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.).

Too Much Too Little: Clarifying the Relationship Between Maternal Iodine Intake and Neurodevelopmental Outcomes.

BACKGROUND: In 2009, the Australian government mandated the fortification of bread salt with iodine. In 2010, pregnant and lactating women were also advised to take an iodine-containing supplement. Our assessment of this policy in an iodine-sufficient population showed that children whose mothers were in the highest and lowest quartiles of iodine intake performed more poorly on early childhood tests of cognition and language than those in the second quartile. However, we did not quantify the iodine intake associated with optimal neurodevelopment. OBJECTIVES: The aim was to establish the iodine intake range in pregnancy associated with optimal child neurodevelopment. METHODS: A prospective cohort study of pregnant women and their young children (n = 699). Iodine intake was assessed by a validated food frequency questionnaire at 16 and 28 wk of gestation. Child neurodevelopment at 18 mo of age was measured using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). The relationship between average iodine intake during pregnancy and child neurodevelopment was assessed using linear regression with fractional polynomials and adjustment for confounders. RESULTS: Mean (SD) iodine intake was similar at study entry and 28 wk, 308 (120) µg/d, with 82% of women taking iodine supplements at study entry. The relationship between iodine intake during pregnancy and Bayley-III cognitive and language scores was curvilinear (P = 0.001 and P = 0.004, respectively), with the lowest Bayley-III scores observed at lower and higher iodine intakes. The inflection point that drove the association between lower iodine intake in pregnancy and poorer child neurodevelopment scores was around 185 µg/d; for the higher pregnancy iodine intakes, language and cognitive scores were negatively affected from ∼350 µg/d to 370 µg/d, respectively. Higher iodine intakes were being driven by supplement use. CONCLUSIONS: Targeted, not blanket, iodine supplementation may be needed for pregnant women with low-iodine intake from food.

The Effect of Iron Supplements on the Gut Microbiome of Females of Reproductive Age: A Randomized Controlled Trial.

BACKGROUND: Iron deficiency is the most common nutritional deficiency worldwide, particularly for young children and females of reproductive age. Although oral iron supplements are routinely recommended and generally considered safe, iron supplementation has been shown to alter the fecal microbiota in low-income countries. Little is known about the effect of iron supplementation on the fecal microbiota in high-income settings. OBJECTIVES: To assess the effect of oral iron supplementation compared with placebo on the gut microbiome in nonpregnant females of reproductive age in a high-income country. METHODS: A 21-d prospective parallel design double-blind, randomized control trial conducted in South Australia, Australia. Females (18-45 y) were randomly assigned to either iron (65.7 mg ferrous fumarate) or placebo. Fecal samples were collected prior to commencing supplements and after 21 d of supplementation. The primary outcome was microbiota ß-diversity (paired-sample weighted unique fraction metric dissimilarity) between treatment and placebo groups after 21 d of supplementation. Exploratory outcomes included changes in the relative abundance of bacterial taxa. RESULTS: Of 82 females randomly assigned, 80 completed the trial. There was no significant difference between the groups for weighted unique fraction metric dissimilarity (mean difference: 0.003; 95% confidence interval: -0.007, 0.014; P = 0.52) or relative abundance of common bacterial taxa or Escherichia-Shigella (q > 0.05). CONCLUSIONS: Iron supplementation did not affect the microbiome of nonpregnant females of reproductive age in Australia. This trial was registered at clinicaltrials.gov as NCT05033483.

Maternal serum unmetabolized folic acid concentration following multivitamin and mineral supplementation with or without folic acid after 12 weeks gestation: A randomized controlled trial.

Pregnant women are advised to take folic acid (FA) supplements before conception and during the first trimester of pregnancy. Many women continue FA supplementation throughout pregnancy, and concerns have been raised about associations between excessive FA intake and adverse maternal and child health outcomes. Unmetabolized folic acid (UMFA) is found in serum after high FA intakes and is proposed as a biomarker for excessive FA intake. We aimed to determine if removing FA from prenatal micronutrient supplements after 12 weeks of pregnancy reduces serum UMFA concentrations at 36 weeks gestation. In this double-blind, randomized controlled trial conducted in South Australia, 103 women with a singleton pregnancy were randomly assigned at 12-16 weeks gestation to take a micronutrient supplement containing no FA or 800 µg/day FA from enrollment until 36 weeks gestation. Ninety women (0 µg/day FA n = 46; 800 µg/day FA n = 44) completed the study. Mean, UMFA concentration was lower in the women randomized to the 0 µg/day group compared to the 800 µg/day FA group, 0.6 ± 0.7 and 1.4 ± 2.7 nmol/L, respectively. The adjusted mean difference (95% CI) in UMFA between the groups was [-0.85 (-1.62, -0.08) nmol/L, p = 0.03]. Maternal serum and red blood cell folate concentrations were lower in the 0 µg/day FA group than in the 800 µg/day group (median 23.2 vs. 49.3 and 1335 vs. 1914 nmol/L, respectively; p < 0.001). Removing FA at 12-16 weeks gestation from prenatal micronutrient supplements reduced the concentration of UMFA at 36 weeks gestation.

A Randomized Trial of Prenatal n-3 Fatty Acid Supplementation and Preterm Delivery.

BACKGROUND: Previous studies have suggested that maternal supplementation with n-3 long-chain polyunsaturated fatty acids may reduce the incidence of preterm delivery but may also prolong gestation beyond term; however, more data are needed regarding the role of n-3 long-chain polyunsaturated fatty acids in pregnancy. METHODS: We performed a multicenter, double-blind, randomized trial in which women who were pregnant with single or multiple fetuses were assigned to receive either fish-oil capsules that contained 900 mg of n-3 long-chain polyunsaturated fatty acids (n-3 group) or vegetable-oil capsules that contained trace n-3 long-chain polyunsaturated fatty acids (control group) daily, beginning before 20 weeks of gestation and continuing to 34 weeks of gestation or delivery, whichever occurred first. The primary outcome was early preterm delivery, defined as delivery before 34 completed weeks of gestation. Other pregnancy and neonatal outcomes were also assessed. RESULTS: A total of 5544 pregnancies in 5517 women were randomly assigned at six centers in Australia; 5486 pregnancies were included in the primary analysis. Early preterm delivery occurred in the case of 61 of 2734 pregnancies (2.2%) in the n-3 group and 55 of 2752 pregnancies (2.0%) in the control group; the between-group difference was not significant (adjusted relative risk, 1.13; 95% confidence interval [CI], 0.79 to 1.63; P = 0.50). There were no significant differences between the groups in the incidence of interventions in post-term (>41 weeks of gestation) deliveries, in adverse events, or in other pregnancy or neonatal outcomes, except that a higher percentage of infants born to women in the n-3 group than in the control group were very large for gestational age at birth (adjusted relative risk, 1.30; 95% CI, 1.02 to 1.65). Percentages of serious adverse events did not differ between the groups. Minor gastrointestinal disturbances were more commonly reported in the n-3 group than in the control group. CONCLUSIONS: Supplementation with n-3 long-chain polyunsaturated fatty acids from early pregnancy (<20 weeks of gestation) until 34 weeks of gestation did not result in a lower incidence of early preterm delivery or a higher incidence of interventions in post-term deliveries than control. (Funded by the Australian National Health and Medical Research Council and the Thyne Reid Foundation; ORIP Australian New Zealand Clinical Trials Registry number, ACTRN12613001142729.).

Maternal Late-Pregnancy Serum Unmetabolized Folic Acid Concentrations Are Not Associated with Infant Allergic Disease: A Prospective Cohort Study.

BACKGROUND: The increase in childhood allergic disease in recent decades has coincided with increased folic acid intakes during pregnancy. Circulating unmetabolized folic acid (UMFA) has been proposed as a biomarker of excessive folic acid intake. OBJECTIVE: We aimed to determine if late-pregnancy serum UMFA and total folate concentrations were associated with allergic disease risk in the offspring at 1 y of age in a population at high risk of allergy. METHODS: The cohort consisted of 561 mother-infant pairs from Western Australia. To be eligible the infant had to have a first-degree relative (mother, father, or sibling) with a history of medically diagnosed allergic disease. Maternal venous blood was collected between 36 and 40 wk of gestation. Serum UMFA was measured by LC-tandem MS. Serum total folate was determined using a microbiological method with chloramphenicol-resistant Lactobacillus rhamnosus as the test organism, and was collected between 36 and 40 wk of gestation. UMFA concentrations were measured by tandem MS using stable isotope dilution; folate concentrations were determined using the microbiological method with standardized kits. Infant allergic disease outcomes of medically diagnosed eczema, steroid-treated eczema, atopic eczema, IgE-mediated food allergy, allergen sensitization, and medically diagnosed wheeze were assessed at 1 y of age. RESULTS: Median (IQR) concentrations for UMFA and serum folate were 1.6 (0.6-4.7) and 53.2 (32.6-74.5) nmol/L, respectively. Of the infants, 34.6% had medically diagnosed eczema, 26.4% allergen sensitization, and 14.9% had an IgE-mediated food allergy. In both adjusted and unadjusted models there was little evidence of association between UMFA or serum folate and any of the infant allergy outcomes. CONCLUSIONS: In this cohort of children at high risk of allergic disease there was no association between maternal UMFA or serum folate concentrations measured in late pregnancy and allergic disease outcomes at 1 y of age.

Prenatal Nutritional Strategies to Reduce the Risk of Preterm Birth.

Worldwide, around 15 million preterm babies are born annually, and despite intensive research, the specific mechanisms triggering preterm birth (PTB) remain unclear. Cost-effective primary prevention strategies to reduce PTB are required, and nutritional interventions offer a promising alternative. Nutrients contribute to a variety of mechanisms that are potentially important to preterm delivery, such as infection, inflammation, oxidative stress, and muscle contractility. Several observational studies have explored the association between dietary nutrients and/or dietary patterns and PTB, often with contrasting results. Randomized trial evidence on the effects of supplementation with zinc, multiple micronutrients (iron and folic acid), and vitamin D is promising; however, results are inconsistent, and many studies are not adequately powered for outcomes of PTB. Large-scale clinical trials with PTB as the primary outcome are needed before any firm conclusions can be drawn for these nutrients. The strongest evidence to date for a nutritional solution exists for omega-3 long-chain polyunsaturated fatty acids (LCPUFAs), key nutrients in fish. In 2018, a Cochrane Review (including 70 studies) showed that prenatal supplementation with omega-3 LCPUFAs reduced the risk of PTB and early PTB (EPTB) compared with no omega-3 supplementation. However, the largest trial of omega-3 supplementation in pregnancy, the Omega-3 to Reduce the Incidence of Prematurity (ORIP) trial (n = 5,544), showed no reduction in EPTB and a reduction in PTB only in a prespecified analysis of singleton pregnancies. Exploratory analyses from the ORIP trial found that women with low baseline total omega-3 status were at higher risk of EPTB, and that this risk was substantially reduced with omega-3 supplementation. In contrast, women with replete or high baseline total omega-3 status were already at low risk of EPTB and additional omega-3 supplementation increased the risk of EPTB compared to control. These findings suggest that determining an individual woman's PUFA status may be the most precise way to inform recommendations to reduce her risk of PTB.

Docosahexaenoic Acid and Preterm Birth.

Preterm birth accounts for more than 85% of all perinatal complications and deaths. There are many short- and long-term consequences of being born too soon. These infants often require intensive care and are at increased risk of early morbidities often with life-long sequelae. Approximately 50% of all preterm births have unknown or unclear causes, and there are no effective primary prevention strategies in widespread clinical use. Epidemiological studies have observed an increased length of gestation in populations with high fish consumption. These findings have led to randomised controlled trials of omega-3 (n-3) long-chain polyunsaturated fatty acid (LCPUFA) supplementation which show that these dietary agents may delay the timing of birth and may have value as a prophylactic intervention in some women. This review presents the available evidence and discusses the relationship between prenatal n-3 LCPUFA supplementation during pregnancy and the incidence of preterm birth.

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.

Predictors of compliance with higher dose omega-3 fatty acid supplementation during pregnancy and implications for the risk of prematurity: exploratory analysis of the ORIP randomised trial.

BACKGROUND: Intention-to-treat analyses of the Omega-3 to Reduce the Incidence of Prematurity (ORIP) trial found that omega-3 (n-3) fatty acid supplementation reduces the risk of prematurity in the subgroup of women with a singleton pregnancy and low n-3 status early in pregnancy, but not overall. However, results may have been influenced by less-than-optimal compliance. OBJECTIVES: To identify predictors of compliance with n-3 supplementation and determine treatment effects among compliers. DESIGN: Exploratory analyses of a multicentre-blinded randomised trial. SETTING: 6 tertiary care centres in Australia. PARTICIPANTS: 5328 singleton pregnancies. INTERVENTIONS: Daily capsules containing 900 mg n-3 long-chain polyunsaturated fatty acids or vegetable oil, consumed from before 20 weeks gestation until 34 weeks gestation. OUTCOME MEASURES: Early preterm (<34 weeks gestation) and preterm birth (<37 weeks gestation). Women were considered compliant if they reported missing less than a third of their allocated capsules in the previous week during a mid-pregnancy appointment. RESULTS: Among 2654 singleton pregnancies in the n-3 intervention group, 1727 (65%) were deemed compliant with supplementation. Maternal characteristics associated with compliance included age, years of full-time education, consuming alcohol but not smoking in the 3 months leading up to pregnancy, fewer previous births and taking dietary supplements at enrolment. Based on complier average causal effects, n-3 supplementation reduced the risk of preterm birth in compliers (relative risk=0.76; 95% CI 0.60 to 0.97), but not early preterm birth (relative risk=0.80; 95% CI 0.44 to 1.46). Consistent with intention-to-treat analyses, the lack of an overall effect on early preterm birth in compliers appeared to be due to beneficial effects in women with low n-3 status at enrolment but not women with replete status. CONCLUSIONS: Results in compliers were similar to those from intention-to-treat analyses, suggesting that non-compliance was not a major factor in explaining outcomes from the ORIP trial. TRIAL REGISTRATION NUMBER: ACTRN12613001142729.

Growth of late preterm infants fed nutrient-enriched formula to 120 days corrected age-A randomized controlled trial.

Objectives: We aimed to compare the effects of nutrient-enriched formula with standard term formula on rate of body weight gain of late preterm infants appropriately grown for gestational age. Study design: A multi-center, randomized, controlled trial. Late preterm infants (34-37 weeks' gestation), with weight appropriate for gestational age (AGA), were randomized to nutrient enriched formula (NEF) with increased calories (22 kcal/30 ml) from protein, added bovine milk fat globule membrane, vitamin D and butyrate or standard term formula 20 kcal/30 ml (STF). Breastfed term infants were enrolled as an observational reference group (BFR). Primary outcome was rate of body weight gain from enrollment to 120 days corrected age (d/CA). Planned sample size was 100 infants per group. Secondary outcomes included body composition, weight, head circumference and length gain, and medically confirmed adverse events to 365 d/CA. Results: The trial was terminated early due to recruitment challenges and sample size was substantially reduced. 40 infants were randomized to NEF (n = 22) and STF (n = 18). 39 infants were enrolled in the BFR group. At 120 d/CA there was no evidence of a difference in weight gain between randomized groups (mean difference 1.77 g/day, 95% CI, -1.63 to 5.18, P = 0.31). Secondary outcomes showed a significant reduction in risk of infectious illness in the NEF group at 120 d/CA [relative risk 0.37 (95% CI, 0.16-0.85), P = 0.02]. Conclusion: We saw no difference in rate of body weight gain between AGA late preterm infants fed NEF compared to STF. Results should be interpreted with caution due to small sample size. Clinical Trial Registration: The Australia New Zealand Clinical Trials Registry (ACTRN 12618000092291). "mailto:maria.makrides@sahmri.com" maria.makrides@sahmri.com.

Identifying women who may benefit from higher dose omega-3 supplementation during pregnancy to reduce their risk of prematurity: exploratory analyses from the ORIP trial.

OBJECTIVES: The risk factors for prematurity are multifactorial and include low omega-3 status. Omega-3 supplementation in pregnancy has been found to reduce prematurity risk, particularly among women with low omega-3 levels. This study aimed to identify maternal characteristics that predict whether women with a singleton pregnancy will benefit from omega-3 supplementation to reduce their risk of prematurity. DESIGN: Exploratory analyses of a multicentre, double-blind randomised trial. SETTING: 6 tertiary care centres in four states in Australia. PARTICIPANTS: 5328 singleton pregnancies in 5305 women recruited before 20 weeks of gestation. INTERVENTIONS: Fish oil capsules containing 900 mg omega-3 long-chain polyunsaturated fatty acids per day versus vegetable oil capsules consumed from enrolment until 34 weeks' gestation. OUTCOME MEASURES: Early preterm birth (EPTB, <34 weeks' gestation) and preterm birth (PTB, <37 weeks' gestation) analysed using logistic regression models with interactions between treatment group and a range of maternal biological, clinical and demographic characteristics. RESULTS: Omega-3 supplementation reduced the odds of EPTB for women with low total omega-3 status in early pregnancy (OR=0.30, 95% CI 0.10-0.93). No additional maternal characteristics influenced whether omega-3 supplementation reduced the odds of EPTB. For PTB, women were more likely to benefit from omega-3 supplementation if they were multiparous (OR=0.65, 95% CI 0.49-0.87) or avoided alcohol in the lead up to pregnancy (OR=0.62, 95% CI 0.45-0.86). CONCLUSIONS: Our results support previous findings that women with low total omega-3 levels in early pregnancy are most likely to benefit from taking omega-3 supplements to reduce their risk of EPTB. Understanding how other maternal characteristics influence the effectiveness of omega-3 supplementation on reducing PTB requires further investigation. TRIAL REGISTRATION NUMBER: ACTRN12613001142729.

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.

Translating n-3 polyunsaturated fatty acid status from whole blood to plasma and red blood cells during pregnancy: Translating n-3 status across blood fractions in pregnancy.

Women with low n-3 (omega-3) status in pregnancy can reduce their risk of early preterm birth (<34 weeks' gestation) through n-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation. As investigators measure fatty acid status in different blood fractions, equations are needed to compare results across studies. Similarly, derived cut-points for defining low and replete n-3 status are needed to assist clinical interpretation during early pregnancy. Our aims were to develop equations to convert the percentage of total n-3 fatty acids, EPA+DHA and DHA between whole blood, plasma and red blood cells (RBC), and to derive cut-points for defining low and replete total n-3 fatty acid status in plasma and RBC from those already established in whole blood. Using blood samples from 457 pregnant women in a multicentre randomised controlled trial, equations for these interconversions were developed using simple linear regression models. Measures of n-3 fatty acid status in whole blood and plasma were strongly related (R2 > 0.85), while more moderate relationships were observed between measures in whole blood and RBC (R2 0.55 - 0.71), or plasma and RBC (R2 0.55 - 0.63). Using the conversion equations, established cut-points for low and replete n-3 status in whole blood (<4.2% and >4.9% of total fatty acids) converted to <3.7% and >4.3% of plasma total fatty acids, and to <7.3% and >8.1% of RBC total fatty acids. Agreement to define low and replete n-3 status was better between whole blood and plasma, rather than between whole blood and RBC. Our data also show that total n-3 fatty acids in plasma and serum are interchangeable. We conclude that either whole blood or plasma total n-3 fatty acids can be used to define low status in pregnancy and identify women who will most benefit from n-3 LCPUFA supplementation to reduce their risk of early birth. Further research is needed to determine the clinical utility of other fatty acid measures in various blood lipid fractions.

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.

Breastfeeding outcomes in late preterm infants: A multi-centre prospective cohort study.

OBJECTIVES: To describe (1) infant feeding practices during initial hospitalisation and up to 6 months corrected age (CA) in infants born late preterm with mothers intending to breastfeed, (2) the impact of early feeding practices on hospital length of stay and (3) maternal and infant factors associated with duration of breastfeeding. METHODS: We conducted a prospective cohort study of infants born at 34+0 to 36+6 weeks gestational age during 2018-2020. Families were followed up until the infant reached 6 months of age (corrected for prematurity). Feeding practices during the birth hospitalisation, length of initial hospital stay, and the prevalence of exclusive or any breastfeeding at 6 weeks, 3 months, and 6 months CA were examined. Associations between maternal and infant characteristics and breastfeeding at 6 weeks, 3 months and 6 months CA were assessed using multivariable logistic regression models. RESULTS: 270 infants were enrolled, of these, 30% were multiple births. Overall, 78% of infants received only breastmilk as their first feed, and 83% received formula during the hospitalisation. Seventy-four per cent of infants were exclusively breastfed at discharge, 41% at 6 weeks CA, 35% at 3 months CA, and 29% at 6 months CA. The corresponding combined exclusive and partial breastfeeding rates (any breastfeeding) were 72%, 64%, and 53% of babies at 6 weeks CA, 3 months CA, and 6 months CA, respectively. The mean duration of hospitalisation was 2.9 days longer (95% confidence interval (CI) 0.31, 5.43 days) in infants who received any formula compared with those receiving only breastmilk (adjusted for GA, maternal age, multiple birth, site, and neonatal intensive care unit admission). In multivariable models, receipt of formula as the first milk feed was associated with a reduction in exclusive breastfeeding at 6 weeks CA (odds ratio = 0.22; 95% CI 0.09 to 0.53) and intention to breastfeed >6 months with an increase (odds ratio = 4.98; 95% CI 2.39 to 10.40). Intention to breastfeed >6 months remained an important predictor of exclusive breastfeeding at 3 and 6 months CA. CONCLUSIONS: Our study demonstrates that long-term exclusive breastfeeding rates were low in a cohort of women intending to provide breastmilk to their late preterm infants, with approximately half providing any breastmilk at 6 months CA. Formula as the first milk feed and intention to breastfeed >6 months were significant predictors of breastfeeding duration. Improving breastfeeding outcomes may require strategies to support early lactation and a better understanding of the ongoing support needs of this population.