Mary Fewtrell

Fetal origins of adult disease—the hypothesis revisited

The idea that stimuli or insults during critical or sensitive periods in early life can have lifetime consequences is well established in developmental biology and has been termed “programming.”1 The first evidence for programming, obtained over 100 years ago, confirmed the critical period for imprinting in birds.2 Programming stimuli may be generated endogenously (for instance, internal hormonal signals3) or they may be environmental. One important type of environmental programming is that induced by early nutrition. Since McCances studies in the 1960s on the long term effects of early nutrition in rats,4 numerous animal studies have shown that nutrition in infancy or fetal life can induce lifetime effects on metabolism, growth, and neurodevelopment and on major disease processes such as hypertension, diabetes, atherosclerosis, and obesity.5–8 If these phenomena applied in humans, it would be a matter of major public health and clinical importance.nn#### Summary pointsnnThe hypothesis that adult disease has fetal origins is plausible, but much supportive evidence is flawed by incomplete and incorrect statistical interpretationnnWhen size in early life is related to later health outcomes only after adjustment for current size, it is probably the change in size between these points (postnatal centile crossing) rather than fetal biology that is implicatednnEven when birth size is directly related to later outcome, some studies fail to explore whether this is partly or wholly explained by postnatal rather that prenatal factorsnnThese considerations are critical to understanding the biology and timing of “programming,” the direction of future research, and future public health interventionsnnThe considerable research focused on early programming of adult outcomes in humans has taken two approaches: experimental, using early randomised nutritional interventions with prospective follow up (an approach that we have favoured9), and observational. Inferences from data based on observational approaches …

Measuring body composition

Several aspects of body composition, in particular the amount and distribution of body fat and the amount and composition of lean mass, are now understood to be important health outcomes in infants and children. Their measurement is increasingly considered in clinical practice; however, paediatricians are often unsure as to which techniques are appropriate and suitable for application in specific contexts. This article summarises the pros and cons of measurement technologies currently available for paediatric application. Simple techniques are adequate for many purposes, and simple regional data may often be of greater value than “whole body” values obtained by more sophisticated approaches.

How much loss to follow-up is acceptable in long-term randomised trials and prospective studies?

to test early nutritional interventions and prospective observational cohorts. RCTs are generally accepted as methodologically the best approach for informing health policy. They can equalise unknown as well as known confounding factors and so can demonstrate causation; they permit estimation of effect size and so can be used to assess likely economic

Bone densitometry in children assessed by dual x ray absorptiometry: uses and pitfalls

The importance of bone growth and mineralisation during childhood for bone health in adult life is increasingly accepted, with both nutritional factors1 and exercise2 being recognised as influential for normal skeletal development. The appreciation that infancy and childhood are important periods of life for bone development has led to a need for suitable methods for monitoring bone health, both for research purposes and for clinical monitoring of individuals, and hence to an increasing use of bone densitometry in children. This review discusses the role and potential pitfalls of this technique.

Donor Human Milk for Preterm Infants : Current Evidence and Research Directions

ABSTRACT The Committee on Nutrition of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition aims to document the existing evidence of the benefits and common concerns deriving from the use of donor human milk (DHM) in preterm infants. The comment also outlines gaps in knowledge and gives recommendations for practice and suggestions for future research directions. Protection against necrotizing enterocolitis is the major clinical benefit deriving from the use of DHM when compared with formula. Limited data also suggest unfortified DHM to be associated with improved feeding tolerance and with reduced cardiovascular risk factors during adolescence. Presence of a human milk bank (HMB) does not decrease breast-feeding rates at discharge, but decreases the use of formula during the first weeks of life. This commentary emphasizes that fresh own mothers milk (OMM) is the first choice in preterm infant feeding and strong efforts should be made to promote lactation. When OMM is not available, DHM is the recommended alternative. When neither OMM nor DHM is available, preterm formula should be used. DHM should be provided from an established HMB, which follows specific safety guidelines. Storage and processing of human milk reduces some biological components, which may diminish its health benefits. From a nutritional point of view, DHM, like HM, does not meet the requirements of preterm infants, necessitating a specific fortification regimen to optimize growth. Future research should focus on the improvement of milk processing in HMB, particularly of heat treatment; on the optimization of HM fortification; and on further evaluation of the potential clinical benefits of processed and fortified DHM.

Vitamin D in the Healthy European Paediatric Population

ABSTRACT In recent years, reports suggesting a resurgence of vitamin D deficiency in the Western world, combined with various proposed health benefits for vitamin D supplementation, have resulted in increased interest from health care professionals, the media, and the public. The aim of this position paper is to summarise the published data on vitamin D intake and prevalence of vitamin D deficiency in the healthy European paediatric population, to discuss the health benefits of vitamin D and to provide recommendations for the prevention of vitamin D deficiency in this population. Vitamin D plays a key role in calcium and phosphate metabolism and is essential for bone health. There is insufficient evidence from interventional studies to support vitamin D supplementation for other health benefits in infants, children, and adolescents. The pragmatic use of a serum concentration >50 nmol/L to indicate sufficiency and a serum concentration <25 nmol/L to indicate severe deficiency is recommended. Vitamin D deficiency occurs commonly among healthy European infants, children, and adolescents, especially in certain risk groups, including breast-fed infants, not adhering to the present recommendation for vitamin D supplementation, children and adolescents with dark skin living in northern countries, children and adolescents without adequate sun exposure, and obese children. Infants should receive an oral supplementation of 400 IU/day of vitamin D. The implementation should be promoted and supervised by paediatricians and other health care professionals. Healthy children and adolescents should be encouraged to follow a healthy lifestyle associated with a normal body mass index, including a varied diet with vitamin D–containing foods (fish, eggs, dairy products) and adequate outdoor activities with associated sun exposure. For children in risk groups identified above, an oral supplementation of vitamin D must be considered beyond 1 year of age. National authorities should adopt policies aimed at improving vitamin D status using measures such as dietary recommendations, food fortification, vitamin D supplementation, and judicious sun exposure, depending on local circumstances.

Bone mineralization and turnover in preterm infants at 8-12 years of age: The effect of early diet

Our previous studies raised two hypotheses: first that suboptimal early nutrition and second that human milk have enhancing effects on long‐term bone mineralization. To test these hypotheses experimentally, we measured whole body and regional bone mineral content (BMC) and bone mineral density (BMD), using dual‐energy X‐ray absorptiometry and single‐photon absorptiometry, and bone turnover at 8–12 years in 244 preterm children (128 boys) who participated in a prospective randomized study of diet during the neonatal period. Dietary randomizations studied were: banked human milk (BBM, n = 87) versus preterm formula (PTF, n = 96) as the sole diet or as a supplement to mothers expressed breast milk (EBM); PTF (n = 25) versus term formula (TF, n = 36) as sole diet. Ninety‐five term children of the same age were also studied. First, preterm children were shorter and lighter than term children (height SD scores −0.49 (1.1) vs. +0.22 (0.9), weight SD scores −0.41 (1.2) vs. +0.38 (1.0) and had significantly lower whole‐body BMC than their peers; decrements were also evident at some regional sites. These differences disappeared after adjusting for bone area, body size, and pubertal status. Second, children previously randomized to BBM versus PTF or TF versus PTF showed no significant differences in anthropometry, BMC, BMD, or osteocalcin (OC). Third, there was no independent effect of the proportion of EBM on BMC, BMD, or OC and no interaction between randomized diet and the amount of EBM received. Fourth, plasma OC was significantly higher in preterm children than in term children (12.4 vs. 11.0 ng/ml, p < 0.005) and in preterm children who had received a low‐nutrient (BBM/TF) as opposed to a high‐nutrient diet (PTF) during the neonatal period (12.9 vs. 11.9 ng/ml, p = 0.03). In conclusion, preterm children are shorter, lighter, and have lower bone mass than their peers at age 8–12 years. The lower BMC is, however, appropriate for the bone and body size achieved. Despite large differences in early mineral intake, early diet does not affect bone mass in preterm children, and fresh human milk has no specific effect. However, poor nutrition during the neonatal period may result in higher bone formation rates during childhood.

Iron requirements of infants and toddlers

ABSTRACT Iron deficiency (ID) is the most common micronutrient deficiency worldwide and young children are a special risk group because their rapid growth leads to high iron requirements. Risk factors associated with a higher prevalence of ID anemia (IDA) include low birth weight, high cows-milk intake, low intake of iron-rich complementary foods, low socioeconomic status, and immigrant status. The aim of this position paper was to review the field and provide recommendations regarding iron requirements in infants and toddlers, including those of moderately or marginally low birth weight. There is no evidence that iron supplementation of pregnant women improves iron status in their offspring in a European setting. Delayed cord clamping reduces the risk of ID. There is insufficient evidence to support general iron supplementation of healthy European infants and toddlers of normal birth weight. Formula-fed infants up to 6 months of age should receive iron-fortified infant formula, with an iron content of 4 to 8 mg/L (0.6–1.2 mg · kg−1 · day−1). Marginally low-birth-weight infants (2000–2500 g) should receive iron supplements of 1–2 mg · kg−1 · day−1. Follow-on formulas should be iron-fortified; however, there is not enough evidence to determine the optimal iron concentration in follow-on formula. From the age of 6 months, all infants and toddlers should receive iron-rich (complementary) foods, including meat products and/or iron-fortified foods. Unmodified cows milk should not be fed as the main milk drink to infants before the age of 12 months and intake should be limited to <500 mL/day in toddlers. It is important to ensure that this dietary advice reaches high-risk groups such as socioeconomically disadvantaged families and immigrant families.

Body composition in normal weight, overweight and obese children: matched case–control analyses of total and regional tissue masses, and body composition trends in relation to relative weight

Background:Childhood obesity is defined on the basis of weight and height, using body mass index (BMI). There is little detailed information on the body composition characteristic of overweight and obesity.Objective:To evaluate total and regional body composition in overweight, obese and control children aged 7–14 years.Design:Body composition was measured by the four-component model and dual X-ray absorptiometry in 38 age- and sex-matched pairs of obese and control children. Body composition trends were also evaluated by quintile of BMI standard deviation score (SDS) in these and 31 other children (n=107; BMI SDS range −1.0 to 4.3).Results:Obese children were taller than controls (Δ=0.6 SDS; P=0.01) and had greater hydration of fat-free mass (FFM) (Δ=1.8 %, P<0.0001). After adjusting for these variables, obese children had greater FFM, fat mass (FM) and mineral (P<0.0001). Regional analyses showed that these differences were apparent in the arm, leg and trunk, but the three tissues had different proportional distributions of the excess. Fat was primarily in the trunk, but mineral in the leg. FM, FFM, hydration and mineral mass all increased across BMI SDS quintiles (P<0.0001), but the trend for FM was much the steepest.Discussion:The greater weight of obese children is due to excess FFM including mineral as well as excess fatness. Increasing weight has a strong continuous relationship with increasing FM across the whole spectrum of weight.

Effects of size at birth, gestational age and early growth in preterm infants on glucose and insulin concentrations at 9–12 years

Aims/hypothesis. To test the hypothesis that small size for gestation and poor postnatal growth in preterm infants is associated with higher fasting and post-load plasma glucose and insulin concentrations at 9–12 years of age.¶Methods. Prospective follow-up at 9–12 years of 385 preterm children with birth weight less than 1850 g, who had anthropometry recorded at birth, 18 months and 7 years. Fasting plasma glucose, insulin, proinsulin and 32,33 split proinsulin concentrations and glucose and insulin concentrations 30 min after a standard glucose load were measured.¶Results. Post-load glucose concentrations were negatively related to birth weight, independently of gestation or subsequent growth. Fasting split proinsulin and 30-min insulin concentrations were highest in children who showed the greatest increase in weight centile between birth and current follow-up, regardless of gestation. When weight during childhood was included, birthweight centile was, however, no longer statistically significant: concentrations of fasting, split, proinsulin and 30-min insulin were highest in those children who had shown the greatest increase in weight centile between 18 months of age and current follow-up, with no evidence of a greater effect in those who were smallest at 18 months.¶Conclusion/interpretation. Our findings suggest that fetal growth influences plasma glucose 30 min after a glucose load in preterm children at 9–12 years. In contrast, childhood weight gain is the most important factor influencing insulin concentrations and this effect is the same regardless of early size. [Diabetologia (2000) 43: 714–717]