Neonatal Docosahexaenoic Acid in Preterm Infants and Intelligence at 5 Years.

BACKGROUND: Docosahexaenoic acid (DHA) is a component of neural tissue. Because its accretion into the brain is greatest during the final trimester of pregnancy, infants born before 29 weeks' gestation do not receive the normal supply of DHA. The effect of this deficiency on subsequent cognitive development is not well understood. METHODS: We assessed general intelligence at 5 years in children who had been enrolled in a trial of neonatal DHA supplementation to prevent bronchopulmonary dysplasia. In the previous trial, infants born before 29 weeks' gestation had been randomly assigned in a 1:1 ratio to receive an enteral emulsion that provided 60 mg of DHA per kilogram of body weight per day or a control emulsion from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first. Children from 5 of the 13 centers in the original trial were invited to undergo assessment with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) at 5 years of corrected age. The primary outcome was the full-scale intelligence quotient (FSIQ) score. Secondary outcomes included the components of WPPSI. RESULTS: A total of 1273 infants underwent randomization in the original trial; of the 656 surviving children who had undergone randomization at the centers included in this follow-up study, 480 (73%) had an FSIQ score available - 241 in the DHA group and 239 in the control group. After imputation of missing data, the mean (±SD) FSIQ scores were 95.4±17.3 in the DHA group and 91.9±19.1 in the control group (adjusted difference, 3.45; 95% confidence interval, 0.38 to 6.53; P = 0.03). The results for secondary outcomes generally did not support that obtained for the primary outcome. Adverse events were similar in the two groups. CONCLUSIONS: In infants born before 29 weeks' gestation who had been enrolled in a trial to assess the effect of DHA supplementation on bronchopulmonary dysplasia, the use of an enteral DHA emulsion until 36 weeks of postmenstrual age was associated with modestly higher FSIQ scores at 5 years of age than control feeding. (Funded by the Australian National Health and Medical Research Council and Nu-Mega Ingredients; N3RO Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.).

Association of cord blood vitamin D with child neurodevelopment at 7 years of age.

AIM: The role of fetal vitamin D [25-hydroxyvitamin D (25(OH)D)], one of the nuclear steroid transcription regulators, and brain development is unclear. We previously found a weak but persistent association between cord blood 25(OH)D and child language abilities at 18 months and 4 years of age, but no association with cognition or behaviour. The aim of this study was to investigate the association between cord blood 25(OH)D and a range of neurodevelopmental outcomes in these same children at 7 years of age. METHODS: Cord blood samples from 250 Australian mother-child pairs were analysed for 25(OH)D by mass spectroscopy. Children underwent tests of cognition, language, academic abilities and executive functions with a trained assessor at 7 years of age. Caregivers completed questionnaires to rate their child's behaviour and executive functioning in the home environment. Associations between standardised 25(OH)D and outcomes were assessed using regression models, taking into account possible social and demographic confounders. RESULTS: Standardised 25(OH)D in cord blood was not associated with any test or parent-rated scores. Nor was there any association with the risk of having a poor test or parent-rated score. Likewise, cord blood 25(OH)D categorised as <25, 25-50 and >50 nmol/L was not associated with test scores or parent-rated scores. CONCLUSIONS: There was no evidence that cord blood vitamin D concentration or deficiency was associated with cognition, language, academic abilities, executive functioning or behaviour at 7 years of age.

Parent concerns for child development following admission to neonatal intensive or special care: From birth to adolescence.

AIM: To describe the presence and nature of parent concerns regarding the development of their children admitted to Australian neonatal units (NNUs), comprising neonatal intensive care or special care. METHODS: In a cross-sectional survey, mothers and fathers provided information regarding concerns for their child's development. The self-administered survey was completed by two separate cohorts; (i) parents of child graduates from Australian NNUs (n = 381); (ii) parents of infant's inpatient in two South Australian NNUs (n = 209). Data were analysed using thematic analysis and descriptive statistics. RESULTS: Information was provided for 730 children. Developmental concern was reported for 39% of NNU graduates and 35% of inpatients. Children born very preterm (< 32 weeks' gestation) elicited greater parent concern than those born more mature (Cohort 1: 41% vs 36%; Cohort 2: 49% vs 22%), including in multiple developmental domains (Cohort 1: 17% vs 15%; Cohort 2: 28% vs 4%). Parents with inpatient infants were predominantly concerned about general development-milestones (19.1%) and the potential impact of medical or CNS issues (13.7%). Graduate parents commonly focused on specific domains, such as their child's speech-language (13.7%) and motor (12.9%) development. CONCLUSION: Neurodevelopment is a substantial source of concern for mothers and fathers during NNU admission and childhood, particularly for children born very preterm. However, in the first year of life, developmental concerns are poorly defined. This highlights the need for clinical education resources detailing infant developmental expectations and supportive strategies for parents of these high-risk infants.

DHA supplementation in infants born preterm and the effect on attention at 18 months' corrected age: follow-up of a subset of the N3RO randomised controlled trial.

Infants born preterm miss out on the peak period of in utero DHA accretion to the brain during the last trimester of pregnancy which is hypothesised to contribute to the increased prevalence of neurodevelopmental deficits in this population. This study aimed to determine whether DHA supplementation in infants born preterm improves attention at 18 months' corrected age. This is a follow-up of a subset of infants who participated in the N3RO randomised controlled trial. Infants were randomised to receive an enteral emulsion of high-dose DHA (60 mg/kg per d) or no DHA (soya oil - control) from within the first days of birth until 36 weeks' post-menstrual age. The assessment of attention involved three tasks requiring the child to maintain attention on toy/s in either the presence or absence of competition or a distractor. The primary outcome was the child's latency of distractibility when attention was focused on a toy. The primary outcome was available for seventy-three of the 120 infants that were eligible to participate. There was no evidence of a difference between groups in the latency of distractibility (adjusted mean difference: 0·08 s, 95 % CI -0·81, 0·97; P = 0·86). Enteral DHA supplementation did not result in improved attention in infants born preterm at 18 months' corrected age.

Can the Bayley Scales of Infant Development at 18 months predict child behaviour at 7 years?

AIM: Infants born preterm (<37 weeks' gestation) are at risk of poor neurodevelopmental outcomes; hence, many neonatal centres routinely follow up infants using the Bayley Scales of Infant Development (BSID), although the predictive validity of the BSID for children born preterm is questionable. Our objective is to evaluate the predictive capacity of the BSID for behavioural functioning at school age of children born preterm. METHODS: Children (n = 657 children born <33 weeks' gestation) were enrolled at birth from five neonatal centres around Australia. A psychologist assessed child development at 18 months using the BSID-II. When children were 7 years (corrected age) of age, parents completed the Strengths and Difficulties Questionnaire, the Behavior Rating Inventory of Executive Function and the Conners 3rd Edition Attention Deficit Hyperactivity Disorder Index. We explored associations between BSID-II at 18 months and behaviour scores at 7 years and examined the interaction effect of the use of an allied health service between the BSID-II and behaviour assessments. RESULTS: For every one-point increase on the BSID-II Mental Development Index, behaviour scores decreased by 0.07 points for the Strengths and Difficulties Questionnaire Total Difficulties (95% confidence interval (CI) -0.10, -0.03), 0.12 points for the Behavior Rating Inventory of Executive Function Global Executive Composite (95% CI -0.21, -0.04) and 0.16 points for the Conners 3rd Edition Attention Deficit Hyperactivity Disorder Index (95% CI -0.26, -0.05). CONCLUSION: The BSID-II at 18 months was weakly associated with parent-reported behaviour at 7 years in children born preterm.

Omega-3 fatty acid addition during pregnancy.

BACKGROUND: Higher intakes of foods containing omega-3 long-chain polyunsaturated fatty acids (LCPUFA), such as fish, during pregnancy have been associated with longer gestations and improved perinatal outcomes. This is an update of a review that was first published in 2006. OBJECTIVES: To assess the effects of omega-3 LCPUFA, as supplements or as dietary additions, during pregnancy on maternal, perinatal, and neonatal outcomes and longer-term outcomes for mother and child. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 August 2018), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing omega-3 fatty acids (as supplements or as foods, stand-alone interventions, or with a co-intervention) during pregnancy with placebo or no omega-3, and studies or study arms directly comparing omega-3 LCPUFA doses or types. Trials published in abstract form were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data, assessed risk of bias in trials and assessed quality of evidence for prespecified birth/infant, maternal, child/adult and health service outcomes using the GRADE approach. MAIN RESULTS: In this update, we included 70 RCTs (involving 19,927 women at low, mixed or high risk of poor pregnancy outcomes) which compared omega-3 LCPUFA interventions (supplements and food) compared with placebo or no omega-3. Overall study-level risk of bias was mixed, with selection and performance bias mostly at low risk, but there was high risk of attrition bias in some trials. Most trials were conducted in upper-middle or high-income countries; and nearly half the trials included women at increased/high risk for factors which might increase the risk of adverse maternal and birth outcomes.Preterm birth < 37 weeks (13.4% versus 11.9%; risk ratio (RR) 0.89, 95% confidence interval (CI) 0.81 to 0.97; 26 RCTs, 10,304 participants; high-quality evidence) and early preterm birth < 34 weeks (4.6% versus 2.7%; RR 0.58, 95% CI 0.44 to 0.77; 9 RCTs, 5204 participants; high-quality evidence) were both lower in women who received omega-3 LCPUFA compared with no omega-3. Prolonged gestation > 42 weeks was probably increased from 1.6% to 2.6% in women who received omega-3 LCPUFA compared with no omega-3 (RR 1.61 95% CI 1.11 to 2.33; 5141 participants; 6 RCTs; moderate-quality evidence).For infants, there was a possibly reduced risk of perinatal death (RR 0.75, 95% CI 0.54 to 1.03; 10 RCTs, 7416 participants; moderate-quality evidence: 62/3715 versus 83/3701 infants) and possibly fewer neonatal care admissions (RR 0.92, 95% CI 0.83 to 1.03; 9 RCTs, 6920 participants; moderate-quality evidence - 483/3475 infants versus 519/3445 infants). There was a reduced risk of low birthweight (LBW) babies (15.6% versus 14%; RR 0.90, 95% CI 0.82 to 0.99; 15 trials, 8449 participants; high-quality evidence); but a possible small increase in large-for-gestational age (LGA) babies (RR 1.15, 95% CI 0.97 to 1.36; 6 RCTs, 3722 participants; moderate-quality evidence, for omega-3 LCPUFA compared with no omega-3. Little or no difference in small-for-gestational age or intrauterine growth restriction (RR 1.01, 95% CI 0.90 to 1.13; 8 RCTs, 6907 participants; moderate-quality evidence) was seen.For the maternal outcomes, there is insufficient evidence to determine the effects of omega-3 on induction post-term (average RR 0.82, 95% CI 0.22 to 2.98; 3 trials, 2900 participants; low-quality evidence), maternal serious adverse events (RR 1.04, 95% CI 0.40 to 2.72; 2 trials, 2690 participants; low-quality evidence), maternal admission to intensive care (RR 0.56, 95% CI 0.12 to 2.63; 2 trials, 2458 participants; low-quality evidence), or postnatal depression (average RR 0.99, 95% CI 0.56 to 1.77; 2 trials, 2431 participants; low-quality evidence). Mean gestational length was greater in women who received omega-3 LCPUFA (mean difference (MD) 1.67 days, 95% CI 0.95 to 2.39; 41 trials, 12,517 participants; moderate-quality evidence), and pre-eclampsia may possibly be reduced with omega-3 LCPUFA (RR 0.84, 95% CI 0.69 to 1.01; 20 trials, 8306 participants; low-quality evidence).For the child/adult outcomes, very few differences between antenatal omega-3 LCPUFA supplementation and no omega-3 were observed in cognition, IQ, vision, other neurodevelopment and growth outcomes, language and behaviour (mostly low-quality to very low-quality evidence). The effect of omega-3 LCPUFA on body mass index at 19 years (MD 0, 95% CI -0.83 to 0.83; 1 trial, 243 participants; very low-quality evidence) was uncertain. No data were reported for development of diabetes in the children of study participants. AUTHORS' CONCLUSIONS: In the overall analysis, preterm birth < 37 weeks and early preterm birth < 34 weeks were reduced in women receiving omega-3 LCPUFA compared with no omega-3. There was a possibly reduced risk of perinatal death and of neonatal care admission, a reduced risk of LBW babies; and possibly a small increased risk of LGA babies with omega-3 LCPUFA.For our GRADE quality assessments, we assessed most of the important perinatal outcomes as high-quality (e.g. preterm birth) or moderate-quality evidence (e.g. perinatal death). For the other outcome domains (maternal, child/adult and health service outcomes) GRADE ratings ranged from moderate to very low, with over half rated as low. Reasons for downgrading across the domain were mostly due to design limitations and imprecision.Omega-3 LCPUFA supplementation during pregnancy is an effective strategy for reducing the incidence of preterm birth, although it probably increases the incidence of post-term pregnancies. More studies comparing omega-3 LCPUFA and placebo (to establish causality in relation to preterm birth) are not needed at this stage. A further 23 ongoing trials are still to report on over 5000 women, so no more RCTs are needed that compare omega-3 LCPUFA against placebo or no intervention. However, further follow-up of completed trials is needed to assess longer-term outcomes for mother and child, to improve understanding of metabolic, growth and neurodevelopment pathways in particular, and to establish if, and how, outcomes vary by different types of omega-3 LCPUFA, timing and doses; or by characteristics of women.

Association of cord blood vitamin D with early childhood growth and neurodevelopment.

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.

Association of cord blood vitamin D at delivery with postpartum depression in Australian women.

BACKGROUND: Observational studies have implicated low serum vitamin D (25-hydroxyvitamin D (25(OH)D)) levels in the development of mood disorders. Postpartum depression (PPD) is an important public health issue, although little is known about its association with serum 25(OH)D. AIMS: To determine the association between 25(OH)D at delivery and the subsequent risk of PPD at six weeks and six months postpartum in a large cohort of Australian women. MATERIALS AND METHODS: Cord blood samples from 1040 women participating in the docosahexaenoic acid (DHA) to Optimise Maternal Infant Outcome randomised controlled trial were analysed for 25(OH)D by mass spectroscopy. Maternal PPD was assessed using the Edinburgh Postnatal Depression Scale at six weeks and six months postpartum. The association between standardised 25(OH)D and PPD was assessed, taking into account DHA treatment, social and demographic variables. RESULTS: There was no association between cord blood 25(OH)D concentration at delivery and PPD at either six weeks or six months postpartum. Cord blood 25(OH)D 25-50 and >50 nmol/L at delivery was associated with decreased risk of PPD at six weeks postpartum compared with 25(OH)D <25 nmol/L in the control group, but not the DHA group. There was no association between cord blood 25(OH)D <25 nmol/L at delivery and PPD at six months postpartum. CONCLUSIONS: This largest study to date of 25(OH)D levels at delivery and PPD did not reveal a consistent link with PPD.

Child development education in the Neonatal Unit: Understanding parent developmental literacy needs, priorities and preferences.

OBJECTIVE: To describe child development knowledge needs, priorities, and preferences for education to enhance developmental literacy among parents with children admitted to the neonatal unit (NNU). METHODS: Two separate cohorts completed a survey; 1) Parents with children graduated from Australian NNUs (n = 316); 2) Parents with infants' inpatient at two South Australian NNUs (n = 209). RESULTS: Parents considered it extremely important to understand child development (Graduates: 80%; Inpatients: 71%). Inpatient parents reported lower child development knowledge. Almost half (42%) of graduate parents described the child development education provided by neonatal staff as poor or inadequate. There was consistency in preferences for developmental literacy education provision. Parents desired education to commence during NNU and continue post discharge. Priorities included content specific to preterm birth and how to support child development over the first two years of life. Individualised education by a Neonatal Nurse/Midwife was most preferred. CONCLUSION: Mothers and fathers value guidance to support their child's development during NNU admission and early childhood. Our study highlights the importance of improved early developmental literacy education for parents with children admitted to the neonatal unit. PRACTICE IMPLICATIONS: Our findings can be used to inform the creation of future educational resources targeting improved parent developmental literacy.

The Effects of Prenatal Iron Supplementation on Offspring Neurodevelopment in Upper Middle- or High-Income Countries: A Systematic Review.

Iron supplementation is commonly recommended for the prevention and treatment of maternal iron deficiency (ID) or iron deficiency anemia (IDA). However, the impacts of prophylactic of therapeutic prenatal iron supplementation on child neurodevelopment in upper middle-income (UMI) and high-income countries (HICs), where broad nutritional deficiencies are less common, are unclear. To investigate this, we conducted a systematic review, searching four databases (Medline, CINAHL, EMBASE, Cochrane Library) through 1 May 2023. Randomized controlled trials (RCTs) assessing oral or intravenous iron supplementation in pregnant women reporting on child neurodevelopment (primary outcome: age-standardized cognitive scores) were eligible. We included three RCTs (five publications) from two HICs (Spain and Australia) (N = 935 children; N = 1397 mothers). Due to clinical heterogeneity of the RCTs, meta-analyses were not appropriate; findings were narratively synthesized. In non-anemic pregnant women, prenatal iron for prevention of IDA resulted in little to no difference in cognition at 40 days post-partum (1 RCT, 503 infants; very low certainty evidence). Similarly, the effect on the intelligence quotient at four years was very uncertain (2 RCTs, 509 children, very low certainty evidence). No RCTs for treatment of ID assessed offspring cognition. The effects on secondary outcomes related to language and motor development, or other measures of cognitive function, were unclear, except for one prevention-focused RCT (302 children), which reported possible harm for children's behavioral and emotional functioning at four years. There is no evidence from UMI countries and insufficient evidence from HICs to support or refute benefits or harms of prophylactic or therapeutic prenatal iron supplementation on child neurodevelopment.

Infant formula supplemented with milk fat globule membrane compared with standard infant formula for the cognitive development of healthy term-born formula-fed infants: protocol for a randomised controlled trial.

INTRODUCTION: Milk fat globule membrane (MFGM) is a complex lipid-protein structure in mammalian milk and human milk that is largely absent from breastmilk substitutes. The objective of this trial is to investigate whether providing infant formula enriched with MFGM versus standard infant formula improves cognitive development at 12 months of age in exclusively formula-fed full-term infants. METHODS AND ANALYSIS: This is a randomised, controlled, clinician-blinded, researcher-blinded and participant-blinded trial of two parallel formula-fed groups and a breastfed reference group that were recruited in the suburban Adelaide (Australia) community by a single study centre (a medical research institute). Healthy, exclusively formula-fed, singleton, term-born infants under 8 weeks of age were randomised to either an MFGM-supplemented formula (intervention) or standard infant formula (control) from enrolment until 12 months of age. The reference group was not provided with formula. The primary outcome is the Cognitive Scale of the Bayley Scales of Infant Development, Fourth Edition (Bayley-IV) at 12 months. Secondary outcomes are the Bayley-IV Cognitive Scale at 24 months, other Bayley-IV domains (language, motor, emotional and behavioural development) at 12 and 24 months of age, infant attention at 4 and 9 months of age, parent-rated language at 12 and 24 months of age, parent-rated development at 6 and 18 months of age as well as growth, tolerance and safety of the study formula. To ensure at least 80% power to detect a 5-point difference in the mean Bayley-IV cognitive score, >200 infants were recruited in each group. ETHICS AND DISSEMINATION: The Women's and Children Health Network Human Research Ethics Committee reviewed and approved the study (HREC/19/WCHN/140). Caregivers gave written informed consent prior to enrolling in the trial. Findings of this study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12620000552987; Australian and New Zealand Clinical Trial Registry: anzctr.org.au.

High-Dose Docosahexaenoic Acid in Newborns Born at Less Than 29 Weeks' Gestation and Behavior at Age 5 Years: Follow-Up of a Randomized Clinical Trial.

Importance: Children born at less than 29 weeks' gestation are at risk of behavioral difficulties. This may be due in part to the lack of transplacental supply of docosahexaenoic acid (DHA), a key fatty acid with structural and functional roles in the brain. Objective: To determine whether meeting the neonatal DHA requirement through supplementation is associated with improved behavioral functioning of children born at less than 29 weeks' gestation. Design, Setting and Participants: This was a follow-up of children from 10 Australian participating centers in a multi-center, blinded, parallel group randomized clinical trial of infants born at less than 29 weeks' gestation conducted from June 2012 and September 2015, excluding those with additional fatty acid supplementation or major congenital or chromosomal abnormalities. Follow-up took place from August 2018 to May 2021. Parents of surviving children who had not withdrawn from the original trial were invited to complete questionnaires when the child turned 5 years' corrected age. Interventions: Infants were randomized to receive daily enteral emulsions providing 60 mg/kg/d of DHA or a soy-oil emulsion (with no DHA) from within the first 3 days of enteral feeding until 36 weeks' postmenstrual age or discharge home, whichever occurred first. Main Outcomes and Measures: The primary outcome of this follow-up was parent-rated behavior and emotional functioning as indicated by the Total Difficulties score of the Strengths and Difficulties Questionnaire. Parents also completed questionnaires about their child's behavioral manifestations of executive functioning, as well as a range of health outcomes to assess potential longer-term side effects of DHA intervention. Results: Primary outcome data were available for 731 children (76% of 958 surviving eligible children; 361 in the intervention group and 370 in the control group). Of these 731, 452 (47%) were female, and the mean (SD) corrected age at follow-up was 5.4 (0.5) years. Following imputation for missing data, the mean Total Difficulties score was the same in both groups (intervention group, n = 465; mean [SD], 11.8 [6.3]; control group, n = 493; mean [SD], 11.8 [6.0]; mean difference adjusted for sex, gestational age stratum, and hospital, 0.01; 95% CI, -0.87 to 0.89; P = .98). There was no evidence for differences between the groups in any secondary outcomes of behavior, executive functioning, or health. Conclusions and Relevance: In this follow-up of a randomized clinical trial, enteral DHA supplementation at the equivalent of the estimated in utero dose for infants born at less than 29 weeks' gestation did not improve behavioral functioning at age 5 years. There were no indications of adverse effects with DHA supplementation. Trial Registration: Australian New Zealand Clinical Trial Registry: ACTRN12612000503820.

Effect of Docosahexaenoic Acid (DHA) Supplementation of Preterm Infants on Growth, Body Composition, and Blood Pressure at 7-Years Corrected Age: Follow-Up of a Randomized Controlled Trial.

Aim: To determine if supplementation of infants born <33 weeks' gestation with higher dose docosahexaenoic acid (DHA) affects growth, body composition, and blood pressure at 7 y corrected age (CA) and if treatment effects differed by infant sex at birth and birth weight strata (<1250 and ≥1250 g). Methods: Seven-year follow-up of an Australian multicenter randomized controlled trial in which 657 infants were fed high-DHA (≈1% total fatty acids) enteral feeds or standard-DHA (≈0.3% total fatty acids) from age 2−4 d until term CA. Seven-year CA outcomes were growth (weight, height), body composition (lean body mass, fat mass, waist, and hip circumference), and blood pressure. Results: There was no effect of high-DHA enteral feeds compared with standard-DHA on growth, body composition, and blood pressure at 7-year CA either overall or in subgroup analysis by sex. There was a significant interaction between high-DHA and birthweight strata on height at 7-y CA (p = 0.03). However, the post-hoc analyses by birthweight strata did not reach significance (p > 0.1). High-DHA group infants were more likely to be classified as obese (relative risk 1.6 (95% CI 1.0, 2.6); p = 0.05). Conclusions: DHA supplementation of premature infants did not affect growth, body composition, or blood pressure at 7-year CA overall by sex and birthweight strata. The finding of a higher risk of obesity in children who receive high-DHA needs to be interpreted with caution due to the small number of children classified as obese.

Enteral supplementation with high-dose docosahexaenoic acid on the risk of bronchopulmonary dysplasia in very preterm infants: a collaborative study protocol for an individual participant data meta-analysis.

INTRODUCTION: Severe bronchopulmonary dysplasia (BPD) is a well-known factor consistently associated with impaired cognitive outcomes. Regarding reported benefits on long-term neurodevelopmental outcomes, the potential adverse effects of high-dose docosahexaenoic acid (DHA) supplementation on this short-term neonatal morbidity need further investigations in infants born very preterm. This study will determine whether high-dose DHA enteral supplementation during the neonatal period is associated with the risk of severe BPD at 36 weeks' postmenstrual age (PMA) compared with control, in contemporary cohorts of preterm infants born at less than 29 weeks of gestation. METHODS AND ANALYSIS: As part of an Australian-Canadian collaboration, we will conduct an individual participant data (IPD) meta-analysis of randomised controlled trials targeting infants born at less than 29 weeks of gestation and evaluating the effect of high-dose DHA enteral supplementation in the neonatal period compared with a control. Primary outcome will be severe grades of BPD (yes/no) at 36 weeks' PMA harmonised according to a recent definition that predicts early childhood morbidities. Other outcomes will be survival without severe BPD, death, BPD severity grades, serious brain injury, severe retinopathy of prematurity, patent ductus arteriosus and necrotising enterocolitis requiring surgery, sepsis, combined neonatal morbidities and growth. Severe BPD will be compared between groups using a multivariate generalised estimating equations log-binomial regression model. Subgroup analyses are planned for gestational age, sex, small-for-gestational age, presence of maternal chorioamnionitis and mode of delivery. ETHICS AND DISSEMINATION: The conduct of each trial was approved by institutional research ethics boards and written informed consent was obtained from participating parents. A collaboration and data sharing agreement will be signed between participating authors and institutions. This IPD meta-analysis will document the role of DHA in nutritional management of BPD. Findings will be disseminated through conferences, media interviews and publications to peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42023431063. TRIAL REGISTRATION NUMBER: NCT05915806.

Prenatal iodine supplementation and early childhood neurodevelopment: the PoppiE trial - study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Observational studies suggest both low and high iodine intakes in pregnancy are associated with poorer neurodevelopmental outcomes in children. This raises concern that current universal iodine supplement recommendations for pregnant women in populations considered to be iodine sufficient may negatively impact child neurodevelopment. We aim to determine the effect of reducing iodine intake from supplements for women who have adequate iodine intake from food on the cognitive development of children at 24 months of age. METHODS AND ANALYSIS: A multicentre, randomised, controlled, clinician, researcher and participant blinded trial with two parallel groups. Using a hybrid decentralised clinical trial model, 754 women (377 per group) less than 13 weeks' gestation with an iodine intake of ≥165 µg/day from food will be randomised to receive either a low iodine (20 µg/day) multivitamin and mineral supplement or an identical supplement containing 200) µg/day (amount commonly used in prenatal supplements in Australia), from enrolment until delivery. The primary outcome is the developmental quotient of infants at 24 months of age assessed with the Cognitive Scale of the Bayley Scales of Infant Development, fourth edition. Secondary outcomes include infant language and motor development; behavioural and emotional development; maternal and infant clinical outcomes and health service utilisation of children. Cognitive scores will be compared between groups using linear regression, with adjustment for location of enrolment and the treatment effect described as a mean difference with 95% CI. ETHICS AND DISSEMINATION: Ethical approval has been granted from the Women's and Children's Health Network Research Ethics Committee (HREC/17/WCHN/187). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04586348.

Mediation Analysis to Untangle Opposing Associations of High-Dose Docosahexaenoic Acid With IQ and Bronchopulmonary Dysplasia in Children Born Preterm.

Importance: High-dose omega-3 docosahexaenoic acid (DHA) supplementation of children born at less than 29 weeks' gestation has been shown to improve IQ despite increasing the risk of bronchopulmonary dysplasia (BPD). Given that BPD is associated with poorer cognitive outcomes, it is unclear whether the increased risk of BPD with DHA supplementation is associated with decreased benefit to IQ. Objective: To investigate whether the increased risk of BPD with DHA supplementation was associated with diminished IQ benefit. Design, Setting, and Participants: This cohort study used data collected from a multicenter, blinded, randomized controlled trial of DHA supplementation in children born at less than 29 weeks' gestation. Participants were recruited from 2012 to 2015 and followed up until 5 years' corrected age. Data were analyzed from November 2022 to February 2023. Interventions: Enteral DHA emulsion (60 mg/kg/d, to match the estimated in-utero requirement) or a control emulsion from the first 3 days of enteral feeds until 36 weeks' postmenstrual age or discharge home. Main Outcomes and Measures: Physiological BPD was assessed at 36 weeks' postmenstrual age. IQ was assessed at 5 years' corrected age using the Wechsler Preschool and Primary Scale of Intelligence, 4th Edition; children from the 5 highest-recruiting Australian hospitals were assessed. The total effect of DHA supplementation on IQ was divided into direct and indirect effects using mediation analysis, with BPD as the presumed mediating variable. Results: Among 656 surviving children from hospitals involved in IQ follow-up (mean [SD] gestational age at birth, 26.8 [1.4] weeks; 346 males [52.7%]), there were 323 children with DHA supplementation and 333 children in the control group. Mean IQ was 3.45 points (95% CI, 0.38 to 6.53 points) higher in the DHA group than the control group, despite an increase in the risk of BPD (160 children [49.7%] vs 143 children [42.8%] with BPD). The indirect effect of DHA on IQ via BPD was not statistically significant (-0.17 points; 95% CI, -0.62 to 0.13 points), with most of the effect of DHA on IQ occurring independently of BPD (direct effect = 3.62 points; 95% CI, 0.55 to 6.81 points). Conclusions and Relevance: This study found that associations of DHA with BPD and IQ were largely independent. This finding suggests that if clinicians supplement children born preterm with high-dose DHA, any resulting increase in BPD risk would not be associated with meaningful reductions in the IQ benefit.

A Systematic Review of Vitamin D during Pregnancy and Postnatally and Symptoms of Depression in the Antenatal and Postpartum Period from Randomized Controlled Trials and Observational Studies.

Depression is a common mood disorder associated with childbirth and is hypothesized to be affected by low vitamin D. This systematic review identified two randomized controlled trials (RCT) of vitamin D supplementation for the treatment or prevention of depressive symptoms in the perinatal period, as well as 18 observational studies of vitamin D exposure and depression in the antenatal and postnatal periods. Both RCTs claimed an improvement in depressive symptoms in the vitamin D group, although the sample sizes were too small to draw firm conclusions. The case-control and cohort studies had mixed findings and were limited by study quality. There were inconsistent results within the few studies with a more robust methodology or within samples restricted to women likely to have depression. The current evidence is inconclusive due to the poor quality and heterogeneity of studies, likely contributing to the contradictory findings. Given there are already numerous RCTs of prenatal vitamin D supplementation, we recommend adding an appropriate measure of depression in the perinatal period to assist in resolving the uncertainty.

Estimated Choline Intakes and Dietary Sources of Choline in Pregnant Australian Women.

(1) Background: Despite the postulated importance of choline during pregnancy, little is known about the choline intake of Australians during pregnancy. In this study, we estimated dietary intakes of choline in early and late pregnancy, compared those intakes to recommendations, and investigated food sources of choline in a group of pregnant women in Australia. (2) Methods: 103 pregnant women enrolled in a randomized controlled trial. In early pregnancy (12−16 weeks gestation) and late pregnancy (36 weeks gestation), women completed a food frequency questionnaire designed to assess dietary intake over the previous month. (3) Results: Choline intakes and sources were similar in early and late pregnancy. Median choline intake in early pregnancy was 362 mg/day. Of the women, 39% and 25% had choline intakes above the Australian National Health and Medical Research Council (NHMRC) adequate intake (AI) of >440 mg/day and the European Food Safety Authority (EFSA) AI of >480 mg/day for choline in pregnancy, respectively. Eggs, red meat, nuts, legumes, and dairy accounted for 50% of choline intake, with eggs being the most significant contributor at 17%. (4) Conclusions: Few pregnant women in our study met the AI recommended by the NHMRC and EFSA. In Australia, choline intake in pregnancy may need to be improved, but further work to define choline requirements in pregnancy is required.

Protocol for a multicentre prospective observational study of families with full-term infants on postnatal wards and in the community to capture feeding practices across the first year of life: the Mother Infant Lactation Questionnaire (MILQ) study.

INTRODUCTION: Breastmilk is considered the gold standard for infant nutrition. Breast feeding is recommended as the sole source of nutrition between birth until around 6 months of age and should be continued beyond this age as complementary foods are introduced. While breast feeding initiation is generally high in developed countries, continuation of breast feeding appears to drop rapidly. This is a prospective observational study of life that aims to characterise a current picture of infant feeding practices across the first year, and motivations for feeding practices, and to identify barriers and enablers for breast feeding. METHODS AND ANALYSIS: Caregivers with newborn singleton infants of normal birth weight are approached on the postnatal units of three hospitals in South Australia, or through targeted online advertising campaigns promoting the study. Caregivers are asked to complete surveys when their infant reaches 3, 5 and 7 weeks', and at 3, 4, 5, 6, 9 and 12 months of age. Initially, baseline characteristics, intentions and preferences for infant milk feeds, as well as reasons for preferences are captured. Latter surveys query how infants are being fed, difficulties or barriers to breast feeding, as well as any enablers (if breast feeding). Once infants reach 5 months of age, surveys capture complementary feeding. A large opportunistic sample from the Adelaide community with a minimum of 1000 mother-infant pairs will be enrolled. The data will be analysed descriptively and using regression models. ETHICS AND DISSEMINATION: Women's and Children's Health Network Human Research Ethics Committee reviewed and approved the study (approval no HREC/19/WCHN/140, approval date: 22 November 2019). Study results will be disseminated through academic meetings, peer-reviewed journals, in-services for postnatal healthcare services, results letters for participants and social media. TRIAL REGISTRATION NUMBER: ACTRN12620000529943.