Assessing the safety of bioactive ingredients in infant formula that affect the immune system: recommendations from an expert panel.

Bioactive ingredients for infant formula have been sought to reduce disparities in health outcomes between breastfed and formula-fed infants. Traditional food safety methodologies have limited ability to assess some bioactive ingredients. It is difficult to assess the effects of nutrition on the infant immune system because of coincident developmental adaptations to birth, establishment of the microbiome and introduction to solid foods, and perinatal environmental factors. An expert panel was convened to review information on immune system development published since the 2004 Institute of Medicine report on evaluating the safety of new infant formula ingredients and to recommend measurements that demonstrate the safety of bioactive ingredients intended for that use. Panel members participated in a 2-d virtual symposium in November 2020 and in follow-up discussions throughout early 2021. Key topics included identification of immune system endpoints from nutritional intervention studies, effects of human milk feeding and human milk substances on infant health outcomes, ontologic development of the infant immune system, and microbial influences on tolerance. The panel explored how "nonnormal" conditions such as preterm birth, allergy, and genetic disorders could help define developmental immune markers for healthy term infants. With consideration of breastfed infants as a reference, ensuring proper control groups, and attention to numerous potential confounders, the panel recommended a set of standard clinical endpoints including growth, response to vaccination, infection and other adverse effects related to inflammation, and allergy and atopic diseases. It compiled a set of candidate markers to characterize stereotypical patterns of immune system development during infancy, but absence of reference ranges, variability in methods and populations, and unreliability of individual markers to predict disease prevented the panel from including many markers as safety endpoints. The panel's findings and recommendations are applicable for industry, regulatory, and academic settings, and will inform safety assessments for immunomodulatory ingredients in foods besides infant formula.

Timing of introduction of complementary foods and beverages and growth, size, and body composition: a systematic review.

BACKGROUND: The systematic review described in this article was conducted as part of the USDA and Department of Health and Human Services Pregnancy and Birth to 24 Months Project. OBJECTIVES: The aim was to describe the relationship between timing of introduction of complementary foods and beverages (CFBs) and growth, size, and body-composition outcomes across the life span. METHODS: The literature was searched and selected using predetermined criteria. Data were extracted and risk of bias assessed for each included study. Evidence was qualitatively synthesized, conclusion statements were developed, and the strength of the evidence was graded. RESULTS: Eighty-one articles were included in this systematic review that addressed timing of CFB introduction relative to growth, size, and body-composition outcomes from infancy through adulthood. Moderate evidence suggests that introduction of CFBs between the ages of 4 and 5 mo compared with ∼6 mo is not associated with weight status, body composition, body circumferences, weight, or length among generally healthy, full-term infants. Limited evidence suggests that introduction of CFBs before age 4 mo may be associated with higher odds of overweight/obesity. Insufficient evidence exists regarding introduction at age ≥7 mo. CONCLUSIONS: Although several conclusions were drawn in this systematic review, additional research is needed to address gaps and limitations in the evidence on timing of introduction of CFBs and growth, size, and body composition, such as randomized controlled trials that examine multiple outcomes and/or CFB introduction between the ages of 4 and 6 mo, and research that accounts for potential confounders such as feeding practices and baseline growth status and considers issues of reverse causality.

Complementary feeding and food allergy, atopic dermatitis/eczema, asthma, and allergic rhinitis: a systematic review.

BACKGROUND: Nutrition during infancy and toddlerhood may influence health and disease prevention across the life span. Complementary feeding (CF) starts when human milk or infant formula is complemented by other foods and beverages, beginning during infancy and continuing to age 24 mo. OBJECTIVES: The aim of this study was to describe systematic reviews conducted for the USDA and the Department of Health and Human Services Pregnancy and Birth to 24 Months Project to answer the following question: What is the relationship between the timing of the introduction of complementary foods and beverages (CFBs), or types and amounts of CFBs consumed, and the development of food allergy, atopic dermatitis/eczema, asthma, and allergic rhinitis? METHODS: The literature was searched using 4 databases (CINAHL, Cochrane, Embase, PubMed) to identify articles published from January 1980 to February 2017 that met predetermined inclusion criteria. For each study, data were extracted and risk of bias was assessed. The evidence was qualitatively synthesized to develop a conclusion statement, and the strength of the evidence was graded. RESULTS: Thirty-one included articles addressed the timing of CFB introduction, and 47 articles addressed the types and amounts of CFBs consumed. CONCLUSIONS: Moderate evidence suggests that there is no relationship between the age at which CF first begins and the risk of developing food allergy, atopic dermatitis/eczema, or childhood asthma. Limited to strong evidence, depending on the specific food, suggests that introducing allergenic foods in the first year of life (after 4 mo) does not increase the risk of food allergy and atopic dermatitis/eczema but may prevent peanut and egg allergy. There is not enough evidence to determine a relationship between diet diversity or dietary patterns and atopic disease. Research is needed to address gaps and limitations in the evidence on CF and atopic disease, including research that uses valid and reliable diagnostic measures and accounts for key confounders and potential reverse causality.

Types and amounts of complementary foods and beverages consumed and growth, size, and body composition: a systematic review.

BACKGROUND: Systematic reviews (SRs) were conducted by the Nutrition Evidence Systematic Review (NESR) team for the USDA's and the Department of Health and Human Services' Pregnancy and Birth to 24 Months Project. OBJECTIVES: The aim was to describe the SRs examining the relationship between types and amounts of complementary foods and beverages (CFBs) and growth, size, and body-composition outcomes. METHODS: The NESR team collaborated with subject matter experts to conduct this SR. The literature was searched and screened using predetermined criteria. For each included study, data were extracted and risk of bias was assessed. The evidence was qualitatively synthesized to develop a conclusion statement, and the strength of evidence was graded. RESULTS: This SR includes 49 articles that examined type, amount, or both of CFBs consumed and growth, size, and body-composition outcomes. Moderate evidence suggests that consuming either different amounts of meat, meat instead of iron-fortified cereal, or types of CFBs with different fats or fatty acids does not favorably or unfavorably influence growth, size, or body composition. In relation to overweight/obesity, insufficient evidence is available with regard to the intake of meat or CFBs with different fats or fatty acids. Limited evidence suggests that type and amount of fortified infant cereal does not favorably or unfavorably influence growth, size, body composition, or overweight/obesity. Limited evidence suggests that sugar-sweetened beverage consumption during the complementary feeding period is associated with increased obesity risk in childhood but is not associated with other measures of growth, size, or body composition. Limited evidence showed a positive association between juice intake and infant weight-for-length and child body mass index z scores. Insufficient evidence is available on other CFBs or dietary patterns in relation to outcomes. CONCLUSIONS: Although several conclusions were drawn, additional research is needed that includes randomized controlled trials, examines a wider range of CFBs, considers issues of reverse causality, and adjusts for potential confounders to address gaps and limitations in the evidence.

Complementary feeding and micronutrient status: a systematic review.

BACKGROUND: Proper nutrition during early life is critical for growth and development. OBJECTIVES: The aim was to describe systematic reviews conducted by the Nutrition Evidence Systematic Review team for the USDA and the Department of Health and Human Services Pregnancy and Birth to 24 Months Project to answer the following: What is the relation between 1) timing of introduction of complementary foods and beverages (CFBs) or 2) types and/or amounts of CFBs consumed and micronutrient status (iron, zinc, vitamin D, vitamin B-12, folate, and fatty acid status)? METHODS: A literature search identified articles from developed countries published from January 1980 to July 2016 that met the inclusion criteria. Data were extracted and risk of bias assessed. Evidence was qualitatively synthesized to develop a conclusion statement, and the strength of the evidence was graded. RESULTS: Nine articles addressed the timing of CFB introduction and 31 addressed types or amounts or both of CFBs. Moderate evidence suggests that introducing CFBs at age 4 mo instead of 6 mo offers no advantages or disadvantages in iron status among healthy full-term infants. Evidence is insufficient on the timing of CFB introduction and other micronutrient status outcomes. Strong evidence suggests that CFBs containing iron (e.g., meat, fortified cereal) help maintain adequate iron status or prevent deficiency in the first year among infants at risk of insufficient iron stores or low intake. Benefits for infants with sufficient iron stores (e.g., infant formula consumers) are less clear. Moderate evidence suggests that CFBs containing zinc (e.g., meat, fortified cereal) support zinc status in the first year and CFB fatty acid composition influences fatty acid status. Evidence is insufficient with regard to types and amounts of CFBs and vitamin D, vitamin B-12, and folate status, or the relation between lower-iron-containing CFBs and micronutrient status. CONCLUSIONS: Several conclusions on CFBs and micronutrient status were drawn from these systematic reviews, but more research that addresses specific gaps and limitations is needed.

Complementary feeding and developmental milestones: a systematic review.

BACKGROUND: Systematic reviews were conducted as part of the USDA and the US Department of Health and Human Services Pregnancy and Birth to 24 Months Project to examine the relation between complementary feeding and developmental milestones. OBJECTIVES: The aim of this study was to describe systematic reviews examining the relationship between timing of introduction of complementary foods and beverages (CFB), and the types and amounts of CFB consumed, and developmental milestones. METHODS: The literature was searched using 4 databases (PubMed, Cochrane, Embase, and CINAHL) to identify articles that met predetermined criteria for inclusion. Data extraction and risk of bias assessment were conducted for each included study. The body of evidence for each systematic review was qualitatively synthesized to develop a conclusion statement, and the strength of evidence was graded. RESULTS: Three included articles (1 randomized controlled trial; 2 observational studies) examined timing of introduction of CFB. Eight included articles (3 randomized controlled trials; 5 observational studies) examined types and amounts of CFB. There was insufficient evidence to draw conclusions about the relation between either timing of CFB introduction or types and amounts of CFB, and developmental milestones. CONCLUSIONS: The ability to draw conclusions about the relationship between complementary feeding and developmental milestones was restricted by an inadequate amount of evidence with potential for issues with reverse causality and wide variation in design, type/age of outcome assessment, exposure assessment, and reported results. Additional research to address these gaps and limitations would be useful.

The Effects of Early Nutritional Interventions on the Development of Atopic Disease in Infants and Children: The Role of Maternal Dietary Restriction, Breastfeeding, Hydrolyzed Formulas, and Timing of Introduction of Allergenic Complementary Foods.

This clinical report updates and replaces a 2008 clinical report from the American Academy of Pediatrics, which addressed the roles of maternal and early infant diet on the prevention of atopic disease, including atopic dermatitis, asthma, and food allergy. As with the previous report, the available data still limit the ability to draw firm conclusions about various aspects of atopy prevention through early dietary interventions. Current evidence does not support a role for maternal dietary restrictions during pregnancy or lactation. Although there is evidence that exclusive breastfeeding for 3 to 4 months decreases the incidence of eczema in the first 2 years of life, there are no short- or long-term advantages for exclusive breastfeeding beyond 3 to 4 months for prevention of atopic disease. The evidence now suggests that any duration of breastfeeding ≥3 to 4 months is protective against wheezing in the first 2 years of life, and some evidence suggests that longer duration of any breastfeeding protects against asthma even after 5 years of age. No conclusions can be made about the role of breastfeeding in either preventing or delaying the onset of specific food allergies. There is a lack of evidence that partially or extensively hydrolyzed formula prevents atopic disease. There is no evidence that delaying the introduction of allergenic foods, including peanuts, eggs, and fish, beyond 4 to 6 months prevents atopic disease. There is now evidence that early introduction of peanuts may prevent peanut allergy.

Complementary feeding and bone health: a systematic review.

BACKGROUND: Proper nutrition during infancy and toddlerhood is crucial for supporting healthy growth and development, including bone health. Complementary feeding is the process that starts when human milk or infant formula is complemented by other foods and beverages, beginning during late infancy and continuing to 24 mo of age. OBJECTIVES: This article aims to describe systematic reviews (SRs) conducted by the Nutrition Evidence Systematic Review team for the USDA and the Department of Health and Human Services Pregnancy and Birth to 24 Months Project to answer these questions: what is the relationship between 1) timing of introduction of complementary foods and beverages (CFBs) or 2) types and/or amounts of CFBs consumed and bone health? Methods: The literature was searched with the use of 4 databases (CINAHL, Cochrane, Embase, and PubMed) to identify articles published from January 1980 to July 2016 that addressed these topics and met predetermined criteria for inclusion. For each study, data were extracted and risk of bias was assessed. The evidence was qualitatively synthesized to develop a conclusion statement, and the strength of the evidence was graded. RESULTS: Three articles addressed the timing of introduction of CFBs and bone health during childhood (through 18 y of age), and 2 addressed the types and/or amounts of CFBs consumed relative to bone health. CONCLUSIONS: Insufficient evidence was available to draw conclusions about the relationships between the timing of CFB introduction and types and/or amounts of CFBs consumed and bone health. Therefore, a grade was not assignable for these SRs. The ability to draw conclusions was limited by an overall lack of research, failure to adjust for several key confounding factors, and heterogeneity in studies with regard to methodology, subject populations, and results. Additional research is needed that addresses these gaps and limitations.

Use of Starch and Modified Starches in Infant Feeding: A Historical Perspective.

There is a long history of the use of starch in infant feeding. Proprietary infant foods (1867-1920) contained added starch from either cereal grains or malted carbohydrates. When evaporated milk became available in the 1920s, the use of proprietary foods fell out of favor. Evaporated milk formulas were a mixture of milk, water, and modified starch or milk sugar (lactose). By the late 1920s, however, corn syrup became the most common modified starch added to evaporated milk formulas as it was widely available, inexpensive, and readily accepted. The ongoing development of the modern calorie-based infant formula, made from non-fat cow's milk, lactose, oleo and vegetable oils, largely replaced the evaporated milk formulas in the 1960s. On the other hand, after 1940, added starch and modified starch became increasingly important in the production of pureed fruits and vegetables. Not surprisingly, this included their use in the modern "industrialized" food for use in infants, including their use in a proliferation of grain based fortified infant cereals. This coincided with the increasing production largely due to the earlier introduction of complementary foods, commonly before 3 months of age by 1958. After 1969, the increasing public awareness and media scrutiny of infant foods lead to a growing criticism of the use of modified starches. Even though the National Research Council and the American Academy of Pediatrics concluded that modified starches were safe for use, continued public pressure led to their removal from most infant foods in the 1990s. This paralleled the natural food and organic food movements in the United States. Though modified starches are still used in infant dinners of mixed foods today, their use has been minimized and this issue is not currently of significant concern to the public.

Improving Rates of Screening for Anemia in Infancy.

In 2010, the American Academy of Pediatrics recommended universal screening for anemia at approximately 1 year of age. This quality improvement study sought to improve anemia screening in an ambulatory setting. In a large university-based setting, a best practice alert (BPA) was placed within the electronic health record. The primary outcome was overall screening rate in ambulatory family medicine (DFM) and pediatrics (PEDS) clinics. From 2545 pre-BPA clinic visits over a 12-month period, the screening rate was 48.2%. Among 2186 post-BPA clinic visits over an 8-month period, the screening rate improved to 72.7%, P < .0001. Follow-up over a second 7-month period demonstrated sustained improvements (70.8%) but was not higher after educational sessions between the periods. Screening rates were higher in PEDS than DFM at each time point; P < .0001. This technology-based intervention increased and maintained higher screening rates for anemia at 1 year, with higher rates in PEDS.

How Much Iron is Needed for Breastfeeding Infants?

The iron requirement for breastfed infants remains controversial. Given the impact of iron on neurodevelopmental outcomes and the questionable impact of iron supplements after iron deficiency has occurred, its importance as a nutrient in this population cannot be down played. Infants are born with relatively large body stores of iron that are marginally related to maternal iron status in developed countries. Delayed cord clamping may increase these fetal stores, but at the present time this is only recommended for preterm infants who are born with low iron stores. The diagnosis of iron deficiency (ID) and iron deficiency anemia (IDA) remains problematic though new laboratory tests (measures of reticulocyte hemoglobin concentration and serum transferrin receptor) hold promise in developed countries. The present evidence supports the potential benefits of iron supplementation of exclusively breastfed infants after 4 months of age, by which time the iron stores present at birth are depleted. This deficit cannot be made up even if the small amounts of iron in human milk are completely absorbed.

Protein needs early in life and long-term health.

The objective of this review was to summarize selected health aspects of protein intake during the first 2 y of life. During this period there is a marked increase in protein intake from an intake of ∼ 5% of energy from protein (PE%) in an exclusively breastfed infant to ∼ 15 PE% when complementary foods have been introduced. At this age, mean protein intake is ∼ 3 times as high as the physiologic requirement, but some children receive 4-5 times their physiologic requirement. Protein from cow milk constitutes a main part of protein intake in toddlers and seems to have a specific effect on insulin-like growth factor I concentrations and growth. Meat has a high protein content, but the small amounts of meat needed to ensure good iron status have less impact on total protein intake. The difference in protein intake between breastfed and formula-fed infants is likely to play a role in the difference between breastfed and formula-fed infants. There is emerging evidence that high protein intake during the first 2 y of life is a risk factor for later development of overweight and obesity. It therefore seems prudent to avoid a high protein intake during the first 2 y of life. This could be accomplished by decreasing the upper allowable limit of the protein content of infant formulas for the first year of life and limiting the intake of cow milk in the second year of life.