Publications by authors named "Maria Makrides"

180 Publications

The Influence of Prenatal DHA Supplementation on Individual Domains of Behavioral Functioning in School-Aged Children: Follow-Up of a Randomized Controlled Trial.

Nutrients 2021 Aug 27;13(9). Epub 2021 Aug 27.

Women and Kids, South Australian Health and Medical Research Institute, 72 King William Road, Adelaide 5006, Australia.

Docosahexaenoic acid (DHA) accumulates in the fetal brain during pregnancy and is thought to have a role in supporting neurodevelopment. We conducted a multicenter, double-blind, randomized controlled trial in women with a singleton pregnancy who were <21 weeks' gestation at trial entry. Women were provided with 800 mg DHA/day or a placebo supplement from trial entry until birth. When children reached seven years of age, we invited parents to complete the Strengths and Difficulties Questionnaire (SDQ), the Behavior Rating Inventory of Executive Function (BRIEF), and the Conners 3rd Edition Attention-Deficit Hyperactivity Disorder (ADHD) Index to assess child behavior and behavioral manifestations of executive dysfunction. There were 543 parent-child pairs (85% of those eligible) that participated in the follow-up. Scores were worse in the DHA group than the placebo group for the BRIEF Global Executive, Behavioral Regulation and Metacognition Indexes, and the Shift, Inhibit, Monitor, Working Memory, and Organization of Materials scales, as well as for the Conners 3 ADHD index, and the SDQ Total Difficulties score, Hyperactivity/Inattention score, and Peer Relationship Problems score. In this healthy, largely term-born sample of children, prenatal DHA supplementation conferred no advantage to childhood behavior, and instead appeared to have an adverse effect on behavioral functioning, as assessed by standardized parental report scales.
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http://dx.doi.org/10.3390/nu13092996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472059PMC
August 2021

Consequences of using chronological age versus corrected age when testing cognitive and motor development in infancy and intelligence quotient at school age for children born preterm.

PLoS One 2021 2;16(9):e0256824. Epub 2021 Sep 2.

Women and Kids, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

Background: Children born preterm (<37 weeks' gestation) have an increased risk of poor neurodevelopment, including lower intelligence quotient (IQ) scores compared with their term-born counterparts.

Objective: To explore the differences in psychometric scores for cognition and motor skills when they are age-standardized according to chronological age instead of corrected age for children born preterm.

Methods: We assessed = 554 children born <33 weeks' gestation with the Bayley Scales of Infant Development, 2nd edition (mental and motor scores) at 18 months and the Weschler Abbreviated Scale of Intelligence (IQ score) at seven years of age. Scores were standardized according to chronological age and corrected age and differences between mean chronological and corrected scores were compared, along with the proportion of children whose scores could be classified as impaired.

Results: When scores were standardized according to chronological age instead of corrected age there was a large significant difference of 17.3 points on the mental scale (79.5 vs. 96.8, respectively) and 11.8 points on the motor scale (84.8 vs. 96.6, respectively) at 18 months. By seven years, the difference in IQ scores remained, although of a smaller magnitude at 1.9 points between mean chronological and corrected age scoring (97.2 vs. 99.1, respectively).

Conclusion: Consistent with previous literature, outcome assessments for preterm infants consistently differed according to use of chronological or corrected age to standardized scores. Cognitive scores were impacted more severely than motor scores, and differences were more substantial in early childhood than later in childhood. For clinical purposes, correction for preterm birth is only likely to have an impact during early childhood, however assessments for research purposes should continue to correct into childhood to account for the persistent bias due to preterm birth.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256824PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412365PMC
September 2021

Tailoring Human Milk Oligosaccharides to Prevent Necrotising Enterocolitis Among Preterm Infants.

Front Nutr 2021 29;8:702888. Epub 2021 Jul 29.

SAHMRI Women and Kids, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.

Necrotising enterocolitis (NEC) is a devastating disease affecting preterm infants, with little improvement in mortality rates and treatment strategies in the last 30 years. Human milk oligosaccharides (HMOs) are emerging as a potential preventive therapy, with multiple protective functions postulated. Our aim is to summarise the evidence concerning the role of HMOs in NEC development and emerging strategies to tailor the delivery of HMOs to preterm infants. Most research efforts to date have focused on supplementing preterm infants with simple oligosaccharides, which are structurally different to HMOs and derived mainly from plants. Clinical trials demonstrate limited benefits for NEC prevention arising from the use of these supplements. Alternative strategies under investigation include optimising HMOs for infants receiving donor human milk, concentrating oligosaccharides from donor human milk and from animal milks, as well as more sophisticated synthetic oligosaccharide production strategies. Critically, high quality evidence to support implementation of any of these approaches in the neonatal unit is lacking. Whether it is a specific HMO alone or a combination of HMOs that exert protective effects remains to be elucidated. Further challenges include how best to manufacture and administer oligosaccharides whilst retaining bioactivity and safety, including evaluation of the long-term effects of altering the balance of HMOs and gut microbiota in preterm infants. While several human clinical trials are underway, further research is needed to understand whether a tailored approach to oligosaccharide supplementation is beneficial for preterm infants.
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http://dx.doi.org/10.3389/fnut.2021.702888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357978PMC
July 2021

The Inclusion of Folic Acid in Weekly Iron-Folic Acid Supplements Confers no Additional Benefit on Anemia Reduction in Nonpregnant Women: A Randomized Controlled Trial in Malaysia.

J Nutr 2021 Aug;151(8):2264-2270

Food, Nutrition, and Health, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Weekly iron-folic acid (IFA) supplements are recommended for all menstruating women in countries where anemia prevalence is ≥20%; however, it is unknown whether the inclusion of folic acid in weekly IFA supplements reduces anemia.

Objectives: We examined whether the inclusion of folic acid in weekly IFA supplements conferred any benefit on hemoglobin (Hb) concentration, anemia reduction, or iron status [ferritin and soluble transferrin receptor (sTfR)], over iron alone.

Methods: In this secondary analysis of a randomized controlled trial in Malaysia, n = 311 nonpregnant women (18-45 y old) received 60 mg Fe with either 0, 0.4, or 2.8 mg folic acid once-weekly for 16 wk. Fasting blood was collected at baseline and 16 wk. A generalized linear model (normal distribution with identity link) was used to assess Hb concentration at 16 wk (primary outcome).

Results: At baseline, 84% of women had low folate status (plasma folate < 14 nmol/L). At 16 wk, marginal mean (95% CI) Hb was 131 (130, 133), 131 (129, 132), and 132 (130, 133) g/L; ferritin was 58.2 (53.9, 62.5), 56.5 (52.2, 60.9), and 58.0 (53.7, 62.3) μg/L; and sTfR was 5.8 (5.5, 6.1), 5.8 (5.5, 6.1), and 5.9 (5.6, 6.2) mg/L in the 0, 0.4, and 2.8 mg/wk groups, respectively, with no differences between groups (P > 0.05). Baseline plasma folate concentration did not modify the effect of treatment on Hb concentration at 16 wk. Among all women, the risks of anemia [risk ratio (RR): 0.65; 95% CI: 0.45, 0.96; P = 0.03] and iron deficiency based on ferritin (RR: 0.30; 95% CI: 0.20, 0.44; P < 0.001) were lower at 16 wk than at baseline.

Conclusions: Despite the low folate status among these nonpregnant Malaysian women, the inclusion of folic acid in weekly IFA supplements did not reduce anemia or improve iron status, over iron alone. However, the benefits of folic acid for neural tube defect prevention still warrant its retention in weekly IFA supplements.This trial was registered at www.anzctr.org.au as ACTRN12619000818134.
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http://dx.doi.org/10.1093/jn/nxab115DOI Listing
August 2021

Protocol for assessing if behavioural functioning of infants born <29 weeks' gestation is improved by omega-3 long-chain polyunsaturated fatty acids: follow-up of a randomised controlled trial.

BMJ Open 2021 05 5;11(5):e044740. Epub 2021 May 5.

Discipline of Paediatrics, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia.

Introduction: During the last trimester of pregnancy, the fetal brain undergoes a rapid growth spurt and accumulates essential nutrients including docosahexaenoic acid (DHA). This takes place ex-utero for infants born <29 weeks' gestation, without the in-utero provisions of DHA. Infants born <29 weeks' are more likely to experience behavioural and emotional difficulties than their term-born counterparts. It has been hypothesised that supplementing preterm infants with dietary DHA may alleviate insufficiency and subsequently prevent or minimise behavioural problems. This protocol describes a follow-up of infants born <29 weeks gestation who were enrolled in a randomised controlled trial (RCT) of DHA supplementation. We aim to determine whether DHA supplementation improves the behaviour, and general health of these infants.

Methods And Analysis: Infants born <29 weeks' gestation were enrolled in a multicentre blinded RCT of enteral DHA supplementation. Infants were randomised to receive an enteral emulsion that provided 60 mg/kg/day of DHA or a control emulsion commenced within the first 3 days of enteral feeding, until 36 weeks' postmenstrual age or discharge home, whichever occurred first. Families of surviving children (excluding those who withdrew from the study) from the Australian sites (up to 955) will be invited to complete a survey. The survey will include questions regarding child behavioural and emotional functioning, executive functioning, respiratory health and general health. We hypothesise that the DHA intervention will have a benefit on the primary outcome, parent-rated behaviour and emotional status as measured using the Total Difficulties score of the Strengths and Difficulties Questionnaire. Detecting a 2-point difference between groups (small effect size of 0.25 SD) with 90% power will require follow-up of 676 participants.

Ethics And Dissemination: The Women's and Children Health Network Human Research Ethics Committee reviewed and approved the study (HREC/16/WCHN/184). Results will be disseminated in peer-reviewed publications and conference presentations.

Trial Registration Number: ACTRN12612000503820.
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http://dx.doi.org/10.1136/bmjopen-2020-044740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103387PMC
May 2021

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

J Nutr 2021 Jun;151(6):1553-1560

School of Medicine, The University of Western Australia, Crawley, Australia.

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.
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http://dx.doi.org/10.1093/jn/nxab040DOI Listing
June 2021

New Methodologies for Conducting Maternal, Infant, and Child Nutrition Research in the Era of COVID-19.

Nutrients 2021 Mar 15;13(3). Epub 2021 Mar 15.

Women and Kids, South Australian Health and Medical Research Institute, 72 King William Road, Adelaide 5006, Australia.

The severe acute respiratory syndrome coronavirus disease 2019 (COVID-19) outbreak rapidly became a worldwide pandemic in early 2020. In Australia, government-mandated restrictions on non-essential face-to-face contact in the healthcare setting have been crucial for limiting opportunities for COVID-19 transmission, but they have severely limited, and even halted, many research activities. Our institute's research practices in the vulnerable populations of pregnant women and young infants needed to adapt in order to continue without exposing participants, or staff, to an increased risk of exposure to COVID-19. Here, we discuss our pre-and-post COVID-19 methods for conducting research regarding nutrition during pregnancy, infancy, and early childhood. We discuss modifications to study methods implemented to avoid face-to-face contact when identifying and recruiting potential participants, gaining informed consent, conducting appointments, and collecting outcome data, and the implications of these changes. The COVID-19 pandemic has required numerous changes to the conduct of research activities, but many of those modifications will be useful in post-COVID-19 research settings.
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http://dx.doi.org/10.3390/nu13030941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002090PMC
March 2021

Plasma long-chain omega-3 fatty acid status and risk of recurrent early spontaneous preterm birth: a prospective observational study.

Acta Obstet Gynecol Scand 2021 08 4;100(8):1401-1411. Epub 2021 May 4.

Harris-Wellbeing Research Centre, University of Liverpool, Liverpool, KE, UK.

Introduction: A 2018 Cochrane review found that omega-3 supplementation in pregnancy was associated with a risk reduction of early preterm birth of 0.58; prompting calls for universal supplementation. Recent analysis suggests the benefit may be confined to women with a low baseline omega-3 fatty acid status. However, the contemporary omega-3 fatty acid status of pregnant women in the UK is largely unknown. This is particularly pertinent for women with a previous preterm birth, in whom a small relative risk reduction would have a larger reduction of absolute risk. This study aimed to assess the omega-3 fatty acid status of a UK pregnant population and determine the association between the long-chain omega-3 fatty acids and recurrent spontaneous early preterm birth.

Material And Methods: A total of 283 high-risk women with previous early preterm birth were recruited to the prospective observational study in Liverpool, UK. Additionally, 96 pregnant women with previous term births and birth ≥39 weeks in the index pregnancy provided a low-risk population sample. Within the high-risk group we assessed the odds ratio of recurrent early preterm birth compared with birth at ≥37 weeks of gestation according to plasma eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) at 15-22 weeks of gestation.

Results: Our participants had low EPA+DHA; 62% (143/229) of women with previous preterm birth and 69% (68/96) of the population sample had levels within the lowest two quintiles of a previously published pregnancy cohort. We found no association between long-chain omega-3 status and recurrent early preterm birth (n = 51). The crude odds ratio of a recurrent event was 0.91 (95% CI 0.38-2.15, p = 0.83) for women in the lowest, compared with the highest three quintiles of EPA+DHA.

Conclusions: In the majority of our participants, levels of long-chain omega-3 were low; within the range that may benefit from supplementation. However, levels showed no association with risk of recurrent early spontaneous preterm birth. This could be because our population levels were too low to show benefit in being omega-3 "replete"; or else omega-3 levels may be of lesser importance in recurrent early preterm birth.
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http://dx.doi.org/10.1111/aogs.14147DOI Listing
August 2021

The iron content of healthy diets for one day for breastfed babies and young children.

Nutr Diet 2021 09 16;78(4):415-423. Epub 2021 Feb 16.

South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

Aims: Early childhood anaemia due to iron deficiency is widespread in remote communities across northern Australia. Current recommendations for healthy food to complement breastfeeding at age 6 to 23 months include iron-rich and iron-enriched foods. An electronic nutrient analysis was undertaken to assess the iron content of hypothetical healthy diets for breastfed babies and young children aged 6 to 23 months in Australia, in comparison with their estimated requirements.

Methods: Hypothetical diets for 1 day were developed that were consistent with the Foundation Diets for breastfed infants 6 to 12 months and for toddlers 13 to 23 months. Nutrient content was derived using the Australian Food Composition database in FoodWorks 10. The iron content of these two diets were compared with Estimated Average Requirements (EARs) and Recommended Dietary Intakes (RDIs) for iron for infants aged 7 to 12 months and children aged 1 to 3 years.

Results: The iron content of the hypothetical diet for breastfed infants aged 6 to 12 months (5.8 mg) was less than the EAR (7 mg, 83%) and the RDI (11 mg, 53%). For young breastfed children aged 13 to 23 months, the iron content of the hypothetical diet was 4.4 mg; above the EAR (4 mg, 110%) but less than RDI (9 mg, 49%).

Conclusions: Breastfeeding has health and neurodevelopmental benefits for infants and young children that are particularly important in remote Australia where food insecurity and poor nutrition compromise health and wellbeing. Adequate iron intake is also important for neurodevelopment in early life but healthy diets for breastfed babies and young children may have insufficient iron content to meet requirements. The upcoming revision of the Australian Dietary Guidelines provides an opportunity to consider this issue.
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http://dx.doi.org/10.1111/1747-0080.12655DOI Listing
September 2021

Protocol for assessing whether cognition of preterm infants <29 weeks' gestation can be improved by an intervention with the omega-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA): a follow-up of a randomised controlled trial.

BMJ Open 2021 02 5;11(2):e041597. Epub 2021 Feb 5.

Women and Kids, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

Introduction: Docosahexaenoic acid (DHA) is an omega-3 (n-3) fatty acid that accumulates into neural tissue during the last trimester of pregnancy, as the fetal brain is undergoing a growth spurt. Infants born <29 weeks' gestation are deprived the normal in utero supply of DHA during this period of rapid brain development. Insufficient dietary DHA postnatally may contribute to the cognitive impairments common among this population. This follow-up of the N-3 fatty acids for improvement in respiratory outcomes (N3RO) randomised controlled trial aims to determine if enteral DHA supplementation in infants born <29 weeks' gestation during the first months of life improves cognitive development at 5 years of age corrected for prematurity.

Methods And Analysis: N3RO was a randomised controlled trial of enteral DHA supplementation (60 mg/kg/day) or a control emulsion (without DHA) in 1273 infants born <29 weeks' gestation to determine the effect on bronchopulmonary dysplasia (BPD). We showed that DHA supplementation did not reduce the risk of BPD and may have increased the risk.In this follow-up at 5 years' corrected age, a predefined subset (n=655) of children from five Australian sites will be invited to attend a cognitive assessment with a psychologist. Children will be administered the Wechsler Preschool and Primary Scale of Intelligence (fourth edition) and a measure of inhibitory control (fruit stroop), while height, weight and head circumference will be measured.The primary outcome is full-scale IQ. To ensure 90% power, a minimum of 592 children are needed to detect a four-point difference in IQ between the groups.Research personnel and families remain blinded to group assignment.

Ethics And Dissemination: The Women's and Children Health Network Human Research Ethics Committee reviewed and approved the study (HREC/17/WCHN/187). Caregivers will give informed consent prior to taking part in this follow-up study. Findings of this study will be disseminated through peer-reviewed publications and conference presentations.

Trial Registration Number: ACTRN12612000503820.
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http://dx.doi.org/10.1136/bmjopen-2020-041597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925903PMC
February 2021

The Influence of Omega-3 Long-Chain Polyunsaturated Fatty Acid, Docosahexaenoic Acid, on Child Behavioral Functioning: A Review of Randomized Controlled Trials of DHA Supplementation in Pregnancy, the Neonatal Period and Infancy.

Nutrients 2021 Jan 28;13(2). Epub 2021 Jan 28.

Women and Kids, South Australian Health and Medical Research Institute, 72 King William Road, 5006 Adelaide, Australia.

This is a review of randomized controlled trials using docosahexaenoic acid (DHA) interventions in the first 1000 days of life with assessments of behavioral functioning in childhood. Electronic databases were searched for trials with a DHA intervention (compared with a placebo group that received no or less DHA) at any time to either women or infants during the first 1000 days, with a subsequent assessment of child behavior. There were 25 trials involving 10,320 mother-child pairs, and 71 assessments of behavior in 6867 of the children (66.5% of those originally enrolled). From the 71 assessments administered, there were 401 comparisons between a DHA group and a control group, with most reporting a null effect. There were no findings of a positive effect of DHA, and 23 instances where the DHA group had worse scores compared with the control group. There was limited evidence that DHA supplementation had any effect on behavioral development, although two of the largest trials with behavioral measures detected adverse effects. Future trials, and future follow-ups of existing trials, should make an effort to evaluate the effect of DHA intervention on behavioral functioning.
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http://dx.doi.org/10.3390/nu13020415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911027PMC
January 2021

Associations between newborn thyroid-stimulating hormone concentration and neurodevelopment and growth of children at 18 months.

Br J Nutr 2021 Nov 26;126(10):1478-1488. Epub 2021 Jan 26.

School of Agriculture Food and Wine, Faculty of Sciences, The University of Adelaide, Adelaide, Australia.

The study aimed to assess the associations between newborn thyroid-stimulating hormone (TSH) concentration, a marker of iodine nutrition in early life, and childhood neurodevelopment and growth using data collected from two pregnancy studies, one in a borderline iodine-deficient setting (DHA to Optimize Mother Infant Outcome (DOMInO) Study) and one in an iodine-sufficient setting (Pregnancy Iodine and Neurodevelopment in Kids (PINK) Study). TSH data were obtained from routine newborn screening. Neurodevelopment was assessed at 18 months using the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III). Weight, height and head circumference were measured at 18 months. In total, 1467 children were included in the analysis. Comparing the highest with the lowest TSH quartile, the mean differences (MD) in the Bayley-III scores ranged from -2·0 (95 % CI -4·7, 0·7) to -2·2 (95 % CI -5·8, 1·3) points in DOMInO and 1·0 (95 % CI -1·6, 3·6) to 2·0 (95 % CI -0·4, 4·4) points in PINK in the cognitive, language and motor scales; the MD in the anthropometric z scores ranged from -0·01 (95 % CI -0·5, 0·5) to -0·5 (95 % CI -0·9, -0·1) in both studies. A 1 mIU/l increase in TSH was associated with -0·3 (95 % CI -0·9, 0·2) point and 0·2 (95 % CI -0·3, 0·7) point changes in the mean cognitive score in the DOMInO and PINK, respectively. A null association between TSH and growth was also observed in both studies. Longitudinal studies that utilise newborn TSH data and examine neurodevelopmental outcomes at later ages are warranted, as neurodevelopmental assessments in older children are more predictive of later achievement.
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http://dx.doi.org/10.1017/S0007114521000325DOI Listing
November 2021

Associations between diet, the gut microbiome and short chain fatty acids in youth with islet autoimmunity and type 1 diabetes.

Pediatr Diabetes 2021 05 1;22(3):425-433. Epub 2021 Feb 1.

Women's and Children's Hospital, Adelaide, South Australia, Australia.

Aim: We aimed to characterize associations between diet and the gut microbiome and short chain fatty acid (SCFA) products in youth with islet autoimmunity or type 1 diabetes (IA/T1D) in comparison with controls.

Research Design And Methods: Eighty participants (25 diagnosed with T1D, 17 with confirmed IA, 38 sibling or unrelated controls) from the Australian T1D Gut Study cohort were studied (median [IQR] age 11.7 [8.9, 14.0] years, 43% female). A Food Frequency Questionnaire characterized daily macronutrient intake over the preceding 6 months. Plasma and fecal SCFA were measured by gas chromatography; gut microbiome composition and diversity by 16S rRNA gene sequencing.

Results: A 10 g increase in daily carbohydrate intake associated with higher plasma acetate in IA/T1D (adjusted estimate +5.2 (95% CI 1.1, 9.2) μmol/L p = 0.01) and controls (adjusted estimate +4.1 [95% CI 1.7, 8.5] μmol/L p = 0.04). A 5 g increase in total fat intake associated with lower plasma acetate in IA/T1D and controls. A 5% increase in noncore (junk) food intake associated with reduced richness (adjusted estimate -4.09 [95%CI -7.83, -0.35] p = .03) and evenness (-1.25 [95% CI -2.00, -0.49] p < 0.01) of the gut microbiome in IA/T1D. Fiber intake associated with community structure of the microbiome in IA/T1D.

Conclusions: Modest increments in carbohydrate and fat intake associated with plasma acetate in all youth. Increased junk food intake associated with reduced diversity of the gut microbiome in IA/T1D alone. These associations with the gut microbiome in IA/T1D support future efforts to promote SCFA by using dietary interventions.
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http://dx.doi.org/10.1111/pedi.13178DOI Listing
May 2021

Prenatal Nutritional Strategies to Reduce the Risk of Preterm Birth.

Ann Nutr Metab 2020 19;76 Suppl 3:31-39. Epub 2021 Jan 19.

Women and Kids Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

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.
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http://dx.doi.org/10.1159/000509901DOI Listing
September 2021

Weekly iron-folic acid supplements containing 2.8 mg folic acid are associated with a lower risk of neural tube defects than the current practice of 0.4 mg: a randomised controlled trial in Malaysia.

BMJ Glob Health 2020 12;5(12)

SAHMRI Women and Kids, South Australia Health and Medical Research Institute, Adelaide, South Australia, Australia

Introduction: Weekly iron-folic acid (IFA) supplements are recommended for all menstruating women in countries where anaemia prevalence is >20%. Anaemia caused by folate deficiency is low worldwide, and the need to include folic acid is in question. Including folic acid might reduce the risk of a neural tube defect (NTD) should a woman become pregnant. Most weekly supplements contain 0.4 mg folic acid; however, WHO recommends 2.8 mg because it is seven times the daily dose effective in reducing NTDs. There is a reluctance to switch to supplements containing 2.8 mg of folic acid because of a lack of evidence that this dose would prevent NTDs. Our aim was to investigate the effect of two doses of folic acid, compared with placebo, on red blood cell (RBC) folate, a biomarker of NTD risk.

Methods: We conducted a three-arm double-blind efficacy trial in Malaysia. Non-pregnant women (n=331) were randomised to receive 60 mg iron and either 0, 0.4, or 2.8 mg folic acid once weekly for 16 weeks.

Results: At 16 weeks, women receiving 0.4 mg and 2.8 mg folic acid per week had a higher mean RBC folate than those receiving 0 mg (mean difference (95% CI) 84 (54 to 113) and 355 (316 to 394) nmol/L, respectively). Women receiving 2.8 mg folic acid had a 271 (234 to 309) nmol/L greater mean RBC folate than those receiving 0.4 mg. Moreover, women in the 2.8 mg group were seven times (RR 7.3, 95% CI 3.9 to 13.7; p<0.0001) more likely to achieve an RBC folate >748 nmol/L, a concentration associated with a low risk of NTD, compared with the 0.4 mg group.

Conclusion: Weekly IFA supplements containing 2.8 mg folic acid increases RBC folate more than those containing 0.4 mg. Increased availability and access to the 2.8 mg formulation is needed.

Trail Registration Number: This trial is registered with the Australian New Zealand Clinical Trial Registry (ACTRN12619000818134).
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http://dx.doi.org/10.1136/bmjgh-2020-003897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716666PMC
December 2020

Study protocol for a randomised controlled trial evaluating the effect of folic acid supplementation beyond the first trimester on maternal plasma unmetabolised folic acid in late gestation.

BMJ Open 2020 11 16;10(11):e040416. Epub 2020 Nov 16.

SAHMRI Women and Kids Theme, South Australia Health and Medical Research Institute, Adelaide, South Australia, Australia

Introduction: Taking folic acid containing supplements prior to and during early pregnancy reduces the risk of neural tube defects. Neural tube defects occur prior to 28 days postconception, after which, there is no proven benefit of continuing to take folic acid. However, many women continue to take folic acid containing supplements throughout the pregnancy. At higher intakes, folic acid is not converted to its active form and accumulates in circulation as unmetabolised folic acid (UMFA). Recently, concerns have been raised about possible links between late gestation folic acid supplementation and childhood allergy, metabolic disease and autism spectrum disorders. We aim to determine if removing folic acid from prenatal micronutrient supplements after 12 weeks gestation reduces circulating levels of maternal UMFA at 36 weeks gestation.

Methods And Analysis: This is a parallel-design, double-blinded randomised controlled trial. Women ≥12 and <16 weeks' gestation with a singleton pregnancy and able to give informed consent are eligible to participate. Women (n=100; 50 per group) will be randomised to receive either a micronutrient supplement containing 0.8 mg of folic acid or a micronutrient supplement without folic acid daily from enrolment until delivery. The primary outcome is plasma UMFA concentration at 36 weeks gestation. Secondary outcomes include red blood cell folate and total plasma folate concentration. We will assess whether there is a difference in mean UMFA levels at 36 weeks gestation between groups using linear regression with adjustment for baseline UMFA levels and gestational age at trial entry. The treatment effect will be 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/19/WCHN/018). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals.

Trial Registration Number: ACTRN12619001511123.
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http://dx.doi.org/10.1136/bmjopen-2020-040416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670954PMC
November 2020

The Influence of DHA on Language Development: A Review of Randomized Controlled Trials of DHA Supplementation in Pregnancy, the Neonatal Period, and Infancy.

Nutrients 2020 Oct 12;12(10). Epub 2020 Oct 12.

Women and Kids, South Australian Health and Medical Research Institute, 72 King William Road, North Adelaide 5006, Australia.

This review summarizes randomized controlled trials (RCTs) assessing the effect of docosahexaenoic acid (DHA) supplementation in the first 1000 days on child language. Six databases were searched and RCTs were included if they involved supplementation with DHA during pregnancy, to preterm infants, or during the postpartum period, included a placebo group with less or no DHA, and reported a language outcome. We included 29 RCTs involving = 10,405 participants from 49 publications. There was a total of 84 language measures at ages ranging from 3 months to 12 years. Of the 84 assessments, there were 4 instances where the DHA group had improved scores, and 2 instances where the DHA group had worse scores (with the majority of these significant effects found within one RCT). The remaining comparisons were null. A few RCTs that included subgroup analyses reported (inconsistent) effects. There was limited evidence that DHA supplementation had any effect on language development, although there were some rare instances of both possible positive and adverse effects, particularly within population subgroups. It is important that any subgroup effects are verified in future trials that are adequately powered to confirm such effects.
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http://dx.doi.org/10.3390/nu12103106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599780PMC
October 2020

Longitudinal egg-specific regulatory T- and B-cell development: Insights from primary prevention clinical trials examining the timing of egg introduction.

Allergy 2021 05 29;76(5):1385-1397. Epub 2020 Oct 29.

Department of Allergy and Immunology, The Children's Hospital at Westmead, Westmead, NSW, Australia.

Background: Egg allergy affects almost 1 in 10 Australian infants. Early egg introduction has been associated with a reduced risk in developing egg allergy; however, the immune mechanisms underlying this protection remain unclear.

Objective: To examine the role of regulatory immune cells in tolerance induction during early egg introduction.

Methods: Cryopreserved peripheral blood mononuclear cells (PBMC) were obtained from infants from 2 randomized controlled trials of early introduction of egg for the primary prevention of egg allergy; BEAT (at 12 months, n = 42) and STEP (at 5 months n = 82; 12 months n = 82) study cohorts. In vitro ovalbumin-stimulated PBMC were analyzed by flow cytometry for presence of ovalbumin-specific regulatory T cells, using activation markers, FoxP3, and IL-10 expression. Ovalbumin-specific regulatory B cells were identified by co-expression of fluorescence-conjugated ovalbumin and IL-10.

Results: Specific, age-dependent expansion of ovalbumin-specific regulatory T cells was only observed in infants who (a) had early egg introduction and (b) did not have egg allergy at 12 months. This expansion was blunted or impaired in children who did not undergo early egg introduction and in those with clinical egg allergy at 12 months. Infants with egg allergy at 12 months of age also had reduced frequency of ovalbumin-specific regulatory B cells compared to egg-tolerant infants.

Conclusion: Early egg introduction and clinical tolerance to egg were associated with expansion of ovalbumin-specific T and B regulatory cells, which may be an important developmental process for tolerance acquisition to food allergens.
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http://dx.doi.org/10.1111/all.14621DOI Listing
May 2021

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.

Br J Nutr 2021 02 14;125(4):420-431. Epub 2020 Jul 14.

SAHMRI Women and Kids, South Australian Health and Medical Research Institute, North Adelaide, SA5006, Australia.

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.
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http://dx.doi.org/10.1017/S0007114520002500DOI Listing
February 2021

Association of Poor Postnatal Growth with Neurodevelopmental Impairment in Infancy and Childhood: Comparing the Fetus and the Healthy Preterm Infant References.

J Pediatr 2020 10 7;225:37-43.e5. Epub 2020 Jun 7.

Division of Neonatology and Newborn Medicine, Department of Pediatrics, Massachusetts General Hospital, Boston, MA.

Objectives: To compare the classification of preterm postnatal poor growth using healthy preterm vs fetal growth references and to examine associations with neurodevelopmental impairment in infancy and childhood.

Study Design: We included 613 infants born at <33 weeks of gestation. Using the INTERGROWTH-21 (healthy-preterm growth) reference and the Fenton and Olsen (fetal growth) references, we classified poor growth as a decline in z-score from birth to term-equivalent >0.8 SD (weight), >1 SD (head), and >2 SD (length). We used generalized estimating equations to estimate aOR for neurodevelopmental impairment at 18 months and 7 years of corrected age, comparing infants with and without poor growth by each reference, accounting for multiple births and covariates.

Results: The prevalence of poor growth was higher with INTERGROWTH-21 than with fetal references for all measurements. Agreement was higher between the Fenton and Olsen (fetal) growth references (0.72-0.81) than between INTERGROWTH-21 and fetal references (0.41-0.59). Poor growth by fetal references (but not by INTERGROWTH-21) was associated with low neurodevelopmental scores in infancy and childhood. Poor weight gain using the Fenton reference was associated with 18-month Mental Developmental Index <85 (aOR 1.6, 95%CI: 1.1, 2.4) whereas poor weight gain by the INTERGROWTH-21 reference was not (aOR 1.0, 95%CI: 0.6, 1.7). Poor linear growth by the Olsen reference, but not INTERGROWTH-21, was associated with 7-year verbal intelligence quotient <70 (aOR 3.5, 95%CI: 1.1, 12.7).

Conclusions: Poor neonatal growth categorized using fetal references showed stronger associations with long term neurodevelopment than poor growth categorized using the INTERGROWTH-21 standards.
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http://dx.doi.org/10.1016/j.jpeds.2020.05.063DOI Listing
October 2020

Linking data from a large clinical trial with the Australian Cerebral Palsy Register.

Dev Med Child Neurol 2020 10 8;62(10):1170-1175. Epub 2020 May 8.

Discipline of Obstetrics and Gynaecology, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.

Aim: To link data from a large maternal perinatal trial with the Australian Cerebral Palsy Register (ACPR) to identify children with cerebral palsy (CP).

Method: Deidentified data from the Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO ) and the ACPR were linked. Children born from 1996 to 2000 at Australian hospitals who survived and had 2-year paediatric assessments were included. Children identified with CP in: (1) both the ACTOMgSO (2y) and the ACPR (5y), (2) the ACTOMgSO only, and (3) the ACPR only were compared.

Results: We included 913 children (492 males, 421 females; mean gestational age at birth 27.8wks [standard deviation 2.1wks]; range 23.0-40.0wks). Eighty-four children received a CP diagnosis: 35 by the ACTOMgSO and the ACPR, 29 by the ACTOMgSO only, and 20 by the ACPR only. The ACTOMgSO diagnosed 76.2% (95% confidence interval [CI] 65.9-84.1) and the ACPR identified 65.5% (95% CI 54.7-74.9). Children born in states/territories with long-standing versus more recently established registers were more likely to be included on the ACPR (p<0.05).

Interpretation: Linking deidentified perinatal trial data with the ACPR was achieved. Limitations of both strategies for identifying children with CP in this era (late 1990s and early 2000s) probably explain many of the differences observed, and inform future linkage studies and evaluations of CP-preventive interventions.

What This Paper Adds: Randomized trial data were linked with the Australian Cerebral Palsy Register. Trial (2y) and register (up to 5y) diagnoses of cerebral palsy (CP) differed. States with long-standing registers were more likely to include children with CP.
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http://dx.doi.org/10.1111/dmcn.14556DOI Listing
October 2020

Red Blood Cell Folate Likely Overestimated in Australian National Survey: Implications for Neural Tube Defect Risk.

Nutrients 2020 May 1;12(5). Epub 2020 May 1.

Women and Kids Theme, South Australian Health and Medical Research Institute, Adelaide 5000, South Australia, Australia.

In 2009, the Australian government mandated the addition of folic acid to bread flour to reduce the incidence of neural tube defects (NTD)-affected pregnancies. In 2011-2012, the Australian Health Measures Survey (AHMS) reported a mean red blood cell (RBC) folate in women of reproductive age (16-44 y) of 1647 nmol/L. Over 99% of women had an RBC folate ≥ 906 nmol/L, a concentration consistent with a very low risk of NTDs if a woman became pregnant. However, RBC folate was measured using an immunoassay, which is not a recommended method due to questionable accuracy. The microbiological assay is the preferred method for RBC folate measurement. To determine whether the immunoassay method may have led to spurious conclusions about the folate status of Australian women, we collected fasting blood samples from 74 healthy non-pregnant, non-lactating women (18-44 y) and measured RBC folate using both the immunoassay and microbiological methods. Mean RBC folate (95% confidence interval) concentration measured with the immunoassay method was 1735 (1666, 1804) nmol/L compared with 942 (887, 1012) nmol/L using the microbiological method. No woman had an RBC folate < 906 nmol/L using the immunoassay method, whereas 46% of women had an RBC folate < 906 nmol/L using the microbiological method. The NTD risk was estimated to be 0.06% using the immunoassay method and 0.14% using the microbiological method. RBC folate using AHMS survey may have underestimated NTD risk in Australian women.
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http://dx.doi.org/10.3390/nu12051283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281964PMC
May 2020

Effect of once weekly folic acid supplementation on erythrocyte folate concentrations in women to determine potential to prevent neural tube defects: a randomised controlled dose-finding trial in Malaysia.

BMJ Open 2020 02 5;10(2):e034598. Epub 2020 Feb 5.

Food, Nutrition, and Health, University of British Columbia, Vancouver, British Columbia, Canada

Introduction: Folic acid (0.4 mg) taken prior to and during early pregnancy reduces the risk of neural tube defects (NTDs). Because these birth defects occur early in pregnancy, before women may know they are pregnant, many countries have mandated the addition of folic acid to food staples. In countries where fortification is not possible, and weekly iron folic acid programmes exist to reduce anaemia, the WHO recommends that 2.8 mg (7×0.4 mg) folic acid be given instead of the current weekly practice of 0.4 mg. Currently, there is a lack of evidence to support if the 2.8 mg folic acid per week dose is sufficient to raise erythrocyte folate concentrations to a level associated with a reduced risk of a NTD-affected pregnancy. We aim to conduct a three-arm randomised controlled trial to determine the effect of weekly folic acid with iron on erythrocyte folate, a biomarker of NTD risk.

Methods And Analysis: We will recruit non-pregnant women (n=300; 18-45 years) from Selangor, Malaysia. Women will be randomised to receive either 2.8, 0.4 or 0.0 (placebo) mg folic acid with 60 mg iron weekly for 16 weeks, followed by a 4-week washout period. The primary outcome will be erythrocyte folate concentration at 16 weeks and the mean concentration will be compared between randomised treatment groups (intention-to-treat) using a linear regression model adjusting for the baseline measure.

Ethics And Dissemination: Ethical approval was obtained from the University of British Columbia (H18-00768) and Universiti Putra Malaysia (JKEUPM-2018-255). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals.

Trial Registration Numbers: ACTRN12619000818134 and NMRR-19-119-45736.
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http://dx.doi.org/10.1136/bmjopen-2019-034598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044827PMC
February 2020

Plasma oxylipins and unesterified precursor fatty acids are altered by DHA supplementation in pregnancy: Can they help predict risk of preterm birth?

Prostaglandins Leukot Essent Fatty Acids 2020 02 13;153:102041. Epub 2019 Dec 13.

School of Agriculture, Food and Wine, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.

Oxidized lipids derived from omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids, collectively known as oxylipins, are bioactive signaling molecules that play diverse roles in human health and disease. Supplementation with n-3 docosahexaenoic acid (DHA) during pregnancy has been reported to decrease the risk of preterm birth in singleton pregnancies, which may be due to effects of DHA supplementation on oxylipins or their precursor n-6 and n-3 fatty acids. There is only limited understanding of the levels and trajectory of changes in plasma oxylipins during pregnancy, effects of DHA supplementation on oxylipins and unesterified fatty acids, and whether and how oxylipins and their unesterified precursor fatty acids influence preterm birth. In the present study we used liquid chromatography-tandem mass spectrometry to profile oxylipins and their precursor fatty acids in the unesterified pool using plasma samples collected from a subset of pregnant Australian women who participated in the ORIP (Omega-3 fats to Reduce the Incidence of Prematurity) study. ORIP is a large randomized controlled trial testing whether daily supplementation with n-3 DHA can reduce the incidence of early preterm birth compared to control. Plasma was collected at study entry (≈pregnancy week 14) and again at ≈week 24, in a subgroup of 48 ORIP participants-12 cases with spontaneous preterm (<37 weeks) birth and 36 matched controls with spontaneous term (≥40 weeks) birth. In the combined preterm and term pregnancies, we observed that in the control group without DHA supplementation unesterified AA and AA-derived oxylipins 12-HETE, 15-HETE and TXB2 declined between weeks 14-24 of pregnancy. Compared to control, DHA supplementation increased unesterified DHA, EPA, and AA, DHA-derived 4-HDHA, 10-HDHA and 19,20-EpDPA, and AA-derived 12-HETE at 24 weeks. In exploratory analysis independent of DHA supplementation, participants with concentrations above the median for 5-lipoxygenase derivatives of AA (5-HETE, Odds Ratio (OR) 8.2; p = 0.014) or DHA (4-HDHA, OR 8.0; p = 0.015) at 14 weeks, or unesterified AA (OR 5.1; p = 0.038) at 24 weeks had higher risk of spontaneous preterm birth. The hypothesis that 5-lipoxygenase-derived oxylipins and unesterified AA could serve as mechanism-based biomarkers predicting spontaneous preterm birth should be evaluated in larger, adequately powered studies.
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http://dx.doi.org/10.1016/j.plefa.2019.102041DOI Listing
February 2020

Early childhood anaemia more than doubles the risk of developmental vulnerability at school-age among Aboriginal and Torres Strait Islander children of remote Far North Queensland: Findings of a retrospective cohort study.

Nutr Diet 2020 07 8;77(3):298-309. Epub 2020 Jan 8.

Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia.

Aims: Early childhood anaemia, usually attributed to iron deficiency, is associated with persistent detrimental effects on child development. This study investigates the association of anaemia between age six and 23 months with indicators of childhood development at school-age among children of remote Aboriginal and Torres Strait Islander communities of Far North Queensland.

Methods: The triennial Australian Early Development Census (AEDC) encompasses five domains of early childhood development-physical health and wellbeing, social competence, emotional maturity, language and cognitive skills (school-based), communication skills and general knowledge. AEDC 2012 and 2015 assessments were linked with health information for children and their mothers from remote Aboriginal and Torres Strait Islander communities of Far North Queensland.

Results: AEDC assessments were available for 250 children who had measurements of haemoglobin recorded at age 6 to 23 months. More children who had had early childhood anaemia (n = 66/143, 46.2%, [37.9%, 54.4%]) were developmentally vulnerable on two or more domains compared to those who had not been anaemic (n = 25/107, 23.4% [15.2%, 31.5%], P < .001). Multivariable analysis confirmed that early childhood anaemia more than doubled the risk of developmental vulnerability (OR 2.2 [1.1, 4.3] P = .020) at school age.

Conclusions: Early childhood anaemia is a risk factor for developmental vulnerability at school-age in this setting. Interventions combining nutrition promotion and multi-micronutrient food fortification, are effective in prevention of early childhood anaemia. Such interventions could also improve early childhood development and subsequent educational achievement.
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http://dx.doi.org/10.1111/1747-0080.12602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317940PMC
July 2020

Antenatal magnesium sulphate and adverse neonatal outcomes: A systematic review and meta-analysis.

PLoS Med 2019 12 6;16(12):e1002988. Epub 2019 Dec 6.

Robinson Research Institute, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.

Background: There is widespread, increasing use of magnesium sulphate in obstetric practice for pre-eclampsia, eclampsia, and preterm fetal neuroprotection; benefit for preventing preterm labour and birth (tocolysis) is unproven. We conducted a systematic review and meta-analysis to assess whether antenatal magnesium sulphate is associated with unintended adverse neonatal outcomes.

Methods And Findings: CINAHL, Cochrane Library, LILACS, MEDLINE, Embase, TOXLINE, and Web of Science, were searched (inceptions to 3 September 2019). Randomised, quasi-randomised, and non-randomised trials, cohort and case-control studies, and case reports assessing antenatal magnesium sulphate for pre-eclampsia, eclampsia, fetal neuroprotection, or tocolysis, compared with placebo/no treatment or a different magnesium sulphate regimen, were included. The primary outcome was perinatal death. Secondary outcomes included pre-specified and non-pre-specified adverse neonatal outcomes. Two reviewers screened 5,890 articles, extracted data, and assessed risk of bias following Cochrane Handbook and RTI Item Bank guidance. For randomised trials, pooled risk ratios (RRs) or mean differences, with 95% confidence intervals (CIs), were calculated using fixed- or random-effects meta-analysis. Non-randomised data were tabulated and narratively summarised. We included 197 studies (40 randomised trials, 138 non-randomised studies, and 19 case reports), of mixed quality. The 40 trials (randomising 19,265 women and their babies) were conducted from 1987 to 2018 across high- (16 trials) and low/middle-income countries (23 trials) (1 mixed). Indications included pre-eclampsia/eclampsia (24 trials), fetal neuroprotection (7 trials), and tocolysis (9 trials); 18 trials compared magnesium sulphate with placebo/no treatment, and 22 compared different regimens. For perinatal death, no clear difference in randomised trials was observed between magnesium sulphate and placebo/no treatment (RR 1.01; 95% CI 0.92 to 1.10; 8 trials, 13,654 babies), nor between regimens. Eleven of 138 non-randomised studies reported on perinatal death. Only 1 cohort (127 babies; moderate to high risk of bias) observed an increased risk of perinatal death with >48 versus ≤48 grams magnesium sulphate exposure for tocolysis. No clear secondary adverse neonatal outcomes were observed in randomised trials, and a very limited number of possible adverse outcomes warranting further consideration were identified in non-randomised studies. Where non-randomised studies observed possible harms, often no or few confounders were controlled for (moderate to high risk of bias), samples were small (200 babies or fewer), and/or results were from subgroup analyses. Limitations include missing data for important outcomes across most studies, heterogeneity of included studies, and inclusion of published data only.

Conclusions: Our findings do not support clear associations between antenatal magnesium sulphate for beneficial indications and adverse neonatal outcomes. Further large, high-quality studies (prospective cohorts or individual participant data meta-analyses) assessing specific outcomes, or the impact of regimen, pregnancy, or birth characteristics on these outcomes, would further inform safety recommendations. PROSPERO: CRD42013004451.
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http://dx.doi.org/10.1371/journal.pmed.1002988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897495PMC
December 2019

Omega-3 fatty acids to prevent preterm birth: Australian pregnant women's preterm birth awareness and intentions to increase omega-3 fatty acid intake.

Nutr J 2019 11 14;18(1):74. Epub 2019 Nov 14.

SAHMRI Women and Kids, South Australian Health and Medical Research Institute, Adelaide, Australia.

Background: Preterm birth is the leading cause of death in children under five. A recent Cochrane review found a 42% reduction in early preterm birth (< 34 weeks' gestation) and 11% reduction in preterm birth (< 37 weeks' gestation) with omega-3 fatty acid supplementation. To assist in the development of implementation strategies to increase pregnant women's omega-3 fatty acid intake, we assessed the awareness of Australian pregnant women about preterm birth, their nutrition and supplementation behaviours during pregnancy, and intentions to increase omega-3 fatty acid intake.

Methods: A ten-minute survey was conducted online to assess the knowledge, attitudes, behaviours, and intentions of Australian pregnant women across three domains: (1) preterm birth; (2) nutrition and supplementation during pregnancy; and (3) omega-3 fatty acid consumption to prevent preterm birth. Participants were recruited from Survey Sampling International's research panels.

Results: Of the 763 women who completed the survey, less than two-thirds had heard of preterm birth. Over 55% of respondents had changed their diet during pregnancy and a prenatal dietary supplement was consumed by 82% of the women surveyed. Respondents' main source of information about preterm birth and nutrition during pregnancy was from a health professional. When asked about their intentions to increase their omega-3 fatty acid intake following a health professional's recommendation, the vast majority of participants indicated they would increase their omega-3 fatty acid intake (90%). When a hypothetical scenario was presented of an omega-3 fatty acid supplement being offered from a health service at no cost, the number of respondents who selected they would increase their intake through supplementation increased from 54 to 79%.

Conclusions: The main information source for women about preterm birth and dietary supplementation recommendations during pregnancy is their health professional. Therefore, informing women about ways to prevent preterm birth, including the role of omega-3 fatty acids, should occur during antenatal visits. The results from our study are useful for clinicians caring for pregnant women and for the next stage of translation of the Cochrane review findings - the design of implementation strategies to increase the intake of omega-3 fatty acids during pregnancy where needed.
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http://dx.doi.org/10.1186/s12937-019-0499-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857157PMC
November 2019

Does maternal smoking in pregnancy explain the differences in the body composition trajectory between breastfed and formula-fed infants?

Br J Nutr 2020 02 8;123(4):402-409. Epub 2019 Nov 8.

South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.

Growth patterns are known to differ between breastfed and formula-fed infants, but little is known about the relative impact of maternal smoking in pregnancy v. feeding mode on growth trajectory in infancy. We conducted a secondary analysis of a trial, the Tolerance of Infant Goat Milk Formula and Growth Assessment trial involving 290 healthy infants, to examine whether smoking in pregnancy modified the association between feeding mode and body composition of infants. Fat mass (FM) and fat-free mass (FFM) were estimated at 1, 2, 3, 4, 6 and 12 months of age using bioimpedance spectroscopy. Formula-fed infants (n 190) had a higher mean FFM at 4 months (mean difference (MD) 160 g, 95 % CI 50·4, 269·5 g, P < 0·05)) and 6 months (MD 179 g, 95 % CI 41·5, 316·9 g, P < 0·05) compared with the breastfed infants (n 100). Sub-group analysis of breastfed v. formula-fed infants by maternal smoking status in pregnancy showed that there were no differences in the FM and FFM between the breastfed and formula-fed infants whose mothers did not smoke in pregnancy. Formula-fed infants whose mothers smoked in pregnancy were smaller at birth and had a lower FM% and higher FFM% at 1 month compared with infants of non-smoking mothers regardless of feeding mode, but the differences were not significant at other time points. Adequately powered prospective studies with an appropriate design are warranted to better understand the relative impact of maternal smoking, feeding practice and the growth trajectory of infants.
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http://dx.doi.org/10.1017/S0007114519002848DOI Listing
February 2020

Changes in the Composition of the Gut Microbiota and the Blood Transcriptome in Preterm Infants at Less than 29 Weeks Gestation Diagnosed with Bronchopulmonary Dysplasia.

mSystems 2019 Oct 29;4(5). Epub 2019 Oct 29.

Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

Bronchopulmonary dysplasia (BPD) is a common chronic lung condition in preterm infants that results in abnormal lung development and leads to considerable morbidity and mortality, making BPD one of the most common complications of preterm birth. We employed RNA sequencing and 16S rRNA gene sequencing to profile gene expression in blood and the composition of the fecal microbiota in infants born at <29 weeks gestational age and diagnosed with BPD in comparison to those of preterm infants that were not diagnosed with BPD. 16S rRNA gene sequencing, performed longitudinally on 255 fecal samples collected from 50 infants in the first months of life, identified significant differences in the relative levels of abundance of , and in the BPD infants in a manner that was birth mode dependent. Transcriptome sequencing (RNA-Seq) analysis revealed that more than 400 genes were upregulated in infants with BPD. Genes upregulated in BPD infants were significantly enriched for functions related to red blood cell development and oxygen transport, while several immune-related pathways were downregulated. We also identified a gene expression signature consistent with an enrichment of immunosuppressive CD71 early erythroid cells in infants with BPD. Intriguingly, genes that were correlated in their expression with the relative abundances of specific taxa in the microbiota were significantly enriched for roles in the immune system, suggesting that changes in the microbiota might influence immune gene expression systemically. Bronchopulmonary dysplasia (BPD) is a serious inflammatory condition of the lung and is the most common complication associated with preterm birth. A large body of evidence now suggests that the gut microbiota can influence immunity and inflammation systemically; however, the role of the gut microbiota in BPD has not been evaluated to date. Here, we report that there are significant differences in the gut microbiota of infants born at <29 weeks gestation and subsequently diagnosed with BPD, which are particularly pronounced when infants are stratified by birth mode. We also show that erythroid and immune gene expression levels are significantly altered in BPD infants. Interestingly, we identified an association between the composition of the microbiota and immune gene expression in blood in early life. Together, these findings suggest that the composition of the microbiota may influence the risk of developing BPD and, more generally, may shape systemic immune gene expression.
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http://dx.doi.org/10.1128/mSystems.00484-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819732PMC
October 2019

Temperature and time-dependent effects of delayed blood processing on oxylipin concentrations in human plasma.

Prostaglandins Leukot Essent Fatty Acids 2019 11 5;150:31-37. Epub 2019 Sep 5.

University of Adelaide, Adelaide, SA, Australia.

Background: Oxidized derivatives of polyunsaturated fatty acids, collectively known as oxylipins, are labile bioactive mediators with diverse roles in human physiology and pathology. Oxylipins are increasingly being measured in plasma collected in clinical studies to investigate biological mechanisms and as pharmacodynamic biomarkers for nutrient-based and drug-based interventions. Whole blood is generally stored either on ice or at room temperature prior to processing. However, the potential impacts of delays in processing, and of temperature prior to processing, on oxylipin concentrations are incompletely understood.

Objective: To evaluate the effects of delayed processing of blood samples in a timeframe that is typical of a clinical laboratory setting, using typical storage temperatures, on concentrations of representative unesterified oxylipins measured by liquid chromatography-tandem mass spectrometry.

Design: Whole blood (drawn on three separate occasions from a single person) was collected into 5 mL purple-top potassium-EDTA tubes and stored for 0, 10, 20, 30, 60 or 120 min at room temperature or on wet ice, followed by centrifugation at 4 °C for 10 min with plasma collection. Each sample was run in duplicate, therefore there were six tubes and up to six data points at each time point for each oxylipin at each condition (ice/room temperature). Representative oxylipins derived from arachidonic acid, docosahexaenoic acid, and linoleic acid were quantified by liquid chromatography tandem mass spectrometry. Longitudinal models were used to estimate differences between temperature groups 2 h after blood draw.

Results: We found that most oxylipins measured in human plasma in traditional potassium-EDTA tubes are reasonably stable when stored on ice for up to 2 h prior to processing, with little evidence of auto-oxidation in either condition. By contrast, in whole blood stored at room temperature, substantial time-dependent increases in the 12-lipoxygenase-derived (12-HETE, 14-HDHA) and platelet-derived (thromboxane B2) oxylipins were observed.

Conclusion: These findings suggest that certain plasma oxylipins can be measured with reasonable accuracy despite delayed processing for up to 2 h when blood is stored on ice prior to centrifugation. 12-Lipoxygenase- and platelet-derived oxylipins may be particularly sensitive to post-collection artifact with delayed processing at room temperature. Future studies are needed to determine impacts of duration and temperature of centrifugation on oxylipin concentrations.
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http://dx.doi.org/10.1016/j.plefa.2019.09.001DOI Listing
November 2019
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