Long-chain polyunsaturated fatty acids and infant formula.
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Dietary Supplements↗
Biomedical subjects
R Morley
Publications and source records attributed to R Morley.
Syndrome X in 8-y-old Australian children: stronger associations with current body fatness than with infant size or growth.
OBJECTIVE: Syndrome X (clustering of insulin resistance, dyslipidaemia and hypertension) in adults with central obesity has been suggested to be a consequence of poor foetal development. We investigated clustering of syndrome X factors in a sample of 8-y-old Australian children, and whether the clusters were associated with size at birth and childhood obesity. DESIGN: Longitudinal, 1997 follow-up of children enrolled as singleton-born neonates in 1989. SUBJECTS: A total of 298 healthy Australian children (208 boys, 90 girls, age range 7.4-8.9 y). MEASUREMENTS: Anthropometry at birth and at 4 weeks. In 1997, at 8 y of age: fasting insulin and glucose, total and HDL-cholesterol, triglycerides and blood pressure. RESULTS: Adverse levels of insulin and glucose, cholesterol and triglycerides co-existed more often than expected by chance (P<0.01). Three factors were identified in factor analysis: one loading on systolic and diastolic blood pressure ('blood pressure'); a second loading on insulin and glucose ('insulin resistance'); and a third loading negatively on HDL-cholesterol and positively on triglycerides ('dyslipidaemia'). The blood pressure factor was correlated with fatness at age 8 y (eg fat mass estimated from skin folds, r=0.11) and, after adjustment for current size, with birth weight (r=-0.15). Fat mass was also correlated with both 'insulin resistance' (r=0.24) and 'dyslipidaemia' (r=0.19). The increase in 'insulin resistance' (P=0.03) and 'dyslipidaemia' (P<0.01) per category of fat mass was greatest for subjects with higher-than-median subscapular-to-triceps ratio of skin folds. Neither 'insulin resistance' nor 'dyslipidaemia' was associated with anthropometry at birth. CONCLUSIONS: The Syndrome X risk variables clustered among children who had a tendency to deposit fat on the trunk. There was no evidence in this sample that infant size predicts development of the insulin resistance or dyslipidaemic components of the syndrome by age 8.
Adipose Tissue↗
Vitamin D deficiency in veiled or dark-skinned pregnant women.
OBJECTIVES: To determine the vitamin D status of veiled or dark-skinned pregnant women, because of their known increased risk of vitamin D deficiency. DESIGN: An audit of vitamin D status. SETTING: An antenatal clinic in a major metropolitan teaching hospital, Melbourne, Victoria. PARTICIPANTS: Pregnant women attending the clinic who agreed to be screened. MAIN OUTCOME MEASURES: Serum 25-hydroxyvitamin D3 (25OHD3) level at first visit to the antenatal clinic. RESULTS: Of 94 women, 82 were screened. Sixty-six women (80%) had 25OHD3 values below the test reference range (22.5-93.8 nmol/L). CONCLUSIONS: Our findings are a cause for concern, because vitamin D deficient women are at risk of bone disease and their children at risk of neonatal hypocalcaemia and rickets.
Calcifediol↗
Retrospective ethical approval.
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Ethics Committees↗
Impact of low birth weight and cardiovascular risk factors on endothelial function in early adult life.
BACKGROUND: Low birth weight is related to increased risk of coronary heart disease in adults and recently has been associated with vascular endothelial dysfunction in children. We investigated whether the relation between birth weight and endothelial function was still present in early adult life and whether there was an interaction with emerging risk factors. METHODS AND RESULTS: In 315 adults (165 women, 150 men, aged 20 to 28 years), high-resolution ultrasound was used to determine endothelium-dependent and -independent vascular responses of the brachial artery. Vascular measures were related to classic risk factors (smoking history, lipid profile, blood pressure, fasting insulin, exercise capacity, body mass index, and combined risk score) and birth weight. Low birth weight was associated with reduced flow-mediated dilation (coefficient=0.18 kg(-1), 95% CI 0.004 to 0.35, P:=0.04) but not with endothelium-independent dilation. The difference in flow-mediated dilation between the top and bottom fifths of birth weight was the same as between smokers and nonsmokers. Increasing levels of acquired risk factors overwhelmed the association, and there was a significant interaction of risk score with the birth weight-endothelial function relation (coefficient of interaction term [birth weightxrisk score] = -0.12, 95% CI -0.22 to -0.03, P:=0.01). CONCLUSIONS: Low birth weight is associated with endothelial dysfunction in young adults. This is most marked in individuals with lower risk factor profiles and may be relevant to the pathogenesis of atherosclerosis in later life.
Adult↗
Fetal origins of adult disease?
1. Associations between lower birthweight and higher blood pressure, increased risk of type 2 diabetes and coronary heart disease (CHD) have been observed in a number of different populations worldwide. 2. The reason for this is still debated. Some believe that the observed associations can be explained on the basis of differences in postnatal growth, socioeconomic confounding or genetic factors. Two published studies of birthweight and CHD, with information on later size, suggest that both gestational and postnatal exposures are important. Associations between birthweight and blood pressure, seen in cohorts of twins treated as individuals, have generally remained when data are analysed within twin pairs. Furthermore, similar associations are seen in studies of animals with relative genetic homogeneity kept in standard conditions. These findings suggest that neither socioeconomic nor genetic factors are wholly responsible for the observed associations. 3. If then, there is an underlying causal association, two issues are of fundamental importance. First, is fetal growth (for which birthweight is a summary measure) involved in the causal pathway or is the causal factor a fetal exposure independently associated with fetal growth and increased risk of adult cardiovascular disease? The answer is important in terms of our understanding, the potential for intervention and estimation of the public health implications. Second, are the classic risk factors for CHD in the causal chain between fetal exposures or growth and adult CHD? Most prospective studies measure these factors, but their role as intermediates is unproven. 4. Intervention studies are the best way to test causal hypotheses, but our level of understanding is insufficient to justify such studies in humans, so we rely on animal studies to formally test causal hypotheses. In the present paper, we discuss design and statistical issues in relation to animal studies. The challenge in this field is to devise ways to identify and test potential causal hypotheses in humans.
Animals↗
Catch-up growth in small-for-gestational-age term infants: a randomized trial.
BACKGROUND: Small-for-gestational-age (SGA) term infants are at risk of long-term growth deficits. OBJECTIVE: The objectives were to test the hypothesis that postnatal growth in SGA term infants can be altered by dietary intervention and to examine whether there is a critical window for nutritional programming of the growth trajectory during the first 9 mo postnatally. DESIGN: Healthy term (gestation > or =37 wk) infants with birth weights below the 10th centile were randomly assigned to receive standard term formula (TF; n = 147) or nutrient-enriched formula (EF; n = 152) for the first 9 mo; 175 breast-fed SGA term infants formed a reference group. The main outcome measures were weight, length, and occipitofrontal head circumference (OFC) at 9 and 18 mo. RESULTS: The infants fed the EF showed greater gains in length by 9 (1.1 cm; 95% CI: 0.38, 1.79) and 18 (1.0 cm; 0.25, 1.83) mo and in OFC by 9 (0.5 cm; 0.1, 0.9) and 18 (0.6 cm; 0.2, 1.1) mo than did infants fed the TF; the differences were larger in females. The dietary effects were independent of the pattern of growth retardation. Breast-fed infants showed greater gains in weight and OFC by 18 mo than did infants fed the TF; however, these differences disappeared after adjustment for age, parental size, and birth order. CONCLUSIONS: Linear growth and OFC gains in SGA term infants improve after nutritional intervention during the first 9 mo of life and the effects persist for > or =9 mo beyond the intervention period. Further information on whether catch-up growth is beneficial or detrimental to long-term outcomes is required before public health interventions can be recommended.
Analysis of Variance↗
Nutrition and mental development.
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Animals↗
Randomized trial of nutrient-enriched formula versus standard formula for postdischarge preterm infants.
OBJECTIVES: Preterm infants are frequently discharged from the hospital growth retarded and show reduced growth throughout childhood. In a large efficacy and safety trial, we tested the hypothesis that nutritional intervention in the first 9 months postterm would reverse postdischarge growth deficits and improve neurodevelopment without adverse safety outcomes. PARTICIPANTS AND INTERVENTION: Two hundred eighty-four infants (mean gestation: 30.9 weeks) were studied; 229 were randomly assigned a protein, energy, mineral, and micronutrient-enriched postdischarge formula (PDF; N = 113) or standard term formula (TF; N = 116) from discharge (mean 36.5 weeks' postmenstrual age). A reference group (N = 65) was breastfed until at least 6 weeks' postterm. Outcome measures. Anthropometry was performed at 6 weeks and 3, 6, 9, and 18 months. Development was measured at 9 months (Knobloch, Passamanick, and Sherrard's developmental screening inventory) and 18 months (Bayley Scales of Infant Development II; primary outcome) postterm. RESULTS: At 9 months, compared with the TF group, those fed PDF were heavier (difference 370 g; 95% confidence interval [CI]: 84-660) and longer (difference 1.1 cm; 95% CI: 0.3-1.9); the difference in length persisted at 18 months (difference 0.82 cm; 95% CI: -0.04-1.7). There was no effect on head circumference. The effect of diet was greatest in males; at 9 months length deficit with TF was 1.5cm (95% CI: 0.3-2.7), and this remained at 18 months (1.5cm [95% CI: 0.3-2.7]). There was no significant difference in developmental scores at 9 or 18 months, although PDF infants had a 2.8 (-1.3-6.8) point advantage in Bayley motor score scales. At 6 weeks' postterm, exclusively breastfed infants were already 513 g (95% CI: 310-715) lighter and 1.6cm (95% CI: 0.8-2.3) shorter than the PDF group, and they remained smaller up to 9 months' postterm. CONCLUSIONS: 1) Improving postdischarge nutrition in the first 9 months may "reset" subsequent growth-at least until 18 months for body length. We intend to follow-up the children at older ages. The observed efficacy of PDF was not associated with adverse safety outcomes. 2) We cannot reject the hypothesis that postdischarge nutrition benefits motor development and this requires additional study. 3) Our data raise the possibility that breastfed postdischarge preterm infants may require nutritional supplementation, currently under investigation.
Anthropometry↗
Methodological issues in randomized controlled trials.
There is increasing emphasis on the need to practise evidence-based medicine and the strongest evidence comes from well designed and well-conducted randomized controlled trials. Every component is important for the success of a clinical trial; if the design or sample size is inappropriate, then the results of the study will be unreliable, however well the study is conducted. Conversely a well-designed study may founder because of poor outcome measurement or unacceptably high subject loss. The advantages of a well-designed trial apply equally to studies with short term outcomes and to those requiring long-term follow up. This paper therefore focuses on general methodological issues with a discussion, where appropriate, of the special considerations associated with long-term follow-up. This emphasis is motivated by the belief that a trial with methodological weaknesses is both a waste of resources and unethical. Anyone planning to undertake a randomized controlled trial should consult a more comprehensive text [1-4]. Here, some selected issues are highlighted with the choice of topics reflecting the experience and interests of the authors.
Humans↗
Birthweight and social deprivation: influences on serum lipids and fibrinogen.
UNLABELLED: Epidemiological studies have shown that adults with low birthweight have a higher risk of cardiovascular disease and some others have shown that they have a less favourable serum lipid and lipoprotein profile. If cholesterol metabolism were programmed in utero, we would expect to see an influence of birthweight on blood lipids in children. In 422 children aged 11-15 y in Middlesborough, Cleveland, UK, we investigated the association between birthweight and serum lipids and plasma fibrinogen. We also investigated the influence of childhood social deprivation, measured using the Townsend deprivation index, on these measures. CONCLUSIONS: We found a significant inverse association between birthweight and serum triglyceride level, but not with other serum lipid levels. From a regression model we estimate that triglyceride rose by 1.1 mmol l(-1) kg(-1) fall in birthweight after adjustment for sex, current age and weight. Findings were similar in boys and girls separately. This could contribute to the observed inverse association between birthweight and cardiovascular mortality. Social deprivation was associated with higher fibrinogen, but not lipid levels. Our data highlight the importance of considering influences throughout the life course on adult disease.
Adolescent↗
Randomized diet in the neonatal period and growth performance until 7.5-8 y of age in preterm children.
BACKGROUND: Preterm children are at high risk of poor growth performance. In 2 randomized trials, preterm infants fed preterm formula grew better in the neonatal period than those fed banked donor breast milk or standard term formula. OBJECTIVE: Our objective was to test the hypothesis that for preterm infants, the neonatal period is a critical one for programming growth performance and that early diet influences long-term growth. DESIGN: A total of 926 preterm infants were recruited into 2 parallel, randomized trials of neonatal diet. In trial 1, infants were fed either banked donor breast milk or preterm formula whereas in trial 2, infants were fed either standard term formula or preterm formula. Within each trial, the allocated milk was the sole diet for some infants (study A), whereas for others it was a supplement to maternal breast milk, given when not enough expressed breast milk was available (study B). We followed up 781 of 833 survivors (94%) to age 7.5-8 y. Trained assessors obtained anthropometric measurements according to a standard protocol. RESULTS: Despite significantly better neonatal growth performance in infants fed preterm formula (compared with either banked donor breast milk or standard formula), early diet had no influence on weight, height, head circumference, or skinfold thicknesses at 9 or 18 mo postterm or at age 7.5-8 y. CONCLUSIONS: These findings suggest that the preterm period is not a critical window for nutritional programming of growth, which contrasts with evidence from these trials showing that early diet influences later neurodevelopment.
Body Height↗
Mode of delivery and childhood blood pressure.
A number of studies have shown that children born by cesarean section have lower blood pressure during the neonatal period. The aim of this study was to investigate whether mode of delivery influenced childhood blood pressure: at age 7.5 to 8 y in a cohort of 756 children born preterm, at 7 to 9 y in a pilot study of 166 children born at term in the United Kingdom, and in a cohort of 650 Tasmanian children born at term. In the preterm cohort, systolic blood pressure was significantly lower in children born by cesarean section rather than delivered vaginally (99.3+/-10.0 versus 101.4+/-9.4 mm Hg; 95% confidence interval, -0.69 to -3.46; p = 0.003), with a significant trend to having a higher pressure in those born by breech versus forceps versus spontaneous vaginal delivery versus cesarean section. These findings were not replicated in the term cohorts. This raises the hypothesis that there is a sensitive period for programming later blood pressure by factors associated with mode of delivery and that this period does not extend to full-term.
Blood Pressure↗
Clinical safety of iron-fortified formulas.
BACKGROUND: Iron-fortified formulas are recommended throughout infancy and are frequently used beyond, yet safety aspects have been inadequately studied. Iron could theoretically increase pro-oxidant stress, with potential adverse effects, including infection risk, and some clinicians suspect that iron-fortified formulas induce gastrointestinal disturbance. OBJECTIVE: A planned component of a large intervention trial has been to test the hypothesis that infants receiving iron-fortified formula do not have a higher incidence of infections (primary outcome) or gastrointestinal problems (secondary outcome) than infants on low iron-formulas or cow's milk. Methods. Children (n = 493) 9 months old receiving cow's milk were recruited in 3 UK centers and randomized to: 1) cow's milk as before, 2) formula containing.9 mg/L of iron, or 3) an otherwise identical formula but containing 12 mg/L of iron. Children were followed at 3 monthly intervals and the episodes of infections, diarrhea and constipation, and general morbidity to 18 months old were recorded. Hematologic indices of iron status were determined at 18 months old. RESULTS: Serum ferritin concentrations were increased in infants receiving iron-fortified formula but there were no intergroup differences in incidence of infection, gastrointestinal problems, or in general morbidity or weight gain. CONCLUSIONS: We were unable to identify adverse health effects in older infants and toddlers consuming a high iron-containing formula (12 mg/L) even when used in populations with a low incidence of iron deficiency.
Animals↗
Efficacy and safety of long-chain polyunsaturated fatty acid supplementation of infant-formula milk: a randomised trial.
BACKGROUND: We tested whether addition of n-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFA) to infant-formula milk during the first 6 months promotes long-term cognitive and motor development, without adverse consequences. METHODS: We did a double-blind, randomised, controlled, efficacy and safety trial of formula with and without LCPUFAs, with an additional breastfed reference group, in four hospitals in two cities in the UK. The participants were 447 healthy full-term babies. 309 were fed formula (155 without LCPUFAs) and 138 were breastfed for at least 6 weeks. The main outcome measures were: Bayley Mental and Psychomotor Development Indices (MDI, PDI) at 18 months (primary efficacy outcome) and Knobloch, Passamanick, and Sherrards test at 9 months (secondary outcome). Principal safety outcomes were: infection, atopy, growth, and gastrointestinal tolerance. FINDINGS: Babies fed formula with and without LCPUFA did not differ in cognitive or motor development, growth, infection, atopy or tolerance. The mean (95% CI) MDI was 0.5 (-2.7 to 3.8) units and the PDI 0.6 (-1.8 to 3.0) units higher in the supplementation group. Formula-fed infants had similar developmental scores to the breastfed reference group after adjustment for higher social class and maternal education in the latter. INTERPRETATION: There was no evidence of a beneficial or adverse effect on cognitive and motor development or growth up to 18 months. Although no significant differences in safety outcomes were observed, we suggest such data should be collected in future LCPUFA trials. Our trial does not provide support for addition of LCPUFA to standard infant formula but we are now doing further follow-up of this cohort.
Animals↗
Within pair association between birth weight and blood pressure at age 8 in twins from a cohort study.
OBJECTIVES: To study the association between birth weight and blood pressure in children from multiple pregnancies (multiplets), mostly twins, to determine whether maternal or genetic factors are responsible for the association. DESIGN: Cohort study. SETTING: Southern Tasmania. SUBJECTS: 888 children including 104 multiplets (32 monozygotic, 72 dizygotic). MAIN OUTCOME MEASURE: Systolic blood pressure (mm Hg). RESULTS: Blood pressure decreased with birth weight and increased with current body mass. After adjustment for age and body mass, systolic blood pressure changed by -1.94 mm Hg (95% confidence interval -2.89 to -0.98) per 1 kg increase in birth weight of singletons. For multiplets, blood pressure changed by -7.0 mm Hg (-10.1 to -3.9) for each 1 kg increase in birth weight. This was little altered in within pair analyses (-5.3, -13.8 to 3.2) and was similar for both monozygotic (-6.5, -22.5 to 9.4) and dizygotic (-4.9, -15.8 to 6.0) pairs. CONCLUSION: Because the association between birth weight and blood pressure was largely unchanged in within pair analyses, exposures originating in the mother (such as nutritional status) cannot be wholly responsible. The association also remained within monozygotic pairs, suggesting that genetic predisposition is not wholly responsible either. The principal causal pathway must concern mechanisms within the fetoplacental unit. The stronger association in multiplets suggests that factors adversely influencing both blood pressure and birth weight are more prevalent in multiple pregnancies.
Birth Weight↗
Double-blind, randomized trial of a synthetic triacylglycerol in formula-fed term infants: effects on stool biochemistry, stool characteristics, and bone mineralization.
BACKGROUND: The low sn-2 palmitate content of infant formulas results in formation of fatty acid calcium soaps in the stools and reduced calcium absorption. OBJECTIVE: Our objective was to test the hypotheses that increasing the proportion of sn-2 palmitate in formula for term infants would result in greater skeletal mineral deposition and reduced stool hardness. DESIGN: Healthy term neonates were randomly assigned to receive standard formula (n = 103) or formula containing 50% sn-2 palmitate (high-sn-2 formula; n = 100) for 12 wk. One hundred twenty breast-fed infants were also studied. The main outcome measures were 1) radial (single-photon absorptiometry) and whole-body (dual-energy X-ray absorptiometry) bone mineral content (WBBMC) at 12 wk and 2) stool frequency, volume, and consistency at 6 and 12 wk. Secondary outcome measures included stool fatty acid content. RESULTS: Infants receiving high-sn-2 formula had higher WBBMC (128.1 +/- 9.7 compared with 122.7 +/- 10.1 g, adjusted for size and sex), softer stools at 6 and 12 wk, and a lower proportion of stool soap fatty acids than did infants receiving the control formula. Breast-fed infants had adjusted WBBMC values (128.3 +/- 9.1 g) similar to those of infants fed high-sn-2 formula and significantly higher than those of infants fed the control formula. CONCLUSIONS: Changing the stereoisomeric structure of palmitate in infant formula resulted in higher WBBMC, reduced stool soap fatty acids, and softer stools more like those of breast-fed infants. The greater bone mass measured could be important if it persists beyond the trial period; this merits further investigation.
Absorptiometry, Photon↗
Iron fortified follow on formula from 9 to 18 months improves iron status but not development or growth: a randomised trial.
AIMS: Iron deficiency anaemia is associated, in observational studies, with developmental disadvantage. This study tested the hypothesis that feeding iron supplemented formula from 9 to 18 months of age would improve developmental performance. SUBJECTS AND METHODS: 493 healthy children aged 9 months being fed pasteurised cows' milk were recruited from three UK centres. They were randomised to: cows' milk as before, formula containing 0.9 mg/litre iron, or formula containing 1.2 mg/litre iron, until 18 months of age. Bayley mental and psychomotor developmental indices were measured at 18 months, as were growth and haematological indices. RESULTS: Children fed iron fortified formula had higher plasma ferritin concentrations, but there were no significant intergroup differences in development or growth. CONCLUSIONS: There are no developmental or growth advantages in children given iron supplemented formula, but a benefit for a minority who were anaemic, or the possibility that a benefit may emerge at a later age, cannot be excluded.
Anemia, Iron-Deficiency↗