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Growth of late preterm infants fed nutrient-enriched formula to 120 days corrected age-A randomized controlled trial.
Best, KP, Yelland, LN, Collins, CT, McPhee, AJ, Rogers, GB, Choo, J, Gibson, RA, Murguia-Peniche, T, Varghese, J, Cooper, TR, et al
Frontiers in pediatrics. 2023;:1146089
Abstract
OBJECTIVES We aimed to compare the effects of nutrient-enriched formula with standard term formula on rate of body weight gain of late preterm infants appropriately grown for gestational age. STUDY DESIGN A multi-center, randomized, controlled trial. Late preterm infants (34-37 weeks' gestation), with weight appropriate for gestational age (AGA), were randomized to nutrient enriched formula (NEF) with increased calories (22 kcal/30 ml) from protein, added bovine milk fat globule membrane, vitamin D and butyrate or standard term formula 20 kcal/30 ml (STF). Breastfed term infants were enrolled as an observational reference group (BFR). Primary outcome was rate of body weight gain from enrollment to 120 days corrected age (d/CA). Planned sample size was 100 infants per group. Secondary outcomes included body composition, weight, head circumference and length gain, and medically confirmed adverse events to 365 d/CA. RESULTS The trial was terminated early due to recruitment challenges and sample size was substantially reduced. 40 infants were randomized to NEF (n = 22) and STF (n = 18). 39 infants were enrolled in the BFR group. At 120 d/CA there was no evidence of a difference in weight gain between randomized groups (mean difference 1.77 g/day, 95% CI, -1.63 to 5.18, P = 0.31). Secondary outcomes showed a significant reduction in risk of infectious illness in the NEF group at 120 d/CA [relative risk 0.37 (95% CI, 0.16-0.85), P = 0.02]. CONCLUSION We saw no difference in rate of body weight gain between AGA late preterm infants fed NEF compared to STF. Results should be interpreted with caution due to small sample size. CLINICAL TRIAL REGISTRATION The Australia New Zealand Clinical Trials Registry (ACTRN 12618000092291). "mailto:maria.makrides@sahmri.com" maria.makrides@sahmri.com.
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The Influence of Prenatal DHA Supplementation on Individual Domains of Behavioral Functioning in School-Aged Children: Follow-Up of a Randomized Controlled Trial.
Gould, JF, Anderson, PJ, Yelland, LN, Gibson, RA, Makrides, M
Nutrients. 2021;13(9)
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Plain language summary
Omega-3 fatty acids such as docosahexaenoic acid (DHA) are thought to be beneficial for the development of the fetal brain. Women with a singleton pregnancy at <21 weeks’ gestation enrolled in this multicentre, double-blind, randomised controlled trial to assess the fetal neurodevelopment effects of 800 mg/day, which they took until the birth of their children. A follow-up assessment was arranged when the children reached age seven to evaluate their neurodevelopment. Children of women who took DHA supplements showed increased risk scores on hyperactivity, behavioural problems that may impact daily activities, ADHD, peer relationships, Metacognition Indexes, Shift, Inhibit, Monitor, Working Memory, and Organization of Materials scales. Supplementing with high doses of DHA during pregnancy might not have any protective effects on neurodevelopment in women with high baseline DHA levels. However, further robust studies are required to confirm the results to determine the clinical applicability of DHA supplementation in pregnant women. Healthcare professionals can use the results of this study to understand the dose-dependent therapeutic application of DHA and its impact on fetal neurodevelopment.
Abstract
Docosahexaenoic acid (DHA) accumulates in the fetal brain during pregnancy and is thought to have a role in supporting neurodevelopment. We conducted a multicenter, double-blind, randomized controlled trial in women with a singleton pregnancy who were <21 weeks' gestation at trial entry. Women were provided with 800 mg DHA/day or a placebo supplement from trial entry until birth. When children reached seven years of age, we invited parents to complete the Strengths and Difficulties Questionnaire (SDQ), the Behavior Rating Inventory of Executive Function (BRIEF), and the Conners 3rd Edition Attention-Deficit Hyperactivity Disorder (ADHD) Index to assess child behavior and behavioral manifestations of executive dysfunction. There were 543 parent-child pairs (85% of those eligible) that participated in the follow-up. Scores were worse in the DHA group than the placebo group for the BRIEF Global Executive, Behavioral Regulation and Metacognition Indexes, and the Shift, Inhibit, Monitor, Working Memory, and Organization of Materials scales, as well as for the Conners 3 ADHD index, and the SDQ Total Difficulties score, Hyperactivity/Inattention score, and Peer Relationship Problems score. In this healthy, largely term-born sample of children, prenatal DHA supplementation conferred no advantage to childhood behavior, and instead appeared to have an adverse effect on behavioral functioning, as assessed by standardized parental report scales.
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Low-dose thiamine supplementation of lactating Cambodian mothers improves human milk thiamine concentrations: a randomized controlled trial.
Gallant, J, Chan, K, Green, TJ, Wieringa, FT, Leemaqz, S, Ngik, R, Measelle, JR, Baldwin, DA, Borath, M, Sophonneary, P, et al
The American journal of clinical nutrition. 2021;(1):90-100
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Abstract
BACKGROUND Infantile beriberi-related mortality is still common in South and Southeast Asia. Interventions to increase maternal thiamine intakes, and thus human milk thiamine, are warranted; however, the required dose remains unknown. OBJECTIVES We sought to estimate the dose at which additional maternal intake of oral thiamine no longer meaningfully increased milk thiamine concentrations in infants at 24 wk postpartum, and to investigate the impact of 4 thiamine supplementation doses on milk and blood thiamine status biomarkers. METHODS In this double-blind, 4-parallel arm randomized controlled dose-response trial, healthy mothers were recruited in Kampong Thom, Cambodia. At 2 wk postpartum, women were randomly assigned to consume 1 capsule, containing 0, 1.2 (estimated average requirement), 2.4, or 10 mg of thiamine daily from 2 through 24 weeks postpartum. Human milk total thiamine concentrations were measured using HPLC. An Emax curve was plotted, which was estimated using a nonlinear least squares model in an intention-to-treat analysis. Linear mixed-effects models were used to test for differences between treatment groups. Maternal and infant blood thiamine biomarkers were also assessed. RESULTS In total, each of 335 women was randomly assigned to1 of the following thiamine-dose groups: placebo (n = 83), 1.2 mg (n = 86), 2.4 mg (n = 81), and 10 mg (n = 85). The estimated dose required to reach 90% of the maximum average total thiamine concentration in human milk (191 µg/L) is 2.35 (95% CI: 0.58, 7.01) mg/d. The mean ± SD milk thiamine concentrations were significantly higher in all intervention groups (183 ± 91, 190 ± 105, and 206 ± 89 µg/L for 1.2, 2.4, and 10 mg, respectively) compared with the placebo group (153 ± 85 µg/L; P < 0.0001) and did not significantly differ from each other. CONCLUSIONS A supplemental thiamine dose of 2.35 mg/d was required to achieve a milk total thiamine concentration of 191 µg/L. However, 1.2 mg/d for 22 wk was sufficient to increase milk thiamine concentrations to similar levels achieved by higher supplementation doses (2.4 and 10 mg/d), and comparable to those of healthy mothers in regions without beriberi. This trial was registered at clinicaltrials.gov as NCT03616288.
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The influence of DHA supplementation during pregnancy on language development across childhood: Follow-up of a randomised controlled trial.
Gawlik, NR, Makrides, M, Kettler, L, Yelland, LN, Leemaqz, S, Gould, JF
Prostaglandins, leukotrienes, and essential fatty acids. 2020;:102207
Abstract
Numerous randomised controlled trials have explored the effect of docosahexaenoic acid (DHA) supplementation in early life on neurodevelopment, with some suggested positive effects on language. Australian women with a singleton pregnancy <21 weeks' gestation were randomised to receive 800 mg DHA/day or a placebo until birth. A sample of 726 children (all n=96 born preterm, random sample of n=630 born at term) were invited to undergo assessments of language, academic, and language-based cognitive abilities at 1.5, four and seven years of age. No group differences were detected for any group comparison. Exploratory analyses for sex by treatment interactions revealed a possible adverse effect of DHA supplementation on the language of females at 1.5 years but no effects on outcomes at four or seven years. Taken as a whole, evidence of an effect of prenatal DHA supplementation on language abilities across childhood is negligible and could be a chance finding.
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Thiamine dose response in human milk with supplementation among lactating women in Cambodia: study protocol for a double-blind, four-parallel arm randomised controlled trial.
Whitfield, KC, Kroeun, H, Green, T, Wieringa, FT, Borath, M, Sophonneary, P, Measelle, JR, Baldwin, D, Yelland, LN, Leemaqz, S, et al
BMJ open. 2019;(7):e029255
Abstract
INTRODUCTION Thiamine (vitamin B1) deficiency remains a concern in Cambodia where women with low thiamine intake produce thiamine-poor milk, putting their breastfed infants at risk of impaired cognitive development and potentially fatal infantile beriberi. Thiamine fortification of salt is a potentially low-cost, passive means of combating thiamine deficiency; however, both the dose of thiamine required to optimise milk thiamine concentrations as well as usual salt intake of lactating women are unknown. METHODS AND ANALYSIS In this community-based randomised controlled trial, 320 lactating women from Kampong Thom, Cambodia will be randomised to one of four groups to consume one capsule daily containing 0, 1.2, 2.4 or 10 mg thiamine as thiamine hydrochloride, between 2 and 24 weeks postnatal. The primary objective is to estimate the dose where additional maternal intake of thiamine no longer meaningfully increases infant thiamine diphosphate concentrations 24 weeks postnatally. At 2, 12 and 24 weeks, we will collect sociodemographic, nutrition and health information, a battery of cognitive assessments, maternal (2 and 24 weeks) and infant (24 weeks only) venous blood samples (biomarkers: ThDP and transketolase activity) and human milk samples (also at 4 weeks; biomarker: milk thiamine concentrations). All participants and their families will consume study-provided salt ad libitum throughout the trial, and we will measure salt disappearance each fortnight. Repeat weighed salt intakes and urinary sodium concentrations will be measured among a subset of 100 participants. Parameters of Emax dose-response curves will be estimated using non-linear least squares models with both 'intention to treat' and a secondary 'per-protocol' (capsule compliance ≥80%) analyses. ETHICS AND DISSEMINATION Ethical approval was obtained in Cambodia (National Ethics Committee for Health Research 112/250NECHR), Canada (Mount Saint Vincent University Research Ethics Board 2017-141) and the USA (University of Oregon Institutional Review Board 07052018.008). Results will be shared with participants' communities, as well as relevant government and scientific stakeholders via presentations, academic manuscripts and consultations. TRIAL REGISTRATION NUMBER NCT03616288.
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Effects of an antenatal dietary intervention in overweight and obese women on 6 month infant outcomes: follow-up from the LIMIT randomised trial.
Dodd, JM, McPhee, AJ, Deussen, AR, Louise, J, Yelland, LN, Owens, JA, Robinson, JS
International journal of obesity (2005). 2018;(7):1326-1335
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BACKGROUND The immediate impact of providing an antenatal dietary intervention during pregnancy has been extensively studied, but little is known of the effects beyond the neonatal period. Our objective was to evaluate the effect of an antenatal dietary intervention in overweight or obese women on infant outcomes 6 months after birth. METHODS We conducted a follow up study of infants born to women who participated in the LIMIT trial during pregnancy. Live-born infants at 6-months of age, and whose mother provided consent to ongoing follow-up were eligible. The primary follow-up study endpoint was the incidence of infant BMI z-score ≥90th centile for infant sex and age. Secondary study outcomes included a range of infant anthropometric measures, neurodevelopment, general health, and infant feeding. Analyses used intention to treat principles according to the treatment group allocated in pregnancy. Missing data were imputed and analyses adjusted for maternal early pregnancy BMI, parity, study centre, socioeconomic status, age, and smoking status. Outcome assessors were blinded to the allocated treatment group. RESULTS A total of 1754 infants were assessed at age 6 months (Lifestyle Advice n = 869; Standard Care n = 885), representing 82.1% of the eligible sample (n = 2136). There were no statistically significant differences in the incidence of infant BMI z-score ≥90th centile for infants born to women in the Lifestyle Advice group, compared with the Standard Care group (Lifestyle Advice 233 (21.71%) vs. Standard Care 233 (21.90%); adjusted relative risk (aRR) 0.99; 95% confidence interval 0.82 to 1.18; p = 0.88). There were no other effects on infant growth, adiposity, or neurodevelopment. CONCLUSION Providing pregnant women who were overweight or obese with an antenatal dietary and lifestyle intervention did not alter 6-month infant growth and adiposity. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426).
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The effect of an antenatal lifestyle intervention in overweight and obese women on circulating cardiometabolic and inflammatory biomarkers: secondary analyses from the LIMIT randomised trial.
Moran, LJ, Fraser, LM, Sundernathan, T, Deussen, AR, Louise, J, Yelland, LN, Grivell, RM, Macpherson, A, Gillman, MW, Robinson, JS, et al
BMC medicine. 2017;(1):32
Abstract
BACKGROUND Maternal overweight and obesity during pregnancy is associated with insulin resistance, hyperglycaemia, hyperlipidaemia and a low-grade state of chronic inflammation. The aim of this pre-specified analysis of secondary outcome measures was to evaluate the effect of providing antenatal dietary and lifestyle advice on cardiometabolic and inflammatory biomarkers. METHODS We conducted a multicentre trial in which pregnant women who were overweight or obese were randomised to receive either Lifestyle Advice or Standard Care. We report a range of pre-specified secondary maternal and newborn cardiometabolic and inflammatory biomarker outcomes. Maternal whole venous blood was collected at trial entry (mean 14 weeks gestation; non-fasting), at 28 weeks gestation (fasting), and at 36 weeks gestation (non-fasting). Cord blood was collected after birth and prior to the delivery of the placenta. A range of cardiometabolic and inflammatory markers were analysed (total cholesterol, triglycerides, non-esterified fatty acids, high-density lipoprotein cholesterol, insulin, glucose, leptin, adiponectin, C-reactive protein, granulocyte macrophage-colony stimulating factor, interferon gamma, TNF-α, and interleukins 1β, 2, 4, 5, 6, 8, and 10). Participants were analysed in the groups to which they were randomised, and were included in the analyses if they had a measure at any time point. RESULTS One or more biological specimens were available from 1951 women (989 Lifestyle Advice and 962 Standard Care), with cord blood from 1174 infants (596 Lifestyle Advice and 578 Standard Care). There were no statistically significant differences in mean cardiometabolic and inflammatory marker concentrations across pregnancy and in infant cord blood between treatment groups. Estimated treatment group differences were close to zero, with 95% confidence intervals spanning a range of differences that were short of clinical relevance. There was no evidence to suggest that the intervention effect was modified by maternal BMI category. CONCLUSIONS Despite our findings, it will be worth considering potential relationships between cardiometabolic and inflammatory markers and clinical outcomes, including longer-term infant health and adiposity. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry ( ACTRN12607000161426 ; Date Registered 09/03/2007).
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Paternal obesity modifies the effect of an antenatal lifestyle intervention in women who are overweight or obese on newborn anthropometry.
Dodd, JM, Du Plessis, LE, Deussen, AR, Grivell, RM, Yelland, LN, Louise, J, Mcphee, AJ, Robinson, JS, Owens, JA
Scientific reports. 2017;(1):1557
Abstract
The contribution of paternal obesity to pregnancy outcomes has been little described. Our aims were to determine whether the effect of an antenatal maternal dietary and lifestyle intervention among women who are overweight or obese on newborn adiposity, was modified by paternal obesity. We conducted a secondary analysis of a multicenter randomised trial. Pregnant women with BMI ≥25 kg/m2 received either Lifestyle Advice or Standard Care. Paternal anthropometric measures included height, weight, BMI; waist, hip, calf and mid-upper arm circumferences; biceps and calf skinfold thickness measurements (SFTM); and percentage body fat. Newborn anthropometric outcomes included length; weight; head, arm, abdominal, and chest circumferences; biceps, triceps, subscapular, suprailiac, thigh, and lateral abdominal wall SFTM; and percentage body fat. The effect of an antenatal maternal dietary and lifestyle intervention among women who were overweight or obese on neonatal anthropometric measures, was significantly modified by paternal BMI ≥35.0 kg/m2, with a significantly smaller infant triceps, suprailiac, and thigh SFTM, and percent fat mass, compared with that observed in offspring of lean fathers. Further research is required to determine whether our observed associations are causal, and whether paternal weight loss prior to conception is a potential strategy to reduce the intergenerational effects of obesity.
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Seven-Year Follow-up of Children Born to Women in a Randomized Trial of Prenatal DHA Supplementation.
Gould, JF, Treyvaud, K, Yelland, LN, Anderson, PJ, Smithers, LG, McPhee, AJ, Makrides, M
JAMA. 2017;(11):1173-1175
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Association of cord blood vitamin D with early childhood growth and neurodevelopment.
Gould, JF, Anderson, AJ, Yelland, LN, Smithers, LG, Skeaff, CM, Zhou, SJ, Gibson, RA, Makrides, M
Journal of paediatrics and child health. 2017;(1):75-83
Abstract
AIM: The association between fetal vitamin D [25-hydroxyvitamin D (25(OH)D)] exposure and early child growth and neurodevelopment is controversial. The aim of this study was to investigate the association between cord blood 25(OH)D and birth size, childhood growth and neurodevelopment. METHODS Cord blood samples from 1040 Australian women enrolled in a randomised trial of docosahexaenoic acid (DHA) supplementation during pregnancy were analysed for 25(OH)D using mass spectroscopy. Infant length, weight and head circumference were measured at delivery. A sub-sample of 337 infants with cord blood samples were selected for growth and neurodevelopment assessment at 18 months and 4 years of age. Associations between standardised 25(OH)D and outcomes were assessed, taking into account DHA treatment, social and demographic variables. RESULTS Standardised 25(OH)D in cord blood was not associated with length, weight or head circumference at birth, 18 months or 4 years of age. 25(OH)D was not associated with cognitive, motor, social-emotional or adaptive behaviour scores at 18 months, or cognitive score at 4 years of age. A 10 nmol/L increase in cord blood 25(OH)D was associated with a modest increase in average Language scores of 0.60 points at 18 months (adjusted 95% CI 0.04-1.17, P = .04) and 0.68 points at 4 years (adjusted 95% CI 0.07-1.29, P = .03) of age. CONCLUSIONS Cord blood vitamin D was modestly, positively associated with language development in early childhood in our sample, although the magnitude of the association was small. Randomised controlled trials are needed to confirm a causal association and establish the potential clinical significance of the relationship between vitamin D status and language development.