Publications by authors named "Jane E Harding"

176 Publications

Strategies to improve neurodevelopmental outcomes in babies at risk of neonatal hypoglycaemia.

Lancet Child Adolesc Health 2021 Apr 6. Epub 2021 Apr 6.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Neonatal hypoglycaemia is associated with adverse development, particularly visual-motor and executive function impairment, in childhood. As neonatal hypoglycaemia is common and frequently asymptomatic in at-risk babies-ie, those born preterm, small or large for gestational age, or to mothers with diabetes, it is recommended that these babies are screened for hypoglycaemia in the first 1-2 days after birth with frequent blood glucose measurements. Neonatal hypoglycaemia can be prevented and treated with buccal dextrose gel, and it is also common to treat babies with hypoglycaemia with infant formula and intravenous dextrose. However, it is uncertain if screening, prophylaxis, or treatment improves long-term outcomes of babies at risk of neonatal hypoglycaemia. This narrative review assesses the latest evidence for screening, prophylaxis, and treatment of neonates at risk of hypoglycaemia to improve long-term neurodevelopmental outcomes.
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http://dx.doi.org/10.1016/S2352-4642(20)30387-4DOI Listing
April 2021

Effect of Prophylactic Dextrose Gel on Continuous Measures of Neonatal Glycemia: Secondary Analysis of the pre-hPOD Trial.

J Pediatr 2021 Mar 30. Epub 2021 Mar 30.

Liggins Institute, University of Auckland, New Zealand.

Objective: To determine the effects of different doses of prophylactic dextrose gel on glycemic stability assessed using continuous interstitial glucose monitoring (CGM) in the first 48 hours when given to babies at risk of neonatal hypoglycemia.

Study Design: CGM was undertaken for the first 48 hours in 133 infants at risk of hypoglycemia who participated in the pre-hPOD randomized dosage trial of dextrose gel prophylaxis.

Results: Low glucose concentrations were detected in 41% of infants by blood glucose monitoring and 68% by CGM. The mean (SD) duration of low interstitial glucose concentrations was 295 (351) minutes in the first 48 hours. Infants who received any dose of dextrose gel appeared less likely than those who received placebo gel to experience low glucose concentrations (<47mg/dl [2.6mmol/l], p=0.08), particularly if they received a single dose of 200mg/kg (RR 0.70, 95% CI 0.50-0.10, p = 0.049). They also spent a larger proportion of time in the central glucose concentration range of 54 to 72 mg/dl [3 to 4 mmol/l] (any dose: mean (SD) 58.2 (20.3)%; placebo: 50.0 (21.9)%, mean difference 8.20%; 95% CI 0.43-15.9%, p = 0.038). Dextrose gel did not increase recurrent or severe episodes of low glucose concentrations and did not increase the peak glucose concentration. These effects were similar for all trial dosages.

Conclusions: Low glucose concentrations were common in infants at risk of hypoglycemia despite blood glucose monitoring and treatment. Prophylactic dextrose gel reduced the risk of hypoglycemia without adverse effects on glucose stability.
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http://dx.doi.org/10.1016/j.jpeds.2021.03.057DOI Listing
March 2021

Dietary recommendations for women with gestational diabetes mellitus: a systematic review of clinical practice guidelines.

Nutr Rev 2021 Mar 2. Epub 2021 Mar 2.

Affiliation: S.T Mustafa, O.J Hofer, J.E Harding, and C.A. Crowther are with the Liggins Institute, The University of Auckland, Auckland, New Zealand. O.J Hofer is with the Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. C.R Wall is with the Discipline of Nutrition and Dietetics, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.

Context: Dietary advice is the cornerstone of care for women with gestational diabetes mellitus (GDM) to improve maternal and infant health.

Objectives: This study aimed to compare dietary recommendations made in clinical practice guidelines (CPGs) for the management of GDM, evaluate their evidence base, identify research gaps, and assess CPG quality. The PRISMA guidelines were used.

Data Sources: Six databases were searched for CPGs, published between 2000 and 2019, that included dietary advice for the management of GDM.

Data Extraction: Two reviewers independently assessed CPG quality (using the AGREE II tool) with respect to dietary recommendations (their strength, evidence base, and research gaps).

Data Analysis: Of the 31 CPGs, 68% were assessed as low quality, mainly due to lack of editorial independence. Dietary advice was recommended as the first-line treatment by all CPGs, although the dietary recommendations themselves varied and sometimes were contradictory. Most dietary recommendations were strongly made (70%), but they were often based on very low-quality (54%), or low-quality (15%) evidence. Research gaps were identified for all diet-related recommendations.

Conclusion: High-quality research is needed to improve the evidence base and address the research gaps identified.

Systematic Review Registration: PROSPERO registration no. CRD42019147848.
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http://dx.doi.org/10.1093/nutrit/nuab005DOI Listing
March 2021

Early protein intake predicts functional connectivity and neurocognition in preterm born children.

Sci Rep 2021 Feb 18;11(1):4085. Epub 2021 Feb 18.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Nutritional intake can promote early neonatal brain development in very preterm born neonates (< 32 weeks' gestation). In a group of 7-year-old very preterm born children followed since birth, we examined whether early nutrient intake in the first weeks of life would be associated with long-term brain function and neurocognitive skills at school age. Children underwent resting-state functional MRI (fMRI), intelligence testing (Wechsler Intelligence Scale for Children, 5th Ed) and visual-motor processing (Beery-Buktenica, 5th Ed) at 7 years. Relationships were assessed between neonatal macronutrient intakes, functional connectivity strength between thalamic and default mode networks (DMN), and neuro-cognitive function using multivariable regression. Greater functional connectivity strength between thalamic networks and DMN was associated with greater intake of protein in the first week (β = 0.17; 95% CI 0.11, 0.23, p < 0.001) but lower intakes of fat (β = - 0.06; 95% CI - 0.09, - 0.02, p = 0.001) and carbohydrates (β = - 0.03; 95% CI - 0.04, - 0.01, p = 0.003). Connectivity strength was also associated with protein intake during the first month (β = 0.22; 95% CI 0.06, 0.37, p = 0.006). Importantly, greater thalamic-DMN connectivity strength was associated with higher processing speed indices (β = 26.9; 95% CI 4.21, 49.49, p = 0.02) and visual processing scores (β = 9.03; 95% CI 2.27, 15.79, p = 0.009). Optimizing early protein intake may contribute to promoting long-term brain health in preterm-born children.
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http://dx.doi.org/10.1038/s41598-021-83125-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892564PMC
February 2021

Maternal and neonatal glycaemic control after antenatal corticosteroid administration in women with diabetes in pregnancy: A retrospective cohort study.

PLoS One 2021 18;16(2):e0246175. Epub 2021 Feb 18.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Objective: To describe maternal and neonatal glycaemic control following antenatal corticosteroid administration to women with diabetes in pregnancy.

Design: Retrospective cohort study.

Setting: A tertiary hospital in Auckland, New Zealand.

Population: Women with diabetes in pregnancy who received antenatal corticosteroids from 2006-2016.

Methods: Corticosteroid administration, maternal and neonatal glycaemia data were retrieved from electronic patient records. Demographic data were downloaded from the hospital database. Relationships between variables were analysed using multivariate analysis.

Main Outcome Measures: Maternal hyperglycaemia and neonatal hypoglycaemia.

Results: Corticosteroids were administered to 647 of 7317 of women with diabetes (8.8%) who gave birth to 715 babies. After an initial course of corticosteroids, 92% and 52% of women had blood glucose concentrations > 7 and > 10 mmol/L respectively. Median peak blood glucose concentration of approximately 10 mmol/L occurred 9 hours after corticosteroid administration and hyperglycaemia lasted approximately 72 hours. Thirty percent of women gave birth within 72 hours of the last dose of corticosteroids. Babies of women who were hyperglycaemic within 24 hours of birth were more likely to develop hypoglycaemia (< 2.6 mmol/L, OR 1.51 [95% CI 1.10-2.07], p = 0.01) and severe hypoglycaemia (≤ 2.0 mmol/L, OR 2.00 [95% CI 1.41-2.85], p < 0.0001) than babies of non-hyperglycaemic mothers. There was no association between maternal glycaemia within 7 days of the last dose of corticosteroids and neonatal hypoglycaemia.

Conclusions: Hyperglycaemia is common in women with diabetes in pregnancy following antenatal corticosteroid administration. Maternal hyperglycaemia in the 24 hours prior to birth is associated with increased risk of neonatal hypoglycaemia. Limitations included the retrospective study design, so that not all data were available for all women and babies and the glucose testing schedule was variable.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246175PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891747PMC
February 2021

Cost burden and net monetary benefit loss of neonatal hypoglycaemia.

BMC Health Serv Res 2021 Feb 5;21(1):121. Epub 2021 Feb 5.

Liggins Institute, University of Auckland, Private Bag 92019, Grafton, Auckland, 1142, New Zealand.

Background: Neonatal hypoglycaemia is a common but treatable metabolic disorder that affects newborn infants and which, if not identified and treated adequately, may result in neurological sequelae that persist for the lifetime of the patient. The long-term financial and quality-of-life burden of neonatal hypoglycaemia has not been previously examined.

Methods: We assessed the postnatal hospital and long-term costs associated with neonatal hypoglycaemia over 80 year and 18 year time horizons, using a health-system perspective and assessing impact on quality of life using quality-adjusted life year (QALYs). A decision analytic model was used to represent key outcomes in the presence and absence of neonatal hypoglycaemia.

Results: The chance of developing one of the outcomes of neonatal hypoglycaemia in our model (cerebral palsy, learning disabilities, seizures, vision disorders) was 24.03% in subjects who experienced neonatal hypoglycaemia and 3.56% in those who do did not. Over an 80 year time horizon a subject who experienced neonatal hypoglycaemia had a combined hospital and post-discharge cost of NZ$72,000 due to the outcomes modelled, which is NZ$66,000 greater than a subject without neonatal hypoglycaemia. The net monetary benefit lost due to neonatal hypoglycaemia, using a value per QALY of NZ$43,000, is NZ$180,000 over an 80 year time horizon.

Conclusions: Even under the most conservative of estimates, neonatal hypoglycaemia contributes a significant financial burden to the health system both during childhood and over a lifetime. The combination of direct costs and loss of quality of life due to neonatal hypoglycaemia means that this condition warrants further research to focus on prevention and effective treatment.
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http://dx.doi.org/10.1186/s12913-021-06098-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863541PMC
February 2021

Olfactory Cues in Infant Feeds: Volatile Profiles of Different Milks Fed to Preterm Infants.

Front Nutr 2020 15;7:603090. Epub 2021 Jan 15.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Smell is determined by odor-active volatile compounds that bind to specific olfactory receptors, allowing us to discriminate different smells. Olfactory stimulation may assist with digestion and metabolism of feeds in the neonate by activation of the cephalic phase response of digestion. Infants' physiological responses to the smell of different milks suggest they can distinguish between breastmilk and infant formula. We aimed to describe the profile of volatile compounds in preterm breastmilk and investigate how this differed from that of other preterm infant feeding options including pasteurized donor breastmilk, breastmilk with bovine milk-based fortifier, human milk-based products and various infant formulas. Forty-seven milk samples (13 different infant formulas and 34 human milk-based samples) were analyzed. Volatile compounds were extracted using Solid Phase Micro Extraction. Identification and relative quantification were carried out by Gas Chromatography with Mass Spectrometry. Principal Component Analysis (PCA) and one-way Analysis of Variance (ANOVA) with Tukey's HSD (parametric data) or Conover's test (non-parametric data) were used as appropriate to explore differences in volatile profiles among milk types. In total, 122 compounds were identified. Breastmilk containing bovine milk-based fortifier presented the highest number of compounds (109) and liquid formula the lowest (70). The profile of volatile compounds varied with 51 compounds significantly different (adjusted < 0.001) among milk types. PCA explained 47% of variability. Compared to preterm breastmilk, the profile of volatile compounds in breastmilk with added bovine milk-based fortifier was marked by presence of fatty acids and their esters, ketones and aldehydes; infant formulas were characterized by alkyls, aldehydes and furans, and human milk-based products presented high concentrations of aromatic hydrocarbons, terpenoids and specific fatty acids. Sensory-active products of fatty acid oxidation are the major contributors to olfactory cues in infant feeds. Analysis of volatile compounds might be useful for monitoring quality of milk and detection of oxidation products and environmental contaminants. Further research is needed to determine whether these different volatile compounds have biological or physiological effects in nutrition of preterm infants.
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http://dx.doi.org/10.3389/fnut.2020.603090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843498PMC
January 2021

Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial.

PLoS Med 2021 Jan 28;18(1):e1003411. Epub 2021 Jan 28.

Newborn Services, Auckland City Hospital, Auckland, New Zealand.

Background: Neonatal hypoglycemia is common and can cause brain injury. Buccal dextrose gel is effective for treatment of neonatal hypoglycemia, and when used for prevention may reduce the incidence of hypoglycemia in babies at risk, but its clinical utility remains uncertain.

Methods And Findings: We conducted a multicenter, double-blinded, placebo-controlled randomized trial in 18 New Zealand and Australian maternity hospitals from January 2015 to May 2019. Babies at risk of neonatal hypoglycemia (maternal diabetes, late preterm, or high or low birthweight) without indications for neonatal intensive care unit (NICU) admission were randomized to 0.5 ml/kg buccal 40% dextrose or placebo gel at 1 hour of age. Primary outcome was NICU admission, with power to detect a 4% absolute reduction. Secondary outcomes included hypoglycemia, NICU admission for hypoglycemia, hyperglycemia, breastfeeding at discharge, formula feeding at 6 weeks, and maternal satisfaction. Families and clinical and study staff were unaware of treatment allocation. A total of 2,149 babies were randomized (48.7% girls). NICU admission occurred for 111/1,070 (10.4%) randomized to dextrose gel and 100/1,063 (9.4%) randomized to placebo (adjusted relative risk [aRR] 1.10; 95% CI 0.86, 1.42; p = 0.44). Babies randomized to dextrose gel were less likely to become hypoglycemic (blood glucose < 2.6 mmol/l) (399/1,070, 37%, versus 448/1,063, 42%; aRR 0.88; 95% CI 0.80, 0.98; p = 0.02) although NICU admission for hypoglycemia was similar between groups (65/1,070, 6.1%, versus 48/1,063, 4.5%; aRR 1.35; 95% CI 0.94, 1.94; p = 0.10). There were no differences between groups in breastfeeding at discharge from hospital (aRR 1.00; 95% CI 0.99, 1.02; p = 0.67), receipt of formula before discharge (aRR 0.99; 95% CI 0.92, 1.08; p = 0.90), and formula feeding at 6 weeks (aRR 1.01; 95% CI 0.93, 1.10; p = 0.81), and there was no hyperglycemia. Most mothers (95%) would recommend the study to friends. No adverse effects, including 2 deaths in each group, were attributable to dextrose gel. Limitations of this study included that most participants (81%) were infants of mothers with diabetes, which may limit generalizability, and a less reliable analyzer was used in 16.5% of glucose measurements.

Conclusions: In this placebo-controlled randomized trial, prophylactic dextrose gel 200 mg/kg did not reduce NICU admission in babies at risk of hypoglycemia but did reduce hypoglycemia. Long-term follow-up is needed to determine the clinical utility of this strategy.

Trial Registration: ACTRN 12614001263684.
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http://dx.doi.org/10.1371/journal.pmed.1003411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842885PMC
January 2021

Clinical Aspects of Neonatal Hypoglycemia: A Mini Review.

Front Pediatr 2020 8;8:562251. Epub 2021 Jan 8.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Neonatal hypoglycemia is common and a preventable cause of brain damage. The goal of management is to prevent or minimize brain injury. The purpose of this mini review is to summarize recent advances and current thinking around clinical aspects of transient neonatal hypoglycemia. The groups of babies at highest risk of hypoglycemia are well defined. However, the optimal frequency and duration of screening for hypoglycemia, as well as the threshold at which treatment would prevent brain injury, remains uncertain. Continuous interstitial glucose monitoring in a research setting provides useful information about glycemic control, including the duration, frequency, and severity of hypoglycemia. However, it remains unknown whether continuous monitoring is associated with clinical benefits or harms. Oral dextrose gel is increasingly being recommended as a first-line treatment for neonatal hypoglycemia. There is some evidence that even transient and clinically undetected episodes of neonatal hypoglycemia are associated with adverse sequelae, suggesting that prophylaxis should also be considered. Mild transient hypoglycemia is not associated with neurodevelopmental impairment at preschool ages, but is associated with low visual motor and executive function, and with neurodevelopmental impairment and poor literacy and mathematics achievement in later childhood. Our current management of neonatal hypoglycemia lacks a reliable evidence base. Randomized trials are required to assess the effects of different prophylactic and treatment strategies, but need to be adequately powered to assess outcomes at least to school age.
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http://dx.doi.org/10.3389/fped.2020.562251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820332PMC
January 2021

The contributions of intelligence and executive function to behaviour problems in school-age children born very preterm.

Acta Paediatr 2021 Jan 18. Epub 2021 Jan 18.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Aim: To examine the contributions of specific neurocognitive skills to behaviour problems in children born very preterm.

Methods: We assessed children born <30 weeks' gestation or <1500 g at age 7 years using subtests of the Wechsler Intelligence Scale for Children Fourth Edition, performance and questionnaire-based measures of executive function, and Child Behavior Checklist and Teacher Rating Form. We evaluated the contributions of IQ and executive function to behaviour problems and the moderating effect of sex using multiple regression.

Results: The 129 children (mean age = 7.2 years) had lower IQ, inferior executive function and increased internalising problems compared with normative samples. Verbal comprehension skills and working memory were associated with total, internalising and externalising problems at school. Performance-based and questionnaire-based executive function were associated with total and externalising behaviour problems both at home and school. Sex moderated the relationships between information processing and parent-reported total problems, and between teacher-rated executive function and total problems.

Conclusion: Both IQ and executive function are related to behaviour problems in children born very preterm, but the relationships are different in boys and girls. Executive function may be a useful target for intervention.
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http://dx.doi.org/10.1111/apa.15763DOI Listing
January 2021

Alternative Cerebral Fuels in the First Five Days in Healthy Term Infants: The Glucose in Well Babies (GLOW) Study.

J Pediatr 2021 Apr 26;231:81-86.e2. Epub 2020 Dec 26.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Objectives: To determine plasma lactate and beta-hydroxybutyrate (BHB) concentrations of healthy infants in the first 5 days and their relationships with glucose concentrations.

Study Design: Prospective masked observational study in Hamilton, New Zealand. Term, appropriately grown singletons had heel-prick blood samples, 4 in the first 24 hours then twice daily.

Results: In 67 infants, plasma lactate concentrations were higher in the first 12 hours (median, 20; range, 10-55 mg/dL [median, 2.2 mmol/L; range, 1.1-6.2 mmol/L]), decreasing to 12 mg/dL (range, 7-29 mg/dL [median, 1.4 mmol/L; range, 0.8-3.3 mmol/L]) after 48 hours. Plasma BHB concentrations were low in the first 12 hours (median, 0.9 mg/dL; range, 0.5-5.2 mg/dL [median, 0.1 mmol/L; range, 0.05-0.5 mmol/L]), peaked at 48-72 hours (median, 7.3 mg/dL; range, 1.0-25.0 mg/dL [median, 0.7 mmol/L; range, 0.05-2.4 mmol/L]), and decreased by 96 hours (median, 0.9 mg/dL; range, 0.5-16.7 mg/dL [median, 0.1 mmol/L; range, 0.05-1.6 mmol/L]). Compared with infants with plasma glucose concentrations above the median (median, 67 mg/dL [median, 3.7 mmol/L]), those with lower glucose had lower lactate concentrations in the first 12 hours and higher BHB concentrations between 24 and 96 hours. Lower interstitial glucose concentrations were also associated with higher plasma BHB concentrations, but only if the lower glucose lasted greater than 12 hours. Glucose contributed 72%-84% of the estimated potential adenosine triphosphate throughout the 5 days, with lactate contributing 25% on day 1 and BHB 7% on days 2-3.

Conclusions: Lactate on day 1 and BHB on days 2-4 may contribute to cerebral fuels in healthy infants, but are unlikely to provide neuroprotection during early or acute hypoglycemia.

Trial Registration: The Australian and New Zealand Clinical Trials Registry: ACTRN12615000986572.
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http://dx.doi.org/10.1016/j.jpeds.2020.12.063DOI Listing
April 2021

Prolonged transitional neonatal hypoglycaemia: characterisation of a clinical syndrome.

J Perinatol 2020 Dec 5. Epub 2020 Dec 5.

Kidz First, Counties Manukau Health, Auckland, New Zealand.

Background: We performed a case-control study to characterise infants with "prolonged transitional hypoglycaemia".

Methods: Cases were born ≥36 weeks' gestation; had ≥1 hypoglycaemic episode <72 h and ≥72 h; received ongoing treatment for hypoglycaemia ≥72 h; and were without congenital disorders or acute illness. Cases were compared to controls born ≥36 weeks' with brief transitional hypoglycaemia, resolving <72 h.

Results: 39/471 infants screened met case definition: 71.8% were male, 61.5% were small-for-gestational-age (SGA), and most were admitted <6 h. Compared to controls (N = 75), key risk factors for prolonged transitional hypoglycaemia were SGA (OR = 6.4, 95%CI 2.7-15.1), severe/recurrent hypoglycaemia <24 h (OR = 16.7, 95%CI 4.5-16.1), intravenous glucose bolus <24 h (OR = 26.6, 95%CI 9.4-75.1) and maximum glucose delivery rate <48 h of ≥8 mg/kg/min (OR = 25.5, 95%CI 7.7-84.1).

Conclusions: Infants with prolonged transitional hypoglycaemia are predominantly male, SGA and have early severe/recurrent hypoglycaemia requiring glucose boluses and high glucose delivery rates in the first 24-48 h.
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http://dx.doi.org/10.1038/s41372-020-00891-wDOI Listing
December 2020

The relationship between maternal dietary patterns during pregnancy in women with gestational diabetes mellitus and infant appetitive feeding behaviour at 6 months.

Sci Rep 2020 11 25;10(1):20516. Epub 2020 Nov 25.

Liggins Institute, University of Auckland, 85 Park Rd, Grafton, Auckland, 1023, New Zealand.

Early dietary exposure may influence infant appetitive feeding behaviour, and therefore their later health. Maternal diabetes in pregnancy is associated with an increased risk of obesity in the offspring. We, therefore, examined third-trimester dietary patterns of women with gestational diabetes, their offspring's appetitive feeding behaviour at 6 months of age, and relationships between these. We used data from a prospective cohort of women with gestational diabetes and assessed maternal dietary patterns at 36 weeks' gestation using principal component analysis; infant appetitive feeding behaviour at 6 months of age using the Baby Eating Behaviour Questionnaire; and relationships between these using general linear modelling and chi-square tests. In 325 mother-infant dyads, we identified three distinct maternal dietary patterns: 'Junk,' 'Mixed,' and 'Health-conscious.' The maternal 'Health-conscious' pattern was inversely associated with 'enjoyment of food' in their sons (β - 0.24, 95% CI - 0.36 to - 0.11, p = 0.0003), but not daughters (β - 0.02, 95% CI - 0.12 to 0.08, p = 0.70), and was positively associated with 'slowness in eating,' (β 0.13, 95% CI 0.02 to 0.24, p = 0.01). Third-trimester dietary patterns in women with gestational diabetes may have sex-specific effects on infant appetitive feeding behaviour at 6 months of age.
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http://dx.doi.org/10.1038/s41598-020-77388-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689419PMC
November 2020

Effects of maternal periconceptional undernutrition in sheep on offspring glucose-insulin axis function into adulthood.

J Dev Orig Health Dis 2020 Nov 20:1-7. Epub 2020 Nov 20.

Liggins Institute, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.

Maternal periconceptional undernutrition (PCUN) affected fetal pancreatic maturation in late gestation lambs and impaired glucose tolerance in 10-month-old sheep. To examine the importance of the timing of maternal undernutrition around conception, a further cohort was born to PCUN ewes [undernourished for 61 d before conception (PreC), 30 d after conception (PostC), or 61 d before until 30 d after conception (PrePostC)], or normally fed ewes (Control) (n = 15-20/group). We compared glucose tolerance, insulin secretion, and sensitivity at 36 months of age. We also examined protein expression of insulin signalling proteins in muscle from these animals and in muscle from a fetal cohort (132 d of gestation; n = 7-10/group). Adult PostC and PrePostC sheep had higher glucose area under the curve than Controls (P = 0.07 and P = 0.02, respectively), whereas PreC sheep were similar to Controls (P = 0.97). PostC and PrePostC had reduced first-phase insulin secretion compared with Control (P = 0.03 and P = 0.02, respectively). PreC was similar to Control (P = 0.12). Skeletal muscle SLC2A4 protein expression in PostC and PrePostC was increased 19%-58% in fetuses (P = 0.004), but decreased 39%-43% in adult sheep (P = 0.003) compared with Controls. Consistent with this, protein kinase C zeta (PKCζ) protein expression tended to be increased in fetal (P = 0.09) and reduced in adult (P = 0.07) offspring of all PCUN ewes compared with Controls. Maternal PCUN alters several aspects of offspring glucose homeostasis into adulthood. These findings suggest that maternal periconceptional nutrition has a lasting impact on metabolic homeostasis of the offspring.
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http://dx.doi.org/10.1017/S2040174420001063DOI Listing
November 2020

Two-year outcomes after dextrose gel prophylaxis for neonatal hypoglycaemia.

Arch Dis Child Fetal Neonatal Ed 2020 Nov 4. Epub 2020 Nov 4.

Liggins Institute, University of Auckland, Auckland, New Zealand

Objective: To determine the effect of prophylactic dextrose gel for prevention of neonatal hypoglycaemia on neurodevelopment and executive function at 2 years' corrected age.

Design: Prospective follow-up of a randomised trial.

Setting: New Zealand.

Patients: Participants from the pre-hypoglycaemia Prevention with Oral Dextrose (pre-hPOD) trial randomised to one of four dose regimes of buccal 40% dextrose gel or equivolume placebo.

Main Outcome Measures: Coprimary outcomes were neurosensory impairment and executive function. Secondary outcomes were components of the primary outcomes, neurology, anthropometry and health measures.

Results: We assessed 360 of 401 eligible children (90%) at 2 years' corrected age. There were no differences between dextrose gel dose groups, single or multiple dose groups, or any dextrose and any placebo groups in the risk of neurosensory impairment or low executive function (any dextrose vs any placebo neurosensory impairment: relative risk (RR) 0.77, 95% CI 0.50 to 1.19, p=0.23; low executive function: RR 0.50, 95% CI 0.24 to 1.06, p=0.07). There were also no differences between groups in any secondary outcomes. There was no difference between children who did or did not develop neonatal hypoglycaemia in the risk of neurosensory impairment (RR 1.05, 95% CI 0.68 to 1.64, p=0.81) or low executive function (RR 0.73, 95% CI 0.34 to 1.59, p=0.43).

Conclusion: Prophylactic dextrose gel did not alter neurodevelopment or executive function and had no adverse effects to 2 years' corrected age, but this study was underpowered to detect potentially clinically important effects on neurosensory outcomes.
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http://dx.doi.org/10.1136/archdischild-2020-320305DOI Listing
November 2020

Protein supplementation of human milk for promoting growth in preterm infants.

Cochrane Database Syst Rev 2020 09 23;9:CD000433. Epub 2020 Sep 23.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Background: Preterm infants require high protein intake to achieve adequate growth and development. Although breast milk feeding has many benefits for this population, the protein content is highly variable, and inadequate to support rapid infant growth. This is a 2020 update of a Cochrane Review first published in 1999.

Objectives: To determine whether protein-supplemented human milk compared with unsupplemented human milk, fed to preterm infants, improves growth, body composition, cardio-metabolic, and neurodevelopmental outcomes, without significant adverse effects.

Search Methods: We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 8) in the Cochrane Library and MEDLINE via PubMed on 23 August 2019. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection Criteria: Published and unpublished RCTs were eligible if they used random or quasi-random methods to allocate hospitalised preterm infants who were being fed human milk, to additional protein supplementation or no supplementation.

Data Collection And Analysis: Two review authors independently abstracted data, assessed risk of bias and the quality of evidence at the outcome level, using GRADE methodology. We performed meta-analyses, using risk ratio (RR) for dichotomous data, and mean difference (MD) for continuous data, with their respective 95% confidence intervals (CIs). We used a fixed-effect model and had planned to explore potential causes of heterogeneity via subgroup or sensitivity analyses.

Main Results: We included six RCTs, involving 204 preterm infants. The risk of bias for most methodological domains was unclear as there was insufficient detail reported. Low-quality evidence showed that protein supplementation of human milk may increase in-hospital rates of growth in weight (MD 3.82 g/kg/day, 95% CI 2.94 to 4.7; five RCTs, 101 infants; I² = 73%), length (MD 0.12 cm/wk, 95% CI 0.07 to 0.17; four RCTs, 68 infants; I² = 89%), and head circumference (MD 0.06 cm/wk, 95% CI 0.01 to 0.12; four RCTs, 68 infants; I² = 84%). Protein supplementation may lead to longer hospital stays (MD 18.5 days, 95% CI 4.39 to 32.61; one RCT, 20 infants; very low-quality evidence). Very low quality evidence means that the effect of protein supplementation on the risk of feeding intolerance (RR 2.70, 95% CI 0.13 to 58.24; one RCT, 17 infants), or necrotizing enterocolitis (RR 1.11, 95% CI 0.07 to 17.12; one RCT, 76 infants) remains uncertain. No data were available about the effects of protein supplementation on neurodevelopmental outcomes.

Authors' Conclusions: Low-quality evidence showed that protein supplementation of human milk, fed to preterm infants, increased short-term growth. However, the small sample sizes, low precision, and very low-quality evidence regarding duration of hospital stay, feeding intolerance, and necrotising enterocolitis precluded any conclusions about these outcomes. There were no data on outcomes after hospital discharge. Our findings may not be generalisable to low-resource settings, as none of the included studies were conducted in these settings. Since protein supplementation of human milk is now usually done as a component of multi-nutrient fortifiers, future studies should compare different amounts of protein in multi-component fortifiers, and be designed to determine the effects on duration of hospital stay and safety, as well as on long-term growth, body composition, cardio-metabolic, and neurodevelopmental outcomes.
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September 2020

Comparison of risk-of-bias assessment approaches for selection of studies reporting prevalence for economic analyses.

BMJ Open 2020 09 16;10(9):e037324. Epub 2020 Sep 16.

Liggins Institute, The University of Auckland, Auckland, New Zealand

Objectives: Within cost-effectiveness models, prevalence figures can inform transition probabilities. The methodological quality of studies can inform the choice of prevalence figures but no single obvious candidate tool exists for assessing quality of the observational epidemiological studies for selecting prevalence estimates. We aimed to compare different tools to assess the risk of bias of studies reporting prevalence, and develop and compare possible numerical scoring systems using these tools to set a threshold for inclusion of reports of prevalence in an economic analysis of neonatal hypoglycaemia.

Design: Assessments of bias using two tools (Joanna Briggs Institute (JBI) Checklist for Prevalence Studies and a modified version of Risk Of Bias In Non-randomised Studies-of Interventions (ROBINS-I)) were compared for 18 studies relevant to a single setting (neonatal hypoglycaemia). Inclusions of studies for use in a decision analysis model were considered based on summary scores derived from these tools.

Results: Both tools were considered easy to use and produced dispersed scores for each of the 40 study-outcome combinations. The modified ROBINS-I scores were more skewed than the JBI scores, particularly at higher thresholds. The studies selected for inclusion are generally the same using either tool; if 50% was used as the cut-off threshold using the Applicable Score both tools would yield the same results. However, the JBI tool is shorter and may be easier to interpret and apply to studies that do not involve a control group, while the modified ROBINS-I tool assesses more methodological detail in studies that include a control group.

Conclusion: Both tools performed well for systematically assessing studies that report on outcome prevalence and provided similar discrimination between studies for risk of bias. This convergent validity supports use of both tools for the purpose of assessing risk of bias and selecting studies that report prevalence for inclusion in economic analyses.
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http://dx.doi.org/10.1136/bmjopen-2020-037324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497530PMC
September 2020

Carbohydrate supplementation of human milk to promote growth in preterm infants.

Cochrane Database Syst Rev 2020 09 8;9:CD000280. Epub 2020 Sep 8.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Background: Preterm infants are born with low glycogen stores and require higher glucose intake to match fetal accretion rates. In spite of the myriad benefits of breast milk for preterm infants, it may not adequately meet the needs of these rapidly growing infants. Supplementing human milk with carbohydrates may help. However, there is a paucity of data on assessment of benefits or harms of carbohydrate supplementation of human milk to promote growth in preterm infants. This is a 2020 update of a Cochrane Review first published in 1999.

Objectives: To determine whether human milk supplemented with carbohydrate compared with unsupplemented human milk fed to preterm infants improves growth, body composition, and cardio-metabolic and neurodevelopmental outcomes without significant adverse effects.

Search Methods: We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 8) in the Cochrane Library and MEDLINE via PubMed on 22 August 2019. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection Criteria: Published and unpublished controlled trials were eligible if they used random or quasi-random methods to allocate preterm infants in hospital fed human milk to supplementation or no supplementation with additional carbohydrate.

Data Collection And Analysis: Two review authors independently abstracted data and assessed trial quality and the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method. We planned to perform meta-analyses using risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, with their respective 95% confidence intervals (CIs). We planned to use a fixed-effect model and to explore potential causes of heterogeneity via sensitivity analyses. We contacted study authors for additional information.

Main Results: One unblinded, quasi-randomised controlled trial (RCT) assessing effects of carbohydrate supplementation of human milk in the form of a prebiotic in 75 preterm infants was eligible for inclusion in this review. We identified two publications of the same trial, which reported different methods regarding blinding and randomisation. Study authors confirmed that these publications pertain to the same trial, but they have not yet clarified which method is correct. We were unable to reproduce analyses from the data presented. At 30 days of age, the mean weight of preterm infants in the trial was greater in the prebiotic carbohydrate-supplemented group than in the unsupplemented group (MD 160.4 grams, 95% CI 12.4 to 308.4 grams; one RCT, N = 75; very low-quality evidence). We found no evidence of a clear difference in risk of feeding intolerance (RR 0.64, 95% CI 0.36 to 1.15; one RCT, N = 75 infants; very low-quality evidence) or necrotising enterocolitis (NEC) (RR 0.2, 95% CI 0.02 to 1.3; one RCT, N = 75 infants; very low-quality evidence) between the prebiotic-supplemented group and the unsupplemented group. Duration of hospital stay was shorter in the prebiotic group than in the control group at a median (range) of 16 (9 to 45) days (95% CI 15.34 to 24.09) and 25 (11 to 80) days (95% CI 25.52 to 34.39), respectively. No other data were available for assessing effects of carbohydrate supplementation on short- and long-term growth, body mass index, body composition, and neurodevelopmental or cardio-metabolic outcomes.

Authors' Conclusions: We found insufficient evidence on the short- and long-term effects of carbohydrate supplementation of human milk in preterm infants. The only trial included in this review presented very low-quality evidence, and study authors provided uncertain information about study methods and analysis. The evidence may be limited in its applicability because researchers included a small sample of preterm infants from a single centre. However, the outcomes assessed are common to all preterm infants, and this trial demonstrates the feasibility of prebiotic carbohydrate supplementation in upper-middle-income countries. Future trials should assess the safety and efficacy of different types and concentrations of carbohydrate supplementation for preterm infants fed human milk. Although prebiotic carbohydrate supplementation in preterm infants is currently a topic of active research, we do not envisage that further trials of digestible carbohydrates will be conducted, as this is currently done as a component of multi-nutrient human milk fortification. Hence we do not plan to publish any further updates of this review.
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September 2020

Effect of antenatal magnesium sulphate on MRI biomarkers of white matter development at term equivalent age: The magnum study.

EBioMedicine 2020 Sep 25;59:102957. Epub 2020 Aug 25.

Liggins Institute, University of Auckland, Building 503, Level 2, 85 Park Road, Auckland 1142, New Zealand. Electronic address:

Background: Magnesium sulphate given to women immediately prior to very preterm birth protects the perinatal brain, so fewer babies die or develop cerebral palsy. How magnesium sulphate exerts these beneficial effects remains uncertain. The aim of the MagNUM Study was to assess the effect of exposure to antenatal magnesium sulphate on MRI measures of brain white matter microstructure at term equivalent age.

Methods: Nested cohort study within the randomised Magnesium sulphate at 30 to <34 weeks' Gestational age Neuroprotection Trial (MAGENTA). Mothers at risk of preterm birth at 30 to <34 weeks' gestation were randomised to receive either 4 g of magnesium sulphate heptahydrate [8 mmol magnesium ions], or saline placebo, infused over 30 min when preterm birth was planned or expected within 24 h. Participating babies underwent diffusion tensor MRI at term equivalent age. The main outcomes were fractional anisotropy across the white matter tract skeleton compared using Tract-based Spatial Statistics (TBSS), with adjustment for postmenstrual age at birth and at MRI, and MRI site. Researchers and families were blind to treatment group allocation during data collection and analyses.

Findings: Of the 109 participating babies the demographics of the 60 babies exposed to magnesium sulphate were similar to the 49 babies exposed to placebo. In babies whose mothers were allocated to magnesium sulphate, fractional anisotropy was higher within the corticospinal tracts and corona radiata, the superior and inferior longitudinal fasciculi, and the inferior fronto-occipital fasciculi compared to babies whose mothers were allocated placebo (P < 0.05).

Interpretation: In babies born preterm, antenatal magnesium sulphate exposure promotes development of white matter microstructure in pathways affecting both motor and cognitive function. This may be one mechanism for the neuroprotective effect of magnesium sulphate treatment prior to preterm birth.

Funding: Health Research Council of New Zealand.
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http://dx.doi.org/10.1016/j.ebiom.2020.102957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452670PMC
September 2020

Fat supplementation of human milk for promoting growth in preterm infants.

Cochrane Database Syst Rev 2020 08 25;8:CD000341. Epub 2020 Aug 25.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Background: As preterm infants do not experience the nutrient accretion and rapid growth phase of the third trimester of pregnancy, they are vulnerable to postnatal nutritional deficits, including of fat. Consequently, they require higher fat intakes compared to their full term counterparts to achieve adequate growth and development. Human milk fat provides the major energy needs of the preterm infant and also contributes to several metabolic and physiological functions. Although human milk has many benefits for this population, its fat content is highly variable and may be inadequate for their optimum growth and development. This is a 2020 update of a Cochrane Review last published in 2000.

Objectives: To determine whether supplementation of human milk with fat compared with unsupplemented human milk fed to preterm infants improves growth, body composition, cardio-metabolic, and neurodevelopmental outcomes without significant adverse effects.

Search Methods: We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 8) in the Cochrane Library and MEDLINE via PubMed on 23 August 2019. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection Criteria: Published and unpublished randomised controlled trials were eligible if they used random or quasi-random methods to allocate preterm infants fed human milk in hospital to supplementation or no supplementation with additional fat.

Data Collection And Analysis: No new randomised controlled trials matching the selection criteria were found but we extracted data from the previously included trial due to changes in review outcomes from when the protocol was first published. Two reviewers independently abstracted data, assessed trial quality, and the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. We planned to perform meta-analyses using risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, with their respective 95% confidence intervals (CIs). We planned to use a fixed-effect model and to explore potential causes of heterogeneity via sensitivity analyses.

Main Results: One randomised trial involving 14 preterm infants was included. There was no evidence of a clear difference between the fat-supplemented and unsupplemented groups in in-hospital rates of growth in weight (MD 0.6 g/kg/day, 95% CI -2.4 to 3.6; 1 RCT, n = 14 infants, very low-quality evidence), length (MD 0.1 cm/week, 95% CI -0.08 to 0.3; 1 RCT, n = 14 infants, very low-quality evidence) and head circumference (MD 0.2 cm/week, 95% CI -0.07 to 0.4; 1 RCT n = 14 infants, very low-quality evidence). There was no clear evidence that fat supplementation increased the risk of feeding intolerance (RR 3.0, 95% CI 0.1 to 64.3; 1 RCT, n = 16 infants, very low-quality evidence). No data were available regarding the effects of fat supplementation on long-term growth, body mass index, body composition, neurodevelopmental, or cardio-metabolic outcomes.

Authors' Conclusions: The one included trial suggests no evidence of an effect of fat supplementation of human milk on short-term growth and feeding intolerance in preterm infants. However, the very low-quality evidence, small sample size, few events, and low precision diminishes our confidence that these results reflect the true effect of fat supplementation of human milk in preterm infants, and no long-term outcomes were reported. Further high-quality research should evaluate the effect on short and long-term growth, neurodevelopmental and cardio-metabolic outcomes in the context of the development of multicomponent fortifiers. Optimal dosage, adverse effects, and delivery practices should also be evaluated.
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http://dx.doi.org/10.1002/14651858.CD000341.pub3DOI Listing
August 2020

Effects of Neonatal Hyperglycemia on Retinopathy of Prematurity and Visual Outcomes at 7 Years of Age: A Matched Cohort Study.

J Pediatr 2020 08;223:42-50.e2

Department of Paediatrics: Child and Youth Health, University of Auckland, Auckland, New Zealand; Newborn Services, National Women's Health, Auckland City Hospital, Auckland, New Zealand.

Objective: To determine whether neonatal hyperglycemia is associated with retinopathy of prematurity (ROP), visual outcomes, and ocular growth at 7 years of age.

Study Design: Children born preterm (<30 weeks of gestational age) at a tertiary hospital in Auckland, New Zealand, who developed neonatal hyperglycemia (2 blood glucose concentrations ≥153 mg/dL [8.5 mmol/L] 4 hours apart) were matched with children who were not hyperglycemic (matching criteria: sex, gestational age, birth weight, age, socioeconomic status, and multiple birth) and assessed at 7 years of corrected age. The primary outcome, favorable overall visual outcome (visual acuity ≤0.3 logarithm of the minimum angle of resolution, no strabismus, stereoacuity ≤240 arcsec, not requiring spectacles) was compared between groups using generalized matching criteria-adjusted linear regression models.

Results: Assessments were performed on 57 children with neonatal hyperglycemia (hyperglycemia group) and 54 matched children without hyperglycemia (control group). There were no differences in overall favorable visual outcome (OR 0.95, 95% CI 0.42-2.13, P = .90) or severe ROP incidence (OR 2.20, 95% CI 0.63-7.63, P = .21) between groups. Children with hyperglycemia had poorer binocular distance visual acuity (mean difference 0.08, 95% CI 0.03-0.14 logarithm of the minimum angle of resolution, P < .01), more strabismus (OR 6.22, 95% CI 1.31-29.45, P = .02), and thicker crystalline lens (mean difference 0.14, 95% CI 0.04-0.24 mm, P < .01). Maximum blood glucose concentration was greater in the ROP-treated group compared with the ROP-not treated and no ROP groups after adjusting for sex, gestational age, and birth weight z score (P = .02).

Conclusions: Neonatal hyperglycemia was not associated with overall visual outcomes at 7 years of age. However, there were between-group differences for specific outcome measures relating to interocular lens growth and binocular vision. Further follow-up is required to determine implications on long-term visual outcome.
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http://dx.doi.org/10.1016/j.jpeds.2020.04.059DOI Listing
August 2020

Relationships between intelligence, executive function and academic achievement in children born very preterm.

Early Hum Dev 2020 09 3;148:105122. Epub 2020 Jul 3.

Liggins Institute, University of Auckland, Private Bag 92019, Auckland 1023, New Zealand. Electronic address:

Background: Children born very preterm are at higher risk of adverse neurocognitive and educational outcomes. However, how low intelligence (IQ) and low executive function may each contribute to poorer academic outcomes at school age requires clarification.

Aim: To examine the associations between intelligence, executive function and academic achievement in children born very preterm.

Design/methods: This cohort study assessed children born <30 weeks' gestation or <1500 g at age 7 years using the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for IQ, and the Test of Everyday Attention for Children (TEA-Ch) and Behavior Rating Inventory of Executive Function (BRIEF) for executive function. Academic achievement was rated by teachers against curriculum standards.

Results: Of the 76 children (35 girls, 41 boys, mean age = 7.2 year), 22 (28%) were rated below expected level for reading, 32 (42%) for writing and 38 (50%) for mathematics. After adjustment for sex and socioeconomic status, low IQ (OR's 9.0-12.3) and most low executive function measures (OR's 4.1-9.3) were associated with below-expected achievement. After further adjustment for IQ, low cognitive flexibility (OR = 9.3, 95% CI = 1.2-71.5) and teacher ratings of executive function (OR = 5.3, 95% CI = 1.4-20.2) were associated with below-expected achievement. Mediation analysis showed IQ had indirect effects on writing (b = 1.5, 95% CI = 0.6-3.1) via attentional control; and on reading (b = 1.0, 95% CI = 0.2-3.2) and writing (b = 0.8, 95% CI = 0.1-2.5) via cognitive flexibility.

Conclusions: Both low IQ and low executive function are associated with below-expected teacher-rated academic achievement in children born very preterm. IQ may influence academic achievement in part through executive function.
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http://dx.doi.org/10.1016/j.earlhumdev.2020.105122DOI Listing
September 2020

Cost-Utility Analysis of Prophylactic Dextrose Gel vs Standard Care for Neonatal Hypoglycemia in At-Risk Infants.

J Pediatr 2020 Jul 4. Epub 2020 Jul 4.

Liggins Institute, University of Auckland, Auckland, New Zealand. Electronic address:

Objective: To evaluate the long-term costs and impact on quality of life of using prophylactic dextrose gel in patients at increased risk of developing neonatal hypoglycemia.

Study Design: A cost-utility analysis was performed from the perspective of the health system, using a decision tree to model the long-term clinical outcomes of neonatal hypoglycemia, including cerebral palsy, epilepsy, vision disturbances, and learning disabilities, in patients at increased risk of neonatal hypoglycemia who received prophylactic dextrose gel vs standard care. Model parameters including likelihoods of hypoglycemia and admission to a neonatal intensive care unit, were based on the pre-Hypoglycemia Prevention with Oral Dextrose Study. Estimations of the likelihood of long-term condition(s), and their costs, were based on review of published literature.

Results: Patients who received prophylactic dextrose gel incurred costs to the health system of around US $14 000 over an 18-year time horizon, accruing 11.25 quality-adjusted life-years, whereas those who did not receive prophylactic treatment incurred cost of around $16 000 and experienced a utility of 11.10 quality-adjusted life-years.

Conclusions: A prophylactic strategy of using dextrose gel in infants at increased risk of neonatal hypoglycemia is likely to be cost effective compared with standard care, to reduce the direct costs to the health system over an 18-year time horizon, and improve quality of life.
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http://dx.doi.org/10.1016/j.jpeds.2020.06.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779688PMC
July 2020

Reply.

J Pediatr 2020 10 27;225:279-280. Epub 2020 Jun 27.

Liggins Institute, University of Auckland, Auckland, New Zealand.

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October 2020

Neonatal Refeeding Syndrome and Clinical Outcome in Extremely Low-Birth-Weight Babies: Secondary Cohort Analysis From the ProVIDe Trial.

JPEN J Parenter Enteral Nutr 2021 01 4;45(1):65-78. Epub 2020 Jul 4.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Background: Refeeding syndrome (RS) following preterm birth has been linked to high intravenous (IV) protein intake in the presence of low electrolyte supply. In extremely low-birth-weight (ELBW) babies, we aimed to determine the incidence of RS and associations with birth characteristics and clinical outcomes.

Method: Prospective cohort study of ELBW ProVIDe Trial participants in 6 New Zealand neonatal intensive care units. RS was defined as serum phosphate < 1.4 mmol.L and total calcium > 2.8 mmol.L . Relationships between RS and other factors were explored using 2-sample tests and logistic regression adjusted for sex, gestation, and birth-weight z-score.

Results: Of 338 babies (mean [SD] birth-weight, 780 (134) g, gestational age, 25.9 [1.7] weeks), 68 (20%) had RS. Mortality was greater in babies with RS (32% vs 11%; P < .0001). More small- than appropriate-for-gestational-age babies developed RS (22% vs 8%; P = .001). Growth from birth to 36 weeks' corrected age was not different between babies who did and did not have RS. In logistic regression, the odds of RS decreased by 70% for each 1 mmol per kg .d IV phosphate intake (odds ratio [OR], 0.3; CI, 0.1-0.6; P = .002) and increased by 80% for each 1 g.kg .d IV protein intake (OR, 1.8; CI, 1.3-2.7; P = .002).

Conclusions: Neonatal RS is common in this cohort of ELBW babies and is associated with increased morbidity and mortality. Optimizing phosphate and calcium intakes in IV nutrition solutions may reduce RS and its consequences.
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http://dx.doi.org/10.1002/jpen.1934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891336PMC
January 2021

Impact of macronutrient supplements on later growth of children born preterm or small for gestational age: A systematic review and meta-analysis of randomised and quasirandomised controlled trials.

PLoS Med 2020 05 26;17(5):e1003122. Epub 2020 May 26.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Background: Nutritional supplements may improve short-term growth of infants born small (preterm or small for gestational age), but there are few data on long-term effects and concerns that body composition may be adversely affected. Effects also may differ between girls and boys. Our systematic review and meta-analysis assessed the effects of macronutrient supplements for infants born small on later growth.

Methods And Findings: We searched OvidMedline, Embase, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews from inception to January 30, 2020, and controlled-trials.com, clinicaltrials.gov, and anzctr.org.au on January 30, 2020. Randomised or quasirandomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born small and growth was assessed after discharge. Primary outcome was body mass index (BMI) in childhood. Data were pooled using random-effect models. Outcomes were evaluated in toddlers (< 3 years), childhood (3 to 8 years), adolescence (9 to 18 years), and adulthood (>18 years). Forty randomised and 2 quasirandomised trials of variable methodological quality with 4,352 infants were included. Supplementation did not alter BMI in childhood (7 trials, 1,136 children; mean difference [MD] -0.10 kg/m2, [95% confidence interval (CI) -0.37 to 0.16], p = 0.45). In toddlers, supplementation increased weight (31 trials, 2,924 toddlers; MD 0.16 kg, [0.01 to 0.30], p = 0.03) and length/height (30 trials, 2,889 toddlers; MD 0.44 cm, [0.10 to 0.77], p = 0.01), but not head circumference (29 trials, 2,797 toddlers; MD 0.15 cm, [-0.03 to 0.33], p = 0.10). In childhood, there were no significant differences between groups in height (7 trials, 1,136 children; MD 0.22 cm, [-0.48 to 0.92], p = 0.54) or lean mass (3 trials, 354 children; MD -0.07 kg, [-0.98 to 0.85], p = 0.88), although supplemented children appeared to have higher fat mass (2 trials, 201 children; MD 0.79 kg, [0.19 to 1.38], p = 0.01). In adolescence, there were no significant differences between groups in BMI (2 trials, 216 adolescents; MD -0.48 kg/m2, [-2.05 to 1.08], p = 0.60), height (2 trials, 216 adolescents; MD -0.55 cm, [-2.95 to 1.86], p = 0.65), or fat mass (2 trials, 216 adolescents; MD -1.3 5 kg, [-5.76 to 3.06], p = 0.55). In adulthood, there also were no significant differences between groups in weight z-score (2 trials, 199 adults; MD -0.11, [-0.72 to 0.50], p = 0.73) and height z-score (2 trials, 199 adults; MD -0.07, [-0.36 to 0.22], p = 0.62). In subgroup analysis, supplementation was associated with increased length/height in toddler boys (2 trials, 173 boys; MD 1.66 cm, [0.75 to 2.58], p = 0.0003), but not girls (2 trials, 159 girls; MD 0.15 cm, [-0.71 to 1.01], p = 0.74). Limitations include considerable unexplained heterogeneity, low to very low quality of evidence, and possible bias due to low or unbalanced followup.

Conclusions: In this systematic review and meta-analysis, we found no evidence that early macronutrient supplementation for infants born small altered BMI in childhood. Although supplements appeared to increase weight and length in toddlers, effects were inconsistent and unlikely to be clinically significant. Limited data suggested that supplementation increased fat mass in childhood, but these effects did not persist in later life. PROSPERO registration: CRD42019126918.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250404PMC
May 2020

Glucose Profiles in Healthy Term Infants in the First 5 Days: The Glucose in Well Babies (GLOW) Study.

J Pediatr 2020 08 4;223:34-41.e4. Epub 2020 May 4.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Objectives: To determine postnatal changes in plasma and interstitial glucose concentrations of healthy infants receiving current recommended care and to compare the incidence of low concentrations with recommended thresholds for treatment of at-risk infants.

Study Design: A prospective masked observational study in Hamilton, New Zealand. Healthy, term, appropriately grown singletons had continuous glucose monitoring and repeated heel-prick plasma glucose measurements (4 in the first 24 hours then twice daily using the glucose oxidase method) from birth to 120 hours.

Results: The 67 infants had a mean birth weight of 3584 ± 349 g, and gestational age of 40.1 ± 1.2 weeks. The mean glucose concentrations increased over the first 18 hours, remained stable to 48 hours (59 ± 11 mg/dL; 3.3 ± 0.6 mmol/L)] before increasing to a new plateau by the fourth day (89 ± 13 mg/dL; 4.6 ± 0.7 mmol/L). Plasma glucose concentrations of 47 mg/dL (2.6 mmol/L) approximated the 10th percentile in the first 48 hours, and 39% of infants had ≥1 episode below this threshold. Early term infants had lower mean glucose concentrations than those born at later gestational ages and were more likely to have episodes <47 mg/dL (<2.6 mmol/L) (19/32 [59%] vs 7/35 [20%]; relative risk, 3.0; 95% CI, 1.4-6.1; P = .001).

Conclusions: Healthy infants seem to complete their metabolic transition by day 4. Many have glucose concentrations below the accepted thresholds for treatment of hypoglycemia.

Trial Registration: ACTRN: 12615000986572.
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August 2020

Utility of published skinfold thickness equations for prediction of body composition in very young New Zealand children.

Br J Nutr 2020 08 6;124(3):349-360. Epub 2020 Apr 6.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Measurement of body composition is increasingly important in research and clinical settings but is difficult in very young children. Bioelectrical impedance analysis (BIA) and air displacement plethysmography (ADP) are well-established but require specialist equipment so are not always feasible. Our aim was to determine if anthropometry and skinfold thickness measurements can be used as a substitute for BIA or ADP for assessing body composition in very young New Zealand children. We used three multi-ethnic cohorts: 217 children at a mean age of 24·2 months with skinfold and BIA measurements; seventy-nine infants at a mean age of 20·9 weeks and seventy-three infants at a mean age of 16·2 weeks, both with skinfold and ADP measurements. We used Bland-Altman plots to compare fat and fat-free mass calculated using all potentially relevant equations with measurements using BIA or ADP. We also calculated the proportion of children in the same tertile for measured fat or fat-free mass and tertiles (i) calculated using each equation, (ii) each absolute skinfold, and (iii) sum of skinfold thicknesses. We found that even for the best equation for each cohort, the 95 % limits of agreement with standard measures were wide (25-200 % of the mean) and the proportion of children whose standard measures fell in the same tertile as the skinfold estimates was ≤69 %. We conclude that none of the available published skinfold thickness equations provides good prediction of body composition in multi-ethnic cohorts of very young New Zealand children with different birth history and growth patterns.
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http://dx.doi.org/10.1017/S0007114520001221DOI Listing
August 2020

Relationships between Neonatal Nutrition and Growth to 36 Weeks' Corrected Age in ELBW Babies-Secondary Cohort Analysis from the Provide Trial.

Nutrients 2020 Mar 13;12(3). Epub 2020 Mar 13.

Liggins Institute, University of Auckland, 1142 Auckland, New Zealand.

A key modifiable factor for improving neurodevelopment in extremely low birthweight (ELBW) babies may be improving growth, especially head growth, by optimising nutrition in the early neonatal period. We aimed to investigate relationships between nutrient intakes in the 4 weeks after birth, and growth from birth to 36 weeks' corrected age (CA) in ELBW babies. We undertook a prospective cohort study of 434 participants enrolled in a randomised controlled trial (ProVIDe) in eight New Zealand and Australian neonatal intensive care units. Macronutrient intakes from birth to 4 weeks and weight, length and head circumference measurements from birth to 36 weeks' CA were collected. From birth to 36 weeks' CA, the median (IQR) z-score changes were: weight -0.48 (-1.09, 0.05); length -1.16 (-1.86, -0.43), and head circumference -0.82 (-1.51, -0.19). Changes in z-score to 4 weeks and 36 weeks' CA were correlated with protein intake. Each 1 g·Kg·d total protein intake in week 2 was associated with 0.26 z-score increase in head circumference at 36 weeks' CA. Both nutritional intake and change in z-scores to 36 weeks' CA differed widely amongst sites. Correlations between nutrition and growth, and differences in these amongst sites, indicate there may be potential to improve growth with enhanced nutrition practices.
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http://dx.doi.org/10.3390/nu12030760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146349PMC
March 2020

Patterns of antenatal corticosteroid administration in a cohort of women with diabetes in pregnancy.

PLoS One 2020 27;15(2):e0229014. Epub 2020 Feb 27.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Antenatal corticosteroids administered to the mother prior to birth decrease the risk of mortality and major morbidity in infants born at less than 35 weeks' gestation. However, the evidence relating to women with diabetes in pregnancy is limited. Clinical guidelines for antenatal corticosteroid administration recommend that women with diabetes in pregnancy are treated in the same way as women without diabetes, but there are no recent descriptions of whether contemporary practice complies with this guidance. This study is a retrospective review of antenatal corticosteroid administration at a New Zealand tertiary hospital in women with diabetes in pregnancy. We found that in this cohort, for both an initial course at less than 35 weeks' gestation and repeat courses at less than 33 weeks', the administration of antenatal corticosteroid to women with diabetes in pregnancy is largely consistent with current Australian and New Zealand recommendations. However, almost 25% of women received their last dose of antenatal corticosteroid at or beyond the latest recommended gestation of 35 weeks' gestation. Pre-existing diabetes and planned caesarean section were independently associated with an increased rate of antenatal corticosteroid administration. We conclude that diabetes in pregnancy does not appear to be a deterrent to antenatal corticosteroid administration. The high rates of administration at gestations beyond recommendations, despite the lack of evidence of benefit in this group of women, highlights the need for further research into the risks and benefits of antenatal corticosteroid administration to women with diabetes in pregnancy, particularly in the late preterm and early term periods.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229014PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046227PMC
May 2020