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6
Going Beyond Current Clinical Studies
ABSTRACT
Clinical studies are essential to ensure the safety of infant formulas and any systematic deviation from normal physical growth and development attributable to a new ingredient should be considered a safety threat. Growth studies, currently a centerpiece of clinical evaluation of infant formulas, should include precise and reliable measurements of weight and length velocity and head circumference. Appropriate measures of body composition also require assessment. Duration of follow-up measurements should at least cover the period when infant formula remains the sole source of nutrients in the diet of the infant. However the committee believes that growth studies are not sufficient on their own to assess ingredients new to infant formulas. Specific guidelines are needed to determine “normal” growth and to establish what represents a biologically meaningful difference among groups of infants consuming different formulas. Specific recommendations are needed to establish a level of difference that represents a safety concern.
Regulatory guidelines should ensure that infant outcomes encompass, as the Food and Drug Administration (FDA) has proposed, “all aspects of physical growth and normal maturational development.” Any systematic differences in clinical outcomes that can be attributed to an ingredient new to infant formulas should be considered a safety concern that requires careful evaluation and, if needed, further clinical study to identify the pathway through which the infant has been affected. The committee recommends that a hierarchy of two levels of clinical assessment be implemented with regard to growth and organ systems. Level 1 assessments should include checking for signs of all adverse laboratory indicators of the major organ systems. Level 2 assessments should include in-depth measures of organ systems or functions that would be performed to explain abnormalities found in level 1 assessments or specific theoretical concerns not typically addressed by level 1 tests.
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There are a number of reasons why it is equally important to include developmental-behavioral outcomes in future studies of the safety of ingredients new to infant formulas: the measures are sensitive to exposure to toxic substances, they can have long-term predictive value, and bidirectional brain-behavior links exist. Therefore, assessment of clinical endpoints should include measurement of infant sensory-motor, cognitive, affectual, and neural function with instruments that follow recommended criteria. The committee recommends that a hierarchy of three levels of clinical assessment be developed and implemented to determine what levels are appropriate to apply with regard to developmental-behavioral-neural outcomes. The levels of assessment are: level 1 assessments, including developmental screening measures; level 2 assessments, including in-depth measures of infant functions in major developmental areas (single assessment for each area with one instrument); and level 3 assessments, including in-depth measures of infant functions in major developmental areas (repeated assessment with multiple instruments).
The instruments used for these assessments should satisfy the following criteria: be age appropriate, have predictive value for long-term consequences, be adequately sensitive, have documented brain-behavior links, have cross-species generalizability, assess specific function, and be easy to administer. In addition, the committee considers that certain design features (e.g., adequate statistical power) are essential in all clinical studies.
INTRODUCTION
This chapter provides an overview of clinical studies and a brief overview of the current regulatory requirements for them. The first part of the chapter includes a rationale for clinical assessment of growth, specific recommendations on what should be measured, and guidelines for interpretation of results. In the second part, the committee describes more specific clinical endpoints in each of the organ systems likely to be affected by ingredients new to infant formulas. In the last part of the chapter considerable attention is paid to behavioral and developmental endpoints because of the young infant’s heightened sensitivity to potentially toxic substances and the long-term consequences of such exposures.
THE IMPORTANCE OF CLINICAL STUDIES
While preclinical laboratory and animal studies have substantial value for identifying potential safety concerns, they are limited in their ability to predict what may happen in human infants. Clinical studies in human infants are needed for several reasons. First, extrapolation from animal studies may be limited by differences between animal and human structure, physiology, and development. Second, extrapolation from isolated tissue studies is limited by the inability of such models to assess functions in the context of whole organ systems where coordination and integration are the rule. For example, the digestion and absorption of nutrients requires coordination of numerous gastrointestinal functions. Third, there may be no available animal or tissue models to test specific functions. For example, it is not possible to use animal models to duplicate clinically relevant allergic reactions to foreign proteins, to determine the effects of a substance on acceptance or tolerance of an infant formula, or to test some of the higher cognitive functions found only in humans.
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CURRENT REGULATORY GUIDELINES FOR CLINICAL STUDIES
Canada’s Food and Drug Regulations
There are no specific requirements for clinical testing of infant formulas set out under Canada’s Food and Drug Regulations in Division 16 (Food Additives), Division 25 (Infant Formula), or Division 28 (Novel Foods) (Canada, 2001). Division 25 of the Regulations requires that a premarket submission with respect to a new infant formula or an infant formula that has undergone a major change in composition, manufacturing, or packaging include the evidence relied on to establish that the infant formula is nutritionally adequate to promote acceptable growth and development in infants when consumed in accordance with the directions for use. Divisions 16 and 28 require that data be submitted to Health Canada that include information used to establish the safety of a food additive or a novel food, respectively. Health Canada refers manufacturers to internationally accepted guidelines for clinical testing or asks to be consulted because decisions are made on a case-by-case basis.
Sections 409 and 412 of the Federal Food, Drug and Cosmetic Act
There are no explicit requirements for clinical testing of infant formulas specified under Section 409 of the Food, Drug and Cosmetic (FD&C) Act. Section 409 stipulates that a petition to establish safety of a food additive shall contain “all relevant data bearing on the physical or other technical effect such additive is intended to produce …,” but it does not dictate a specific type of clinical study.
Current regulations for infant formulas under Section 412 of the FD&C Act do not define quality factor requirements, such as physical growth, but only describe required nutrient levels, without considering bioavailability. This gap is addressed in a proposed rule (FDA, 1996), where assessment of physical growth, using anthropometry, is proposed “as an integrative indicator of net overall nutritional quality of the formula.” The proposed rule further states, “as the science evolves, FDA anticipates being able to progress beyond generalized, nonspecific indicators of overall nutritional intakes (e.g., measures of physical growth) to more specific and sensitive measures of biochemical and functional nutritional status” (FDA, 1996, P. 36181). Thus neither the current nor the proposed rules identify specific requirements for other clinical studies.
FDA Redbook
FDA does not require petitioners to conduct human clinical studies to support the safety of food additives or color additives used in food, but, if deemed necessary, it recommends that the studies conform to guidelines presented in section VI.A. of the Redbook (OFAS, 2001, 2003). These guidelines are comprehensive and relevant for the clinical testing of ingredients new to infant formulas.
General guidance is provided to identify the scientific and ethical principles for clinical studies, including the need for presentation of a defensible rationale for human studies. The Redbook states that this rationale should be based on:
adequate preclinical investigations,
results of clinical studies conducted elsewhere,
consideration of the organs and organ systems that may be affected, and
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careful attention to the qualifications of investigators and the safety and ethical treatment of subjects in clinical trials.
The Redbook suggests the sequence of and subjects for clinical studies. Early clinical studies are to determine the “metabolism and level of the food or food additive that gives an adverse or toxic response in man” (specifically physiological studies of the additive’s disposition, its potential to induce enzyme levels or increase activity, and its interactions with other nutrients) (OFAS, 2001, P. 183). In general children are to be excluded from these early (typically acute or shorter duration) clinical studies. However tolerance studies, which are to be included among early studies, need to be conducted in infants because of the special nature of infant formulas.
Infants are more likely to be included in what the Redbook describes as chronic intake studies, which are to be conducted once general safety in humans is established in the early adult studies. Here, the Redbook provides specific guidance on protocol design, study population, and statistical analyses, as well as on how reports of clinical studies should be presented. Box 6-1 lists questions that should be answered when conducting studies to determine the safety of a proposed additive.
GENERAL APPROACH TO CONDUCTING CLINICAL STUDIES
In the conceptualization of the range of infant health concerns, the committee was guided by the following: “FDA considers the concept of ‘healthy growth’ to be broad, encompassing all aspects of physical growth and normal maturational development, including maturation of organ systems and achievement of normal functional development of motor, neurocognitive, and immune systems. All of these growth and maturational developmental processes are major determinants of an infant’s ability to achieve his/her biological potential, and all can be affected by the nutritional status of an infant” (FDA, 1996, P. 36179).
The committee proposes the use of a multilevel approach to establish more comprehensive guidelines to ensure that infant outcomes encompass “all aspects of physical growth and normal maturational development.” Figure 6-1 illustrates the three different types of clinical studies recommended by the committee, including assessment of growth, organ systems, and development and behavior. Figures 6-2 and 6-3 further explain the clinical studies through the proposed two-level approach to organ systems and the three-level approach to development-
BOX 6-1 Questions That Should Be Answered When Conducting Clinical Studies
How is the food or food additive absorbed, metabolized, deposited in tissue, and excreted?
What is the half-life of the food or food additive in the human body?
How may interactions between the food or food additive and nutrients or medications compromise the availability of any of these substances (including the consideration of the matrix)?
How does the food or food additive affect the function of human organs and organ systems (including infant growth and development)?
What are the possible adverse reactions to the food or food additive in the general population of individuals who are likely to use the substance and in special (more sensitive) populations?
SOURCE: OFAS (2001, 2003).
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FIGURE 6-1 Proposed clinical assessment algorithm. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.
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FIGURE 6-2 Proposed levels of clinical assessment of major organ, immune, and endocrine systems algorithm. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.
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FIGURE 6-3 Proposed levels of clinical assessment of development and behavior algorithm. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.
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behavior. There are decision-making points within each of these three types of clinical studies that will be discussed in detail in subsequent sections of this chapter. (In keeping with the charge to the committee, proposed guidelines focus on the health and well-being of term infants only.)
The committee recognizes that all clinical studies would need to be reviewed and approved by human-subject research review boards. Because the clinical studies to determine the safety of new ingredients will be carried out in healthy infants, the committee does not recommend the use of highly invasive tests, such as tissue biopsies or gastrointestinal incubations.
OVERVIEW OF RECOMMENDED LEVELS OF ASSESSMENT
RECOMMENDATION: Any adverse systematic differences in clinical outcomes that can be attributed to an ingredient new to infant formulas should be considered a safety concern that requires careful evaluation and, if needed, further clinical study to identify the pathway through which the infant has been affected.
A hierarchy of two levels of clinical assessment should be implemented for organ systems:
Level 1 assessments. Check of signs for all adverse laboratory indicators.
Level 2 assessments. In-depth measures of organ systems or functions that would be performed to explain abnormalities found in level 1 assessments or specific theoretical concerns not typically addressed by level 1 tests.
A hierarchy of three levels of clinical assessment should be implemented for developmental-behavioral measures:
Level 1 assessments. Developmental screening measures.
Level 2 assessments. In-depth measures of infant functions in major developmental areas (single assessment for each area with one instrument).
Level 3 assessments. In-depth measures of infant functions in major developmental areas (repeated assessment with multiple instruments).
GROWTH
Growth is well recognized as a sensitive, but nonspecific, indicator of the overall health and nutritional status of an infant. Monitoring infant growth has always been an integral part of pediatric care and is particularly important for young infants. Growth and nutrient requirements per kilogram of body weight are higher during the first few months of infancy than during any other period of life. Furthermore, the greatest percentage of dietary intake is devoted to supporting growth at this time, and thus nutritional imbalances are likely to be reflected in growth rates.
The committee believes that the inability of a formula to support normal growth represents a significant harm to infants and therefore growth is an essential endpoint for all safety assessments of an ingredient new to infant formulas. Any systematic deviation from normal physical growth attributable to a new ingredient should be considered a safety threat.
Under current regulations the core of the requirements focuses on meeting certain levels of specific nutrients. The concept of quality factors has not been defined, but proposed
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regulations include a subsection on quality factors, with a focus on physical growth. Despite the absence of quality factors in current legislation, there appears to be a strong consensus that growth should be a quality factor for infant formulas. In the United States FDA recognized the need for clear guidelines on the assessment of growth and commissioned a report from the American Academy of Pediatrics’ (AAP) Committee on Nutrition Task Force on clinical testing of infant formulas with respect to nutritional suitability for term infants (AAP, 1988). The task force identified the following types of clinical studies as useful in the premarket evaluation of formulas: acceptance or tolerance studies, gains in weight and length, food intake, body composition, serum chemical indices, and metabolic balance studies. Most of the recommendations of the task force were incorporated into the proposed changes to the infant formula act (FDA, 1996).
Currently clinical studies tend to follow the proposed rule, the 120-day growth study being the main method used to assess the ability of an infant formula to sustain normal infant growth. The proposed rule would codify standards for clinical growth studies by specifying methods (controlled clinical trials), duration (4 months), measurements (weight, recumbent length, and head circumference), and ages at measurement (at 2 and 4 weeks, then at least monthly thereafter), with a further requirement that individual infant data be plotted against Centers for Disease Control and Prevention (CDC) reference curves for weight and length.1
The AAP task force concluded that “rate of gain in weight gain is the single most valuable component of the clinical evaluation of infant formula” (AAP, 1988, P. 7). Further, it judged that length assessment is unnecessary because significant differences in length gain would not occur in the absence of differences in weight gain, and that there is a higher potential for measurement error and thus misclassification of growth in length. While the committee concurs with the centrality of weight gain in clinical assessment, it also believes that length and head circumference should be measured in growth studies in order to evaluate the effects of substances on other aspects of growth, such as skeletal growth and body proportions.
Notably absent from existing and proposed requirements are specific guidelines on what constitutes “normal” growth, or what represents a biologically meaningful difference among groups of infants consuming different formulas. Recommendations are needed both to define the most relevant comparison groups for clinical studies and to establish a level of difference that represents a safety concern. These are challenging and critical questions that will be discussed in later sections.
In addition, the committee recommends that guidelines go beyond growth studies to assess the safety of ingredients new to infant formulas. Deficits in brain function and effects of specific micronutrients may occur in the absence of differences in physical growth. Furthermore, while a “decrease in the growth rate during infancy is the earliest indication of nutritional failure” (Fomon, 1993, P. 48), growth deficits are likely to appear only secondary to effects on specific organs or tissues, and they may not appear for some time after nutritional insult. Thus growth studies should be considered a necessary, but not sufficient, part of human clinical studies of the safety of ingredients new to infant formulas (see Figure 6-1, Box 3).
1
Proposed changes to 21 C.F.R. Parts 106 and 107 specify the reference charts to be used. Since CDC has published updated references for use in the United States (Kuczmarski et al., 2000), the requirement should be updated to specify the new reference values.
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Measuring Growth
Ascertainment of growth status typically relies on anthropometric assessment, which is noninvasive and highly practical, requires relatively little training to achieve reliability, and is accomplished with low-cost, low-tech tools. Further, there are ample descriptions of standard anthropometric methods and reference data for the interpretation of measurements (Kuczmarski et al., 2000; Lohman et al., 1988). Although each has limitations and advantages (Table 6-1), the committee recommends the following measures of infant growth for clinical studies (see Figure 6-1, Box 3):
Weight is an overall measure of body size and is responsive to acute insults, such as infectious morbidity or changes in nutrient intakes. Attained weight is hard to interpret in the absence of length data since an underweight child could be well proportioned or thin, with different implications for morbidity risk.
Recumbent length is an overall indicator of linear or bone growth. Length reflects genetic factors and growth history. It is less responsive to acute insults, and the response of length to varying nutrition levels typically lags behind the response in weight.
Weight for length is an indicator of relative weight (thinness or overweight). These measures are typically expressed as a Z-score or a percentile based on comparison with national reference data.
Head circumference is often used in clinical settings as an overall, nonspecific indicator of brain growth. It has limited usefulness in screening for potential developmental or neurological disabilities, but it is useful in comparison with other anthropometrics to assess proportionality. The ratio of mid-arm to head circumference is a less commonly used index of proportionality.
Body composition is a more sensitive indicator of infant nutritional status than measures of size. Depending on the method used, measurements can provide the mass of lean tissue, fat tissue, total body water, and bone. Methods vary greatly in terms of invasiveness, feasibility, cost, technology, need for trained personnel, accuracy, reliability, and precision. The most feasible methods for assessing infant body composition include anthropometry (e.g., skinfold measurements), dual X-ray absorptiometry (DEXA), and isotope dilution. A recent review concluded that for intergroup comparisons, skinfold thicknesses were useful, but for individual infant assessments, DEXA was recommended (Koo, 2000). In the absence of reference data based on a large sample of infants, the interpretation of body
TABLE 6-1 Limitations and Advantages of Recommended Growth Assessments
Recommended Assessment
Limitations
Advantages
Rate of weight gain
Nonspecific
Good global measure of infant growth and health, easy to measure reliably
Rate of length gain
Difficult to measure accurately, deficits less likely unless weight is also compromised
Provides important additional information about linear/skeletal growth and proportionality
Head circumference
Nonspecific
Easy to measure accurately, adequate global measure of head and brain growth and proportionality
Body composition
Difficult to measure accurately, best method requires expensive equipment (dual-energy X-ray absorptiometry)
More precise information about possible metabolic effects of ingredients, possible better long-term predictor of health outcomes
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TABLE 6-2 Limitations and Advantages of Common Measurements of Body Composition
Method
Relevant Papers/Measurement
Limitations
Advantages
Skinfold
Schmelzle and Fusch (2002); body fat in neonates and young infants: validation of skinfold thickness versus dual-energy X-ray absorptiometry
Can be inaccurate
Rapid, low cost
Dual-energy X-ray absorptiometry
Butte et al. (1999); fat mass in infants and toddlers: comparability of total body water, total body potassium, total body electrical conductivity, and dual-energy X-ray absorptiometry
Requires expensive equipment
Rapid, precisely estimates bone mineral content, fat mass, and lean body mass
Isotope dilution
Expensive and needs specialized equipment
Noninvasive, safe
composition outcomes should rest on the comparison of groups in randomized controlled trials. Additional information on the methods used to assess body composition is provided in Table 6-2.
RECOMMENDATION: Growth studies should include precise and reliable measurements of weight and length velocity and head circumference. Duration of measurements should cover at least the period when infant formula remains the sole source of nutrients in the infant diet. Appropriate measures of body composition also require assessment.
Defining Normal Growth
The purpose of growth assessment is to determine whether a child is growing “normally.” The definition of normal, inadequate, or excess growth rests largely on comparison of individual measurements with reference data that represent the distribution of sizes found in healthy infants of a given age and sex. While there is no clear cut point to define a size at which there is an abrupt elevation in risk of poor outcomes, measurements that fall above the 95th or below the 5th percentiles of an accepted reference are typically cause for concern. While short periods of abnormal growth rate may not be of concern, low or high rates over several months may be related to increased morbidity risk, both in the long and short term. Therefore a single measurement of attained size at a given age is not a sufficient measure of growth. Repeated, appropriately spaced measurements are needed to calculate growth rate. A clinical assessment of infant growth for the purpose of determining the safety of an ingredient new to infant formulas must therefore be based on a longitudinal study, with repeated measures at relatively frequent intervals during the period when growth is most rapid and during the time period when formula serves as the sole source of infant nutrition.
Identifying Appropriate Comparison Groups
As discussed in Chapter 3, there are challenges in selecting appropriate comparison groups for clinical studies to assess the safety of infant formulas. The gold standard design—the double-blind, randomized, controlled trial—randomly assigns comparable groups of
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Structural magnetic resonance imaging
Assesses size and changes in brain volume for different regions of the brain (Posner, 2001)
Can be administered during the first year (Singer, 2001)
Has shown sensitivity to exposure to toxic substances during the first year (Mattson and Riley, 1995)
Documented links to CNS structure or function (Posner, 2001)
Analogous measures available at the nonhuman primate level (Hopkins and Rilling, 2000)
Assesses specific functions (Posner, 2001)
Not recommended for level 2 assessments, but can be used as the alternate instrument for level 3 assessments
Excellent spatial resolution of brain structure, but requires a heavy investment in equipment and training (Posner, 2001)
There would have to be a large impact of a new ingredient to reduce global or regional brain volume; an impact of this degree should have been detected in preclinical studies
Functional magnetic resonance imaging
When a brain region is activated to deal with stimulation or task demands, there is increased blood and oxygen flow to that region; magnetic changes associated with increased hemoglobin flow to a specific brain region can be recorded as an index of increased activation of the region involved (Nelson and Bloom, 1997)
Documented links to CNS structure or function (Posner, 2001)
Analogous measures available at the nonhuman primate level (Nakahara et al., 2002; Sereno, 1998)
Assesses specific functions (Nelson and Bloom, 1997)
Meets few selection criteria; use only under limited or special circumstances
Because of the need to lie quietly and the high noise levels, it is not applicable for children under 6 y; however some recent studies using sedation of infants and passive presentation of stimulation have reported success with this procedure in infancy (Bookheimer, 2000) especially in napping postprandial babies (< 2 mo of age), but sedation would not be appropriate because of effects on cognitive processing (e.g., chloral hydrate)
Brain stem-evoked response
EEG response of auditory brainstem responses to sound stimuli; allows assessment of the functional level of noncortical areas involved in hearing (Cobo-Lewis and Eilers, 2001)
Can be administered during the first year (Cobo-Lewis and Eilers, 2001)
Has shown sensitivity to exposure to toxic substances during the first year (Needlman et al., 1995)
Analogous measures available at the nonhuman level (Needlman et al., 1995)
Assesses specific functions (Cobo-Lewis and Eilers, 2001)
Use only under limited or special circumstances
High number of false negatives and positives limit the utility (Molfese and Molfese, 2001)
Does allow potential assessment of conduction speed of neural circuits involved in auditory processing (Roncagliolo et al., 1998)
NOTE: The petitioner (or manufacturer), in consultation with the expert panel, will determine which tests are required based on a thorough analysis of the potential effects of the new ingredient.
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to toxic substances and can have long-term predictive value. These measures also are important because bidirectional brain-behavior links exist. In the case of neurological and behavioral assessment, the committee recommends that a hierarchy of three levels of clinical assessment be applied.
REFERENCES
AAP (American Academy of Pediatrics). 1988. Clinical Testing of Infant Formulas with Respect to Nutritional Suitability for Term Infants. Report to the FDA. Committee on Nutrition. Elk Grove Village, IL: AAP.
AAP. 1997. Breast feeding and the use of human milk. Pediatrics 100:1035–1039.
ADA (American Dietetic Association). 2001. Position of the American Dietetic Association: Breaking the barriers to breastfeeding. J Am Diet Assoc 101:1213–1220.
Adams J. 1993. Structure-activity and dose-response relationships in the neural and behavioral teratogenesis of retinoids. Neurotoxicol Teratol 15:193–202.
Alessandri SM, Sullivan MW, Imaizumi S, Lewis M. 1993. Learning and emotional responsivity in cocaine-exposed infants. Dev Psychol 29:989–997.
Alessandri SM, Sullivan MW, Bendersky M, Lewis M. 1995. Temperament in cocaine-exposed infants. In: Lewis M, Bendersky M, eds. Mothers, Babies, and Cocaine: The Role of Toxins in Development. Hillsdale, NJ: Lawrence Erlbaum Associates. Pp. 273–286.
Antonowicz I, Lebenthal E. 1977. Developmental pattern of small intestinal enterokinase and disaccharidase activities in the human fetus. Gastroenterology 72:1299–1303.
Arant BS Jr, Edelmann CM Jr, Spitzer A. 1972. The congruence of creatinine and inulin clearances in children: Use of Technicon Autoanalyzer. J Pediatr 81:559–561.
Arendt R, Singer L, Angelopoulos J, Bass-Busdiecker O, Mascia J. 1998. Sensorimotor development in cocaine-exposed infants. Infant Behav Dev 21:627–640.
Armstrong J, Reilly JJ. 2002. Child Health Information Team. Breastfeeding and lowering the risk of childhood obesity. Lancet 359:2003–2004.
Auestad N, Halter R, Hall RT, Blatter M, Bogle ML, Burks W, Erickson JR, Fitzgerald KM, Dobson V, Innis SM, Singer LT, Montalto MB, Jacobs JR, Qiu W, Bornstein MH. 2001. Growth and development in term infants fed long-chain polyunsaturated fatty acids: A double-masked, randomized, parallel, prospective, multivariate study. Pediatrics 108:372–381.
Auricchio S, Rubino A, Murset G. 1965. Intestinal glycosidase activities in the human embryo, fetus and newborn. Pediatrics 35:944–965.
Banks MS, Salapatek P. 1983. Infant visual perception. In: Mussen PH, ed. Handbook of Child Psychology. Formerly Carmichael’s Manual of Child Psychology. 4th ed, vol 2. New York: John Wiley & Sons. Pp. 435–571.
Bates JE. 1989. Concepts and measures of temperament. In: Kohnstamm GA, Bates JE, Rothbart MK, eds. Temperament in Childhood. Chichester, Eng: John Wiley & Sons. Pp. 3–26.
Bates JE. 2001. Adjustment style in childhood as a product of parenting and temperament. In: Wachs TD, Kohnstamm GA, eds. Temperament in Context. Mahwah, NJ: Lawrence Erlbaum Associates. Pp. 173–200.
Bates JE, Bayles K. 1984. Objective and subjective components in mothers’ perceptions of their children from age 6 months to 3 years. Merrill Palmer Q 30:111–130.
Bathurst K, Gottfried AW. 1987. Untestable subjects in child development research: Developmental implications. Child Dev 58:1135–1144.
Batres LA, Maller ES. 2001. Laboratory assessment of liver function and injury in children. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. 2nd ed. Philadelphia: Lippincott Williams & Wilkins. Pp. 155–169.
Bayley N. 1969. Manual for the Bayley Scales of Infant Development. New York: Psychological Corporation.
Bayley N. 1993. The Bayley Scales of Infant Development. 2nd ed. New York: Psychological Corporation.
Bellinger DC. 1995. Interpreting the literature on lead and child development: The neglected role of the “experimental system.” Neurotoxicol Teratol 3:201–212.
Bendersky M, Lewis M. 2001. The Bayley scales of infant development. Is there a role in biobehavioral assessment? In: Singer LT Zeskind P, eds. Biobehavioral Assessment of the Infant. New York: Guilford Press. Pp. 443–459.
Bendersky M, Alessandri SM, Lewis M. 1996. Emotions in cocaine-exposed infants. In: Lewis M, Sullivan MW, eds. Emotional Development in Atypical Children. Mahwah, NJ: Lawrence Erlbaum Associates. Pp. 89–108.
OCR for page 151
Infant Formula: Evaluating the Safety of New Ingredients
Berenthal BI, Campos JJ, Barrett KC. 1984. Self-produced locomotion. In: Emde RN, Harmon RJ, eds. Continuities and Discontinuities in Development. New York: Plenum Press. Pp. 175–210.
Binley K, Askham Z, Iqball S, Spearman H, Martin L, de Alwis M, Thrasher AJ, Ali RR, Maxwell PH, Kingsman S, Naylor S. 2002. Long-term reversal of chronic anemia using a hypoxia-regulated erythropoietin gene therapy. Blood 100:2406–2413.
Bjarnason I, Macpherson A, Hollander D. 1995. Intestinal permeability: An overview. Gastroenterology 108:1566–1581.
Bloom L. 1998. Language acquisition in its developmental context. In: Kuhn D, Siegler RS, eds. Handbook of Child Psychology. 5th ed, vol 2. New York: John Wiley & Sons. Pp. 309–370.
Boehm G, Jakobsson I, Raiha N. 1992. Macromolecular absorption in small-for-gestational-age infants. Acta Paediatr 81:864–867.
Bookheimer SY. 2000. Methodological issues in pediatric neuroimaging. Ment Retard Dev Disabil Res Rev 6:161–165.
Brugnara C, Platt OS. 1998. The neonatal erythrocyte and its disorders. In: Nathan DG, Orkin SH, eds. Nathan and Oski’s Hematology of Infancy and Childhood. 5th ed. Philadelphia: WB Saunders. Pp. 19–52.
Bushnell EW. 1985. The decline of visually guided reaching during infancy. Infant Behav Dev 8:139–155.
Bushnell EW, Boudreau JP. 1993. Motor development and the mind: The potential role of motor abilities as a determinant of aspects of perceptual development. Child Dev 64:1005–1021.
Butte NF. 2001. The role of breastfeeding in obesity. Pediatr Clin North Am 48:189–198.
Butte N, Heinz C, Hopkinhson J, Wong W, Shypailo R, Ellis K. 1999. Fat mass in infants and toddlers: Comparability of total body water, total body potassium, total body electrical conductivity, and dual-energy x-ray absorptiometry. J Pediatr Gastroentrol Nutr 29:184–189.
Butte NF, Wong WW, Hopkinson JM, O’Brian Smith E, Ellis KJ. 2000. Infant feeding mode affects early growth and body composition. Pediatrics 106:1355–1366.
Campbell SK, Osten ET, Kolobe THA, Fisher AG. 1993. Development of the test of infant motor performance. Phys Med Rehabil Clin N Am 4:541–550.
Canada. 2001. Departmental Consolidation of the Food and Drugs Act and the Food and Drug Regulations (Food and Drugs Act). Ottawa: Minister of Public Works and Government Services Canada.
Carey WB, McDevitt SC. 1978. Revision of the infant temperament questionnaire. Pediatrics 61:735–739
Case-Smith J, Bigsby R. 2001. Motor assessment. In: Singer LT, Zeskind P, eds. Biobehavioral Assessment of the Infant. New York: Guilford Press. Pp. 423–441
Chandler LS, Andrews MS, Swanson MW. 1980. Movement Assessment of Infants. A Manual. Rolling Bay, WA: Chandler, Andrews, and Swanson.
Chasnoff IJ, Burns KA, Burns WJ. 1987. Cocaine use in pregnancy: Perinatal morbidity and mortality. Neurotoxicol Teratol 9:291–293.
Christensen L. 1996. Diet-Behavior Relationships: Focus on Depression. Washington, DC: American Psychological Association.
Cobo-Lewis AB, Eilers R. 2001. Auditory assessment in infancy. In: Singer LT, Zeskind P, eds. Biobehavioral Assessment of the Infant. New York: Guilford Press. Pp. 95–106.
Colombo J. 1993. Infant Cognition: Predicting Later Intellectual Functioning. Vol. 5. Newbury Park, CA: Sage Publications.
Cory-Slechta DA. 1990. Bridging experimental animal and human behavioral toxicology studies. In: Russell RW, Flattau PE, Pope AM, eds. Behavioral Measures of Neurotoxicity. Report of a Symposium. Washington, DC: National Academy Press. Pp. 137–158.
Cowin I, Emmett P. 2000. Cholesterol and triglyceride concentrations, birthweight and central obesity in pre-school children. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Int J Obes Relat Metab Disord 24:330–339.
Dawson G, Ashman SB. 2000. On the origins of a vulnerability to depression: The influence of the early social environment on the development of psychobiological systems related to risk for affective disorder. In: Nelson CA, ed. The Minnesota Symposia on Child Psychology. Vol 31: The Effects of Early Adversity on Neurobehavioral Development. Mahwah, NJ: Lawrence Erlbaum Associates. Pp. 245–279.
Dewey KG, Heinig MJ, Nommsen LA, Lonnerdal B. 1991. Adequacy of energy intake among breast-fed infants in the DARLING study: Relationships to growth velocity, morbidity, and activity levels. Davis Area Research on Lactation, Infant Nutrition and Growth. J Pediatr 119:538–547.
Dewey KG, Heinig MJ, Nommsen LA, Peerson JM, Lonnerdal B. 1992. Growth of breast-fed and formula-fed infants from 0 to 18 months: The DARLING Study. Pediatrics 89:1035–1041.
Dewey KG, Heinig MJ, Nommsen LA, Peerson JM, Lonnerdal B. 1993. Breast fed infants are leaner than formula fed infants at 1 y of age: The DARLING study. Am J Clin Nutr 57:140–145.
OCR for page 152
Infant Formula: Evaluating the Safety of New Ingredients
Diamond A. 1990. The development and neural bases of memory functions as indexed by the AB and delayed response tasks in human infants and infant monkeys. Ann N Y Acad Sci 608:267–309.
Dietz WH. 1994. Critical periods in childhood for the development of obesity. Am J Clin Nutr 59:955–959.
Di Lorenzo C, Piepsz A, Ham H, Cadranel S. 1987. Gastric emptying with gastroesophageal reflux. Arch Dis Child 62:449–453.
Dinari G, Rosenbach Y, Zahavi I, Sivan Y, Nitzan M. 1984. Random fecal β1-antitrypsin excretion in children with intestinal disorders. Am J Dis Child 138:971–973.
DiPietro JA, Larson SK, Porges SW. 1987. Behavioral and heart rate pattern differences between breast-fed and bottle-fed neonates. Dev Psychol 4:467–474.
DiPietro JA, Suess PE, Wheeler JS, Smouse PH, Newlin DB. 1995. Reactivity and regulation in cocaine-exposed neonates. Infant Behav Dev 18:407–414.
Dougherty TM, Haith MM. 1997. Infant expectations and reaction times as predictors of childhood speed and processing and IQ. Dev Psychol 33:146–155.
Doussard-Roosevelt JA, McClenny BD, Porges SW. 2001. Neonatal cardiac vagal tone and school-age developmental outcome in very low birth weight infants. Dev Psychobiol 38:56–66.
Dupont C, Barau E, Molkhou P, Raynaud F, Barbet JP, Dehennin L. 1989. Food-induced alterations of intestinal permeability in children with cow’s milk-sensitive enteropathy and atopic dermatitis. J Pediatr Gastroenterol Nutr 8:459–465.
Ellison PH. 1994. The INFANIB. A Reliable Method for the Neuromotor Assessment of Infants. Tucson, AZ: Therapy Skill Builders.
Ellison PH, Horn JL, Browning CA. 1985. Construction of an Infant Neurological International Battery (INFANIB) for the assessment of neurological integrity in infancy. Phys Ther 65:1326–1331.
Esmon CT. 1998. Blood coagulation. In: Nathan DG, Orkin SH, eds. Nathan and Oski’s Hematology of Infancy and Childhood. Philadelphia: WB Saunders. Pp. 1531–1556.
European Task Force on Atopic Dermatitis. 1993. Severity scoring of atopic dermatitis: The SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology 186:23–31.
Evangelista de Duffard AM, Duffard R. 1996. Behavioral toxicology, risk assessment, and chlorinated hydrocarbons. Environ Health Perspect 104:353–360.
Fagan JF 3rd, Singer LT, Montie JE, Shepherd PA. 1986. Selective screening device for the early detection of normal or delayed cognitive development in infants at risk for later mental retardation. Pediatrics 78:1021–1026.
Fagen JW, Ohr PS. 2001. Learning and memory in infancy. Habituation, instrumental conditioning, and expectancy formation. In: Singer L, Zeskind P, eds. Biobehavioral Assessment of the Infant. New York: Guilford Press. Pp. 233–273.
Falth-Magnusson K, Kjellman N-IM, Odelram H, Sundqvist T, Magnusson K-E. 1986. Gastrointestinal permeability in children with cow’s milk allergy: Effect of milk challenge and sodium-cromoglycate as assessed with polyethyleneglycols (PEG 400 and 1000). Clin Allergy 16:543–551.
FDA (Food and Drug Administration). 1996. Current good manufacturing practice, quality control procedures, quality factors, notification requirements, and records and reports, for the production of infant formula; Proposed rule. Fed Regist 61:36153–36219.
Fee B, Weil WM. 1960. Body composition of a diabetic offspring by direct analysis. Am J Dis Child 100:718.
Fernald A. 2001. Hearing, listening, and understanding: Auditory development in infancy. In: Bremner G, Fogel A, eds. Blackwell Handbook of Infant Development. Malden, MA: Blackwell Publishers. Pp. 35–70.
Fernandes J, Vos CE, Douwes AC, Slotema E, Degenhart HJ. 1978. Respiratory hydrogen excretion as a parameter for lactose malabsorption in children. Am J Clin Nutr 31:597–602.
Fetters L, Tronick EZ. 1996. Neuromotor development of cocaine-exposed and control infants from birth through 15 months: Poor and poorer performance. Pediatrics 98:938–943.
Fomon SJ. 1993. Nutrition of Normal Infants. St. Louis: Mosby.
Fomon SJ, Ziegler EE, Thomas LN, Jensen RL, Filer LJ Jr. 1970. Excretion of fat by normal full-term infants fed various milks and formulas. Am J Clin Nutr 23:1299–1313.
Fomon SJ, Nelson SE, Ziegler EE. 2000. Retention of iron by infants. Ann Rev Nutr 1:273–290.
Forse RA, Bell SJ, Blackburn GL, Kabbash LG, eds. 1994. Diet, Nutrition, and Immunity. Boca Raton, FL: CRC Press.
Fox NA, Henderson HA, Rubin KH, Calkins SD, Schmidt LA. 2001. Continuity and discontinuity of behavioral inhibition and exuberance: Psychophysiological and behavioral influences across the first four years of life. Child Dev 72:1–21.
OCR for page 153
Infant Formula: Evaluating the Safety of New Ingredients
Fredrikzon B, Hernell O, Blackberg L, Olivecrona T. 1978. Bile salt-stimulated lipase in human milk: Evidence of activity in vivo and of a role in the digestion of milk retinal esters. Pediatr Res 12:1048–1052.
Garza C, de Onis M. 1999. A new international growth reference for young children. Am J Clin Nutr 70:169S– 172S.
Gaylor DW, Bolger PM, Schwetz BA. 1998. U.S. Food and Drug Administration perspective of the inclusion of effects of low-level exposures in safety and risk assessment. Environ Health Perspect 106:391–394.
Gleim GW. 2000. Renal responses to exercise and training. In: Garrett WE, Krikendall DT, eds. Exercise and Sport Science. Philadelphia: Lippincott Williams & Wilkins. Pp. 217–225.
Godfrey KM, Barker DJ. 2001. Fetal programming and adult health. Public Health Nutr 4:611–624.
Goldsmith DI, Novello AC. 1992. Clinical laboratory evaluation of renal function. In: Edelmann CM, ed. Pediatric Kidney Disease. Boston: Little, Brown. P. 471.
Goldsmith HH, Rothbart MK. 1991. Contemporary instruments for assessing early temperament by questionnaire and in the laboratory. In: Strelau J, Angleitner A, eds. Explorations in Temperament. International Perspectives on Theory and Measurement. New York: Plenum Press. Pp. 249–272.
Goldsmith HH, Losoya SH, Bradshaw DL, Campos JJ. 1994. Genetics of personality: A twin study of the five-factor model and parent-offspring analysis. In: Halverson CF, Kohnstamm GA, Martin RP, eds. The Developing Structure of Temperament and Personality from Infancy to Adulthood. Hillsdale, NJ: Lawrence Erlbaum Associates. Pp. 241–265.
Goldsmith HH, Lemery KS, Aksan N, Buss KA. 2000. Temperamental substrates of personality development. In: Molfese VJ, Molfese DL, eds. Temperament and Personality Development Across the Lifespan. Mahwah, NJ: Lawrence Erlbaum Associates. Pp. 1–32.
Grandjean P, White RF, Weihe P. 1996. Neurobehavioral epidemiology: Application in risk assessment. Environ Health Perspect 104:397–400.
Grant JD, Bezerra JA, Thompson SH, Lemen RJ, Koldovsky O, Udall JN. 1989. Assessment of lactose absorption by measurement of urinary galactose. Gastroenterology 97:895–899.
Grantham-McGregor SM, Walker SP, Chang S. 2000. Nutritional deficiencies and later behavioural development. Proc Nutr Soc 59:47–54.
Grant-Webster KS, Gunderson VM, Brubacher TM. 1990. Behavioral assessment of young nonhuman primates: Perceptual-cognitive development. Neurotoxicol Teratol 12:543–546.
Greenough WT, Black JE. 1992. Induction of brain structure by experience: Substrates for cognitive development. In: Gunnar MR, Nelson CA, eds. Developmental Behavioral Neuroscience. The Minnesota Symposia on Child Psychology. Vol. 24. Hillsdale, NJ: Lawrence Erlbaum Associates. Pp. 155–200.
Gunnar MR. 2000. Early adversity and the development of stress reactivity and regulation. In: Nelson CA, ed. The Effects of Early Adversity on Neurobehavioral Development. The Minnesota Symposia on Child Psychology. Vol. 31. Mahwah, NJ: Lawrence Erlbaum Associates, Publishers. Pp. 163–200.
Gunnar MR, White BP. 2001. Salivary cortisol measures in infant and child assessment. In: Singer LT, Zeskind PS, eds. Biobehavioral Assessment of the Infant. New York: Guilford Press. Pp. 167–189.
Guo SM, Roche AF, Fomon SJ, Nelson SE, Chumlea WC, Rogers RR, Baumgartner RN, Ziegler EE, Siervogel RM. 1991. Reference data on gains in weight and length during the first two years of life. J Pediatr 119:355–362.
Hadorn B, Zoppi G, Shmerling DH, Prader A, McIntyre I, Anderson CM. 1968. Quantitative assessment of exocrine pancreatic function in infants and children. J Pediatr 73:39–50.
Hamilton J. 2000. The pediatric patient: Early development and the digestive system. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, eds. Pediatric Gastrointestinal Disease. 3rd ed. Hamilton, Ont: BC Decker. Pp. 1–11.
Handin RI. 1998. Blood platelets and the vessel wall. In: Nathan DG, Orkin SH, eds. Nathan and Oski’s Hematology of Infancy and Childhood. Philadelphia: WB Saunders. Pp 1511–1529.
Harris SR, Brady DK. 1986. Infant neuromotor assessment instruments: A review. Phys Occup Ther Pediatr 6:121–153.
Harris SR, Swanson MW, Andrews MS, Sells CJ, Robinson NM, Bennett FC, Chandler LS. 1984. Predictive validity of the “movement assessment of infants.” J Dev Behav Pediatr 5:336–342.
Hediger ML, Overpeck MD, Ruan WJ, Troendle JF. 2000. Early infant feeding and growth status of US-born infants and children aged 4–71 mo: Analyses from the Third National Health and Nutrition Examination Survey, 1988–1994. Am J Clin Nutr 72:159–167.
Herskowitz J, Rosman NP. 1985. Pseudoseizure in a child with epilepsy. Am J Psychiatry 142:390–391.
Heyman M, Grasset E, Ducroc R, Desjeux JF. 1988. Antigen absorption by the jejunal epithelium of children with cow’s milk allergy. Pediatr Res 24:197–202.
OCR for page 154
Infant Formula: Evaluating the Safety of New Ingredients
Higley JD, Suomi SJ. 1989. Temperamental reactivity in non-human primates. In: Kohnstamm GA, Bates JE, Rothbart MK, eds. Temperament in Childhood. Chichester, Eng: John Wiley & Sons. Pp. 153–167.
Hill RM, Hegemier S, Tennyson LM. 1989. The fetal alcohol syndrome: A multihandicapped child. Neurotoxicology 10:585–596.
Holm S, Andersson Y, Gothefors L, Lindbert T. 1992. Increased protein absorption after gastroenteritis in children. Acta Paediatr 81:585–588.
Holt PG, Macaubas C, Stumbles PA, Sly PD. 1999. The role of allergy in the development of asthma. Nature 402:B12–B17.
Hopkins WD, Rilling JK. 2000. A comparative MRI study of the relationship between neuroanatomical asymmetry and interhemispheric connectivity in primates: Implication for the evolution of functional asymmetries. Behav Neurosci 4:739–748.
Hurt H, Brodsky NL, Betancourt L, Braitman LE, Malmud E, Giannetta J. 1995. Cocaine-exposed children: Follow-up through 30 months. J Dev Behav Pediatr 16:29–35.
Huynh H, Couper R. 2000. Pancreatic function tests. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, eds. Pediatric Gastrointestinal Disease. 3rd ed. Hamilton, Ont: BC Decker. Pp. 1515–1528.
Hypponen E, Virtanen SM, Kenward MG, Knip M, Akerblom HK. 2000. Obesity, increased linear growth, and risk of type 1 diabetes in children. Diabetes Care 23:1755–1760.
IOM (Institute of Medicine). 1991. Nutrition During Lactation. Washington, DC: National Academy Press.
IOM. 1997. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press.
IOM. 2001. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press.
Jacobs DS, Blakemore C. 1988. Factors limiting the postnatal development of visual acuity in the monkey. Vision Res 28:947–958.
Jacobson JL, Jacobson SW. 1996. Prospective, longitudinal assessment of developmental neurotoxicity. Environ Health Perspect 104:275–283.
Jacobson SW. 1998. Specificity of neurobehavioral outcomes associated with prenatal alcohol exposure. Alcohol Clin Exp Res 22:313–320.
Jacobson SW, Jacobson JL. 2000. Teratogenic insult and neurobehavioral function in infancy and childhood. In: Nelson CA, ed. The Minnesota Symposia on Child Psychology. Vol 31: The Effects of Early Adversity on Neurobehavioral Development. Mahwah, NJ: Lawrence Erlbaum Associates. Pp. 61–112.
Jacobson SW, Jacobson JL, Sokol RJ, Martier SS, Chiodo LM. 1996. New evidence for neurobehavioral effects of in utero cocaine exposure. J Pediatr 129:581–590.
Jakobsson I, Lindberg T, Lothe L, Axelsson I, Benediktsson B. 1986. Human alpha-lactalbumin as a marker of macromolecular absorption. Gut 27:1029–1034.
Jensen C, Prager T, Fraley J, Chen H, Anderson R, Heird W. 1997. Effects of dietary linoleic/alpha-linolenic acid ratio or growth and visual function of term infants. J Pediatr 131:200–209.
Johnson MH. 2001. Functional brain development in humans. Nat Rev Neurosci 2:475–483.
Jusczyk PW. 1985. The high-amplitude sucking technique as a methodological tool in speech perception research. In: Gottlieb G, Krasnegor NA, eds. Measurement of Audition and Vision in the First Year of Postnatal Life: A Methodological Overview. Norwood, NJ: Ablex Publishing. Pp. 195–222.
Juvonen P, Jakobsson I, Lindberg T. 1990. Macromolecular absorption and cows milk allergy. Arch Dis Child 65:300–303.
Kaltenbach KA, Finnegan LP. 1989. Prenatal narcotic exposure: Perinatal and developmental effects. Neurotoxicology 10:597–604.
Kaneko WM, Phillips EL, Riley EP, Ehlers CL. 1996. EEG findings in Fetal Alcohol Syndrome and Down Syndrome children. Electroencephalogr Clin Neurophysiol 98:20–28.
Karpen SJ, Suchy FJ. 2001. Structural and functional development of the liver. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. Philadelphia: Lippincott Williams & Wilkins. Pp. 3–21.
Kay AB. 2001. Allergy and allergic diseases. First of two parts. N Engl J Med 344:30–37.
Kindermann TA. 1993. Fostering independence in mother-child interactions: Longitudinal changes in contingency patterns as children grow competent in developmental tasks. Int J Behav Dev 16:513–535.
Kohnstamm GA, Bates JE, Rothbart MK, eds. 1989. Temperament in Childhood. Chichester, Eng: John Wiley & Sons.
Kok EJ, Kuiper HA. 2003. Comparative safety assessment for biotech crops. Trends Biotechnol 21:439–444.
Koo WW. 2000. Body composition measurements during infancy. Ann N Y Acad Sci 904:383–392.
OCR for page 155
Infant Formula: Evaluating the Safety of New Ingredients
Kramer MS, Guo T, Platt RW, Shapiro S, Collet JP, Chalmers B, Hodnett E, Sevkovskaya Z, Dzikovich I, Vanilovich I. 2002. Breastfeeding and infant growth: Biology or bias? Pediatrics 110:343–347.
Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, Mei Z, Curtin LR, Roche AF, Johnson CL. 2000. CDC growth charts: United States. Adv Data 314:1–27.
Laughlin NK, Bushnell PJ, Bowman RE. 1991. Lead exposure and diet: Differential effects on social development in the rhesus monkey. Neurotoxicol Teratol 13:429–440.
Lawson KR, Ruff HA. 2001. Focused attention: Assessing a fundamental cognitive process in infancy. In: Singer LT, Zeskind PS, eds. Biobehavioral Assessment of the Infant. New York: Guilford Press. Pp. 3–17.
Leeson CP, Kattenhorn M, Deanfield JE, Lucas A. 2001. Duration of breast feeding and arterial distensibility in early adult life: Population based study. Br Med J 322:643–647.
Lester BM, Tronick EZ. 2001. Behavioral assessment scales. The NICU Network Neurobehavioral Scale, the Neonatal Behavioral Assessment Scale, and the Assessment of the Preterm Infant’s Behavior. In: Singer LT, Zeskind PS, eds. Biobehavioral Assessment of the Infant. New York: Guilford Press. Pp. 363–380.
Lester BM, Freier K, LaGasse L. 1995. Prenatal cocaine exposure and child outcome: What do we really know? In: Lewis M, Bendersky M, eds. Mothers, Babies, and Cocaine: The Role of Toxins in Development. Hillsdale, NJ: Lawrence Erlbaum Associates. Pp. 19–39.
Lindberg T. 1966. Intestinal dipeptidases: Characterization, development and distribution of intestinal dipeptidases of the human foetus. Clin Sci 30:505–515.
Lindsay RS, Cook V, Hanson RL, Salbe AD, Tataranni A, Knowler WC. 2002. Early excess weight gain of children in the Pima Indian population. Pediatrics 109:E33.
Lohman TG, Roche AF, Martorell R. 1988. Anthropometric Standardization Reference Manual. Champaign, IL: Human Kinetics Books.
Lothe L, Ivarsson SA, Ekman R, Lindberg T. 1990. Motilin and infantile colic. A prospective study. Acta Paediatr Scand 7:410–416.
Lozoff B, Klein NK, Nelson EC, McClish DK, Manuel M, Chacon ME. 1998. Behavior of infants with iron-deficiency anemia. Child Dev 69:24–36.
Maffei HV, Metz G, Bampoe V, Shiner M, Herman S, Brook CG. 1977. Lactose intolerance, detected by the hydrogen breath test, in infants and children with chronic diarrhoea. Arch Dis Child 52:766–767.
Majamaa H, Miettinen A, Laine S, Isolauri E. 1996. Intestinal inflammation in children with atopic eczema: Faecal eosinophil cationic protein and tumour necrosis factor-alpha as non-invasive indicators of food allergy. Clin Exp Allergy 26:181–187.
Marshall DH, Fox NA. 2001. Electroencephalographic assessment and human brain maturation. A window into emotional and cognitive development in infancy. In: Singer LT, Zeskind PS, eds. Biobehavioral Assessment of the Infant. New York: Guilford Press. Pp. 341–356.
Martin RP, Wisenbaker J, Huttunen M. 1994. Review of factor analytic studies of temperament measures based on the Thomas-Chess structural model: Implications for the big five. In: Halverson CF Jr, Kohnstamm GA, eds. The Developing Structure of Temperament and Personality from Infancy to Adulthood. Hillsdale, NJ: Lawrence Erlbaum Associates. Pp. 157–172.
Masten AS, Coatsworth JD. 1998. The development of competence in favorable and unfavorable environments. Lessons from research on successful children. Am Psychol 53:205–220.
Matheny AP Jr. 1989. Temperament and cognition: Relations between temperament and mental test scores. In: Kohnstamm GA, Bates JE, Rothbart MK, eds. Temperament in Childhood. Chichester, Eng: John Wiley & Sons. Pp. 263–282.
Matheny AP Jr. 1991. Play assessment of infant temperament. In: Schaefer CE, Gitlin K, Sandgrund A, eds. Play Diagnosis and Assessment. New York: John Wiley & Sons. Pp. 39–63.
Matheny AP Jr, Phillips K. 2001. Temperament and context: Correlates of home environment with temperament continuity and change, new born to 30 months. In: Wachs TD, Kohnstamm GA, eds. Temperament in Context. Mahwah, NJ: Lawrence Erlbaum Associates. Pp. 81–101.
Mattson SM, Riley EP. 1995. Prenatal exposure to alcohol. What the images reveal. Alcohol Health Res World 19:273–278.
Mayer DL, Arendt RE. 2001. Visual acuity assessment in infancy. In: Singer LT, Zeskind PS, eds. Biobehavioral Assessment of the Infant. New York: Guilford Press. Pp. 81–94.
Mayes LC, Bornstein MH. 1995. Developmental dilemmas for cocaine-abusing parents and their children. In: Lewis M, Bendersky M, eds. Mothers, Babies, and Cocaine: The Role of Toxins in Development. Hillsdale, NJ: Lawrence Erlbaum Associates. Pp. 251–272.
Mayes LC, Cicchetti DV. 1995. Prenatal cocaine exposure and neurobehavioral development: How subjects lost to follow-up bias study results. Child Neuropsychol 1:128–139.
OCR for page 156
Infant Formula: Evaluating the Safety of New Ingredients
Mayes LC, Bornstein MH, Chawarska K, Granger RH. 1995. Information processing and developmental assessments in 3-month-old infants exposed prenatally to cocaine. Pediatrics 95:539–545.
McCall RB. 1994. What process mediates predictions of childhood IQ from infant habituation and recognition memory? Speculations on the roles of inhibition and rate of information processing. Intelligence 18:107–125.
McCall RB, Appelbaum MI. 1991. Some issues of conducting secondary analyses. Dev Psychol 27:911–917.
McCall RB, Carriger MS. 1993. A meta-analysis of infant habituation and recognition memory performance as predictors of later IQ. Child Dev 64:57–79.
McMurray RG, Hackney AC. 2000. Endocrine responses to exercise and training. In: Garrett WE, Krikendall DT, eds. Exercise and Sport Science. Philadelphia: Lippincott Williams & Wilkins. Pp. 135–161.
Milani-Comparetti A, Gidoni EA. 1967. Routine developmental examination in normal and retarded children. Dev Med Child Neurol 9:631–638.
Miller LJ, Roid GH. 1994. The T.I.M.E. Toddler and Infant Motor Evaluation. A Standardized Assessment. San Antonio: Therapy Skill Builders.
Molfese DL, Molfese VJ. 2001. Cortical electrophysiology and language processes in infancy. In: Singer LT, Zeskind PS, eds. Biobehavioral Assessment of the Infant. New York: Guilford Press. Pp. 323–338.
Montgomery RK, Mulberg AE, Grand RJ. 1999. Development of the human gastrointestinal tract: Twenty years of progress. Gastroenterology 116:702–731.
Moore JM, Wilson WR, Thompson G. 1977. Visual reinforcement of head-turn responses in infants under 12 months of age. J Speech Hear Disord 42:328–334.
Nakahara K, Hayashi T, Konishi S, Miyashita Y. 2002. Functional MRI of macaque monkeys performing a cognitive set-shifting task. Science 295:1532–1536.
Needlman R, Frank DA, Augustyn M, Zuckerman BS. 1995. Neurophysiological effects of prenatal cocaine exposure: Comparison of human and animal investigations. In: Lewis M, Bendersky M, eds. Mothers, Babies, and Cocaine: The Role of Toxins in Development. Hillsdale, NJ: Lawrence Erlbaum Associates. Pp. 229–250.
Nelson CA. 1994. Neural bases of infant temperament. In: Bates JE, Wachs TD, eds. Temperament: Individual Differences at the Interface of Biology and Behavior. Washington, DC: American Psychological Association. Pp. 47–82.
Nelson CA. 1995. The ontogeny of human memory: A cognitive neuroscience perspective. Dev Psychol 31:723–738.
Nelson CA, Bloom FE. 1997. Child development and neuroscience. Child Dev 5:970–987.
Nelson CA, Wewerka S, Thomas KM, Tribby-Walbridge S, deRegnier R, Georgieff M. 2000. Neurocognitive sequelae of infants of diabetic mothers. Behav Neurosci 114:950–956.
Nelson CA, Bloom FE, Cameron JL, Amaral D, Dahl RE, Pine D. 2002. An integrative, multidisciplinary approach to the study of brain-behavior relations in the context of typical and atypical development. Dev Psychopathol 14:499–520.
Nelson SE, Rogers RR, Ziegler EE, Fomon SJ. 1989. Gain in weight and length during early infancy. Early Hum Dev 19:223–239.
Neuspiel DR. 1995. The problem of confounding in research on prenatal cocaine effects on behavior and development. In: Lewis M, Bendersky M, eds. Mothers, Babies, and Cocaine: The Role of Toxins in Development. Hillsdale, NJ: Lawrence Erlbaum Associates. Pp. 95–109.
Norman A, Strandvik B, Ojamae O. 1972. Bile acids and pancreatic enzymes during absorption in the newborn. Acta Paediat Scand 61:571–576.
O’Connor MJ, Sigman M, Kasari C. 1993. Interactional model for the association among maternal alcohol use, mother-infant interaction, and infant cognitive development. Infant Behav Dev 16:177–192.
OFAS (Office of Food Additive Safety). 2001. Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food. Redbook II-Draft. Washington, DC: OFAS, Center for Food Safety and Applied Nutrition, Food and Drug Administration.
OFAS. 2003. Redbook 2000. Toxicological Principles for the Safety of Food Ingredients. Online. Center for Food Safety and Applied Nutrition, Food and Drug Administration. Available at http://www.cfsan.fda.gov/~redbook/red-toca.html. Accessed November 19, 2003.
Olsho LW, Koch EG, Halpin CF, Carter EA. 1987. An observer-based psychoacoustic procedure for use with young infants. Dev Psychol 23:627–640.
Ong KK, Ahmed ML, Emmett PM, Preece MA, Dunger DB. 2000. Association between postnatal catch-up growth and obesity in childhood: Prospective cohort study. Br Med J 320:967–971.
Pelletier DL, Frongillo EA Jr, Habicht JP. 1993. Epidemiologic evidence for a potentiating effect of malnutrition on child mortality. Am J Public Health 83:1130–1133.
Perman JA, Barr RG, Watkins JB. 1978. Sucrose malabsorption in children: Noninvasive diagnosis by interval breath hydrogen determination. J Pediatr 93:17–22.
OCR for page 157
Infant Formula: Evaluating the Safety of New Ingredients
Pinero D, Jones B, Beard J. 2001. Variations in dietary iron alter behavior in developing rats. J Nutr 131:311–318.
Piper MC, Darrah J. 1994. Alberta Infant Motor Scale: Construction of a Motor Assessment Tool for the Developing Infant. Philadelphia: WB Saunders Company. Pp. 25–35.
Plancoulaine S, Charles MA, Lafay L, Tauber M, Thibult N, Borys JM, Eschwege E, Laventie Ville Sante Study Group. 2000. Infant-feeding patterns are related to blood cholesterol concentration in prepubertal children aged 5–11 y: The Fleurbaix-Laventie Ville Santé Study. Eur J Clin Nutr 54:114–119.
Porges SW, Doussard-Roosevelt JA, Portales AL, Greenspan SI. 1996. Infant regulation of the vagal ‘brake’ predicts child behavior problems: A psychobiological model of social behavior. Devel Psychobiol 29:697–712.
Porter FL. 2001. Vagal tone. In: Singer LT, Zeskind PS, eds. Biobehavioral Assessment of the Infant. New York: Guilford Press. Pp. 109–124.
Posner MI. 2001. The developing human brain. Dev Sci 4:253–387.
Rao R, Georgieff MK. 2000. Early nutrition and brain development. In: Nelson C, ed. The Minnesota Symposia on Child Psychology. The Effects of Adversity on Neurobehavioral Development. Vol 31. Mahway, NJ: Lawrence Erlbaum Associates. Pp. 1–30.
Robb TA, Davidson GP. 1981. Advances in breath hydrogen quantitation in paediatrics: Sample collection and normalization to constant oxygen and nitrogen levels. Clin Chim Acta 111:281–285.
Roberton DM, Paganelli R, Dinwiddie R, Levinsky RJ. 1982. Milk antigen absorption in the preterm and term neonate. Arch Dis Child 57:369–372.
Robson AL, Pederson DR. 1997. Predictors of individual differences in attention among low birth weight children. J Dev Behav Pediatr 18:13–21.
Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B. 1998. Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: Delayed maturation of auditory brainstem responses. Am J Clin Nutr 68:683–690.
Rose SA, Feldman JF. 1990. Infant cognition: Individual differences and developmental continuities. In: Colombo J, Fagen J, eds. Individual Differences in Infancy: Reliability, Stability, Prediction. Hillsdale, NJ: Lawrence Erlbaum Associates. Pp. 229–245.
Rose SA, Feldman JF. 1995. Prediction of IQ and specific cognitive abilities at 11 years from infancy measures. Dev Psychol 31:685–696.
Rose SA, Orlian EK. 2001. Visual information processing. In: Singer LT, Zeskind PS, eds. Biobehavioral Assessment of the Infant. New York: Guilford Press. Pp. 274–292.
Rose SA, Feldman JF, Wallace IF, McCarton C. 1989. Infant visual attention: Relation to birth status and developmental outcome during the first 5 years. Dev Psychol 25:560–576.
Rose SA, Feldman JF, Wallace IF, McCarton C. 1991. Information processing at 1 year: Relation to birth status and developmental outcome during the first 5 years. Dev Psychol 5:723–737.
Rossetti Ferreira MC. 1978. Malnutrition and mother-infant asynchrony: Slow mental development. Int J Behav Dev 1:207–219.
Rothbart MK. 1986. Longitudinal observation of infant temperament. Dev Psychol 22:356–365.
Rothbart MK, Bates JE. 1998. Temperament. In: Eisenberg N, ed. Handbook of Child Psychology. 5th ed, vol 3. New York: John Wiley & Sons. Pp. 105–176.
Rothbart MK, Derryberry D, Posner MI. 1994. A psychobiological approach to the development of temperament. In: Bates JE, Wachs TD, eds. Temperament: Individual Differences at the Interface of Biology and Behavior. Washington, DC: American Psychological Association. Pp. 83–116.
Rothbart MK, Derryberry D, Hershey K. 2000. Stability of temperament in childhood: Laboratory infant assessment to parent report at seven years. In: Molfese VJ, Molfese DL, eds. Temperament and Personality Development Across the Life Span. Mahwah, NJ: Lawrence Erlbaum Associates. Pp. 85–118.
Rovee-Collier C, Barr R. 2001. Infant learning and memory. In: Bremner G, Fogel A, eds. Blackwell Handbook of Infant Development. Malden, MA: Blackwell Publishers. Pp. 139–168.
Ruff HA, Rothbart MK. 1996. Attention in Early Development. Themes and Variations. New York: Oxford University Press.
Russell RW. 1992. “Malnutrition” and the vulnerable brain. What a difference a molecule makes. In: Isaacson RL, Jensen KF, eds. The Vulnerable Brain and Environmental Risks. Vol 1. Malnutrition and Hazard Assessment. New York: Plenum Press. Pp. 109–126.
Sampson HA. 1996. Epidemiology of food allergy. Pediatr Allergy Immunol 7:42–50.
Sampson HA. 2000. Peanut allergy. N Engl J Med 346:1294–1299.
Sanderson IR, Walker WA. 1993. Uptake and transport of macromolecules by the intestine: Possible role in clinical disorders (an update). Gastroenterology 104:622–639.
OCR for page 158
Infant Formula: Evaluating the Safety of New Ingredients
Sanson A, Pedlow R, Cann W, Prior M, Oberklaid F. 1996. Shyness ratings: Stability and correlates in early childhood. Int J Behav Dev 19:705–724.
Schmelzle HR, Fusch C. 2002. Body fat neonates and young infants: Validation of skinfold thickness versus dual-energy x-ray absorptimetry. Am J Clin Nutr 76:1096–1100.
Schneider JW, Griffith DR, Chasnoff IJ. 1989. Infants exposed to cocaine in utero: Implications for developmental assessment and intervention. Infants Young Child 2:25–36.
Schore AN. 1994. Affect Regulation and the Origin of the Self. The Neurobiology of Emotional Development. Hillsdale, NJ: Lawrence Erlbaum Associates.
Schrander JJP, Unsalan-Hooyen RWM, Forget PP, Jansen J. 1990. 51Cr EDTA intestinal permeability in children with cow’s milk intolerance. J Pediatr Gastroenterol Nutr 10:189–192.
Scott DT, Janowsky JS, Carroll RE, Taylor JA, Auestad N, Montalto MB. 1998. Formula supplementation with long-chain polyunsaturated fatty acids: Are there developmental benefits? Pediatrics 102:1203–1204.
Scott RB. 2000. Motility disorders. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, eds. Pediatric Gastrointestinal Disease. 3rd ed. Hamilton, Ont: BC Decker. Pp. 103–115.
Sebris SL, Dobson V, Hartmann EE. 1984. Assessment and prediction of visual acuity in 3- to 4-year-old children born prior to term. Hum Neurobiol 3:87–92.
Sereno MI. 1998. Brain mapping in animals and humans. Curr Opin Neurobiol 8:188–194.
Setchell KDR, O’Connell NC. 2001. Disorders of bile acid synthesis and metabolism: A metabolic basis for liver disease. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. Philadelphia: Lippincott Williams & Wilkins. Pp. 701–733.
Shaheen SJ. 1984. Neuromaturation and behavior development: The case of childhood lead poisoning. Develop Psychol 20:542–550.
Shrout PE, Bolger N. 2002. Mediation in experimental and nonexperimental studies. New procedures and recommendations. Psychol Methods 7:422–445.
Sicherer SH, Noone SA, Koerner CB, Christie L, Burks, AW, Sampson HA. 2001. Hypoallergenicity and efficacy of an amino acid based formula in children with cow’s milk and multiple food hypersensitivities. J Pediatr 138:688–693.
Singer LT. 2001. General issues in infant assessment and development. In: Singer LT, Zeskind PS, eds. Biobehavioral Assessment of the Infant. New York: Guilford Press. Pp. 3–17.
Singer L, Arendt R, Farkas K, Minnes S, Huang J, Yamashita T. 1997. Relationship of prenatal cocaine exposure and maternal postpartum psychological distress to child developmental outcome. Dev Psychopathol 9:473–489.
Slater A. 1997. Can measures of infant habituation predict later intellectual ability? Arch Dis Child 77:474–476.
Slater A. 2001. Visual perception. In: Bremner G, Fogel A, eds. Blackwell Handbook of Infant Development. Malden, MA: Blackwell Publishers. Pp. 5–34.
Slota MC. 1983. Neurological assessment of the infant and toddler. Crit Care Nurse 3:87–92.
Smitsman MW. 2001. Action in infancy—Perspectives, concepts, and challenges: The development of reaching and grasping. In: Bremner G, Fogel A, eds. Blackwell Handbook of Infant Development. Malden, MA: Blackwell Publishers. Pp. 71–98.
Sobotka TJ, Ekelman KB, Slikker W Jr, Raffaele K, Hattan DG. 1996. Food and Drug Administration proposed guidelines for neurotoxicological testing of food chemicals. Neurotoxicology 17:825–836.
Sparrow SS, Balla DA, Cicchetti DV. 1984. Vineland Adaptive Behavioral Scales. Circle Pines, MN: American Guidance Service.
Spear LP. 1995. Alterations in cognitive function following prenatal cocaine exposure: Studies in an animal model. In: Lewis M, Bendersky M, eds. Mothers, Babies, and Cocaine: The Role of Toxins in Development. Hillsdale, NJ: Lawrence Erlbaum Associates. Pp. 207–227.
Sperling MA. 1996. Pediatric Endocrinology. Philadelphia: WB Saunders. Pp. 549–584.
Stettler N, Bovert P, Shamlaye H, Zemel BS, Stallings VA, Paccaud F. 2002a. Prevalence and risk factors for overweight and obesity in children from Seycheles, a country in rapid transition: The importance of early growth. Int J Obes Relat Metab Disord 26:214–219.
Stettler N, Zemel BS, Kumanyika S, Stallings VA. 2002b. Infant weight gain and childhood overweight status in a multicenter, cohort study. Pediatrics 109:194–199.
Struthers JM, Hansen RL. 1992. Visual recognition memory in drug-exposed infants. J Dev Behav Pediatr 13:108–111.
Takeda A. 2001. Zinc homeostasis and functions of zinc in the brain. Biometals 14:343–351.
Tanner JM. 1970. Physical growth. In: Mussen PH, ed. Carmichael’s Manual of Child Psychology. 3rd ed, vol 1. New York: John Wiley & Sons. Pp. 77–155.
OCR for page 159
Infant Formula: Evaluating the Safety of New Ingredients
Teller DY, McDonald MA, Preston K, Sebris SL, Dobson V. 1986. Assessment of visual acuity in infants and children: The acuity card procedure. Dev Med Child Neurol 28:779–789.
Thomas DW, Sinatra FR, Merritt RJ. 1981. Random fecal alpha-1-antitrypsin concentration in children with gastrointestinal disease. Gastroenterology 80:776–782.
van de Kamer JH, ten Bokkel Huinink H, Weyers HA. 1949. Rapid method for the determination of fat in feces. J Biol Chem 177:347–355.
Vijayakumar M, Fall CH, Osmond C, Barker DJ. 1995. Birth weight, weight at one year, and left ventricular mass in adult life. Br Heart J 73:363–367.
von Hofsten C. 1991. Structuring of early reaching movements: A longitudinal study. J Mot Behav 23:280–292.
von Hofsten C, Fazel-Zandy S. 1984. Development of visually guided hand orientation in reaching. J Exp Child Psychol 38:208–219.
Vorhees CV. 1986. Principles of behavioral teratology. In: Riley EP, Vorhees CV, eds. Handbook of Behavioral Teratology. New York: Plenum Press. Pp. 23–48.
Wachs TD. 1999. The nature and nurture of child development. Food Nutr Bull 20:7–22.
Wachs TD. 2000. Linking nutrition and temperament. In: Molfese VJ, Molfese DL, eds. Temperament and Personality Development Across the Life Span. Mahwah, NJ: Lawrence Erlbaum Associates. Pp. 57–84.
Wachs TD, Bates JE. 2001. Temperament. In: Bremner G, Fogel A, eds. Blackwell Handbook of Infant Development. Malden, MA: Blackwell Publishers. Pp. 465–501.
Walker WA. 2002. Development of the intestinal mucosal barrier. J Pediatr Gastroenterol Nutr 34:S33–S39.
Watkins JB. 1985. Lipid digestion and absorption. Pediatrics 75:151–156.
Watkins JB, Ingall D, Szczepanik P, Klein PD, Lester R. 1973. Bile-salt metabolism in the newborn. Measurement of pool size and synthesis by stable isotope technique. New Engl J Med 288:431–434.
Weiss B. 1995. Incipient hazards of cocaine: Lessons from environmental toxicology. In: Lewis M, Bendersky M, eds. Mothers, Babies, and Cocaine: The Role of Toxins in Development. Hillsdale, NJ: Lawrence Erlbaum Associates. Pp. 41–55.
Whitaker RC, Wright JA, Pepe MS, Seidel KD, Dietz WH. 1997. Predicting obesity in young adulthood from childhood and parental obesity. N Engl J Med 337:869–873.
WHO (World Health Organization). 2002. The Optimal Duration of Exclusive Breastfeeding. Report of an Expert Consultation. Geneva: WHO.
Wroble M, Mash C, Williams L, McCall R. 2002. Should long chain polyunsaturated fatty acids be added to infant formula to promote development? J App Dev Psychol 23:99–112.
Yajnik CS. 2001. The insulin resistance epidemic in India: Fetal origins, later lifestyle, or both? Nutr Rev 59:1–9.