives of patients with type 1 DM did not affect levels of the diabetes
autoantibodies, suggesting that dietary gluten may not be the diabetogenic
antigen,25 or at least not at that point in
the pathogenesis of disease. MacFarlane et al26 identified
a wheat storage globulin protein, Glb1, which may be associated with islet
cell damage, and showed that antibodies to the Glb1 protein were detected
in serum samples from patients with but not in patients without DM. While
the aforementioned studies focused on gluten as the sole risk factor, our
findings suggest that rice cereal, a nongluten cereal, also contributes to
risk for IA. The observation that all cereals and not just gluten-containing
cereals are associated with IA risk has implications with regard to development
of mechanistic hypotheses as well as effective prevention strategies.
Most commercial infant cereals are supplemented with iron, zinc, thiamin,
riboflavin, nicotinic acid, and vitamin E. While our study could not directly
examine this, it is possible that delaying the introduction of infant cereals
could result in low levels of these nutrients (in the absence of other sources)
at a critical time period of development, thus increasing the risk of IA.
For example, studies suggest that vitamin E27,28 and
associated with a decreased risk of type 1 DM.
Cereals differ from breast milk and infant formulas in the amount of
carbohydrates per calorie that an infant consumes at each feeding. Therefore,
a hypothesis could be explored about increased carbohydrate load in infancy
and its impact on the pancreas and the immune system. The rate of insulin
release has been correlated with expression of GAD,32 suggesting
that carbohydrate loading in infancy may stimulate the pancreas to secrete
more insulin, resulting in an increase in the expression of the autoantigens,
which ultimately may increase the risk of islet cell destruction.
We found no association between exposure to cow's milk and risk of IA
overall or in any of the risk subgroups. We also ruled out cow's milk as a
confounder of the association between cereal exposure and IA risk. Our inability
to reproduce the results of Kimpimäki et al5 may
be due to factors (foods or behaviors) in the infant diet that may be correlated
with breastfeeding and infant formula choices, with these correlations differing
across the 2 populations.
The DAISY birth cohort, which consists of both children from a screened
general population and those with a family history of type 1 DM, gives us
the unique ability to observe that the effect of age at cereal introduction
was similar in each group. Moreover, the independent effects of HLA and family
history of type 1 DM on risk of IA are large and about equal, with HRs greater
than 7. We also observed a suggestion of a gene-environment interaction in
our analyses, in that the association between IA and age at first exposure
to cereals was stronger in individuals who possessed the high-risk genotype,
Of our cohort, 31% were exposed to cereals outside of the 4- to 6-month
age time window, yielding an adjusted HR of 4.3 for IA. Using this to calculate
the population percent attributable risk, we found that 50% of IA would be
eliminated in this population of children at moderate and high risk for type
1 DM if cereals were first introduced to the infant's diet between 4 and 6
months of age. While this population percent attributable risk is not directly
applicable to the general population because it was derived from a population
that was selected for being at increased risk for type 1 DM, it does indicate
that manipulation of this infant diet exposure could have a strong impact
on risk in children at increased risk for type 1 DM and potentially in the
general public as well. We recommend that these results be confirmed in other
prospective cohorts of children at risk for type 1 DM before any interventions
are implemented. Additional studies may shed light on the importance of quantity
of exposure and/or whether the risk is related to exposure to specific antigens
or to other components of cereals. Our results do not suggest any need to
change the current US infant feeding guidelines with regard to cereal introduction.