The influence of DHA supplementation during pregnancy on language development across childhood: Follow-up of a randomised controlled trial.

Numerous randomised controlled trials have explored the effect of docosahexaenoic acid (DHA) supplementation in early life on neurodevelopment, with some suggested positive effects on language. Australian women with a singleton pregnancy <21 weeks' gestation were randomised to receive 800 mg DHA/day or a placebo until birth. A sample of 726 children (all n=96 born preterm, random sample of n=630 born at term) were invited to undergo assessments of language, academic, and language-based cognitive abilities at 1.5, four and seven years of age. No group differences were detected for any group comparison. Exploratory analyses for sex by treatment interactions revealed a possible adverse effect of DHA supplementation on the language of females at 1.5 years but no effects on outcomes at four or seven years. Taken as a whole, evidence of an effect of prenatal DHA supplementation on language abilities across childhood is negligible and could be a chance finding.

Effect of omega-3 lcpufa supplementation on maternal fatty acid and oxylipin concentrations during pregnancy.

INTRODUCTION: Omega-3 long chain polyunsaturated fatty acids (LCPUFA) have been associated with a reduction in risk for preterm birth. However, there is limited understanding of how fatty acids and their bioactive derivatives (oxylipins) change over the course of pregnancy. Here we document the changes in concentration of fatty acids and oxylipins during pregnancy and how fatty acid status and oxylipin concentrations are affected by supplementation with omega-3 LCPUFA. We also investigate the degree to which fatty acid and oxylipin changes across pregnancy are influenced by baseline omega-3 status. MATERIALS AND METHODS: We profiled the fatty acids in all lipids in dried blood spots (total blood fatty acids) by gas chromatography and free (unesterified) fatty acids and their associated oxylipins in separate dried blood spot samples by LC-MS-MS collected from a random sample of 1263 women with a singleton pregnancy who participated in the ORIP (Omega-3 fats to Reduce the Incidence of Prematurity) trial. ORIP is a double-blind, randomized controlled trial involving 5544 participants and designed to determine the effect of supplementing the diets of pregnant women with omega-3 LCPUFA on the incidence of early preterm birth. Maternal whole blood finger prick samples were collected at baseline (~14 weeks gestation) and at completion of the study intervention period (34 weeks gestation). RESULTS: The concentration of most total and free polyunsaturated fatty acids and their associated oxylipins declined over the course of pregnancy. Omega-3 LCPUFA supplementation increased total DHA and 7-HDHA and mitigated the decline in free DHA, 4-HDHA and 14-HDHA. The intervention had minimal or no effect on free EPA, LA, AA and their associated oxylipins. Omega-3 LCPUFA supplementation in women with higher omega-3 status at baseline was associated with a significant increase in 7-HDHA and 4-HDHA between the treatment and control whereas there were no differences between groups in 7-HDHA and 4-HDHA in women with intermediate or lower baseline omega-3 status. CONCLUSION: Our data suggest a differential response with or without omega-3 supplementation for DHA and DHA-derived oxylipins, which may have an important role to play in modulating pregnancy duration. Further work is needed to understand their role, which may allow us to better tailor omega-3 supplementation for preterm birth prevention.

Omega-3 fatty acid supplementation in pregnancy-baseline omega-3 status and early preterm birth: exploratory analysis of a randomised controlled trial.

OBJECTIVE: To identify a polyunsaturated fatty acid (PUFA) biomarker able to detect which women with singleton pregnancies are most likely to benefit from omega-3 supplementation to reduce their risk of early preterm birth. DESIGN: Exploratory analysis of a randomised controlled trial. SETTING: Six Australian hospitals. POPULATION: Women with a singleton pregnancy enrolled in the ORIP trial. METHODS: Using maternal capillary whole blood collected ~14 weeks' gestation, the fatty acids in total blood lipids were quantified using gas chromatography. Interaction tests examined whether baseline PUFA status modified the effect of omega-3 supplementation on birth outcomes. MAIN OUTCOME MEASURE: Early preterm birth (<34 weeks' gestation). RESULTS: A low total omega-3 PUFA status in early pregnancy was associated with a higher risk of early preterm birth. Among women with a total omega-3 status ≤4.1% of total fatty acids, omega-3 supplementation substantially reduced the risk of early preterm birth compared with control (0.73 versus 3.16%; relative risk = 0.23, 95% confidence interval [CI] 0.07-0.79). Conversely, women with higher total omega-3 status in early pregnancy were at lower risk of early preterm birth. Supplementing women with a baseline status above 4.9% increased early preterm birth (2.20 versus 0.97%; relative risk = 2.27, 95% CI 1.13-4.58). CONCLUSIONS: Women with singleton pregnancies and low total omega-3 PUFA status early in pregnancy have an increased risk of early preterm birth and are most likely to benefit from omega-3 supplementation to reduce this risk. Women with higher total omega-3 status are at lower risk and additional omega-3 supplementation may increase their risk. TWEETABLE ABSTRACT: Low total omega-3 fat status helps identify which women benefit from extra omega-3 to reduce early prematurity.

Correlation between neonatal outcomes of twins depends on the outcome: secondary analysis of twelve randomised controlled trials.

OBJECTIVE: To estimate the magnitude of the correlation between neonatal outcomes of twins and demonstrate how this information can be used in the design of randomised controlled trials (RCTs) in women with twin pregnancies. DESIGN: Secondary analysis of data from 12 RCTs. SETTING: Obstetric care in multiple countries, 2004-2012. POPULATION OR SAMPLE: 4504 twin pairs born to women who participated in RCTs to assess treatments given during pregnancy. METHODS: Intraclass correlation coefficients (ICCs) were estimated using log-binomial and linear models. MAIN OUTCOME MEASURES: Perinatal death, respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular haemorrhage, necrotising enterocolitis, sepsis, neonatal intensive care unit admission, birthweight, low birthweight and two composite measures of adverse neonatal outcome. RESULTS: ICCs for the composite measures of adverse neonatal outcome were all above 0.5, indicating moderate to strong correlation between adverse outcomes of twins. For individual neonatal outcomes, median ICCs across trials ranged from 0.13 to 0.79 depending on the outcome. An example illustrates how ICCs can be used in sample size calculations for RCTs in women with twin pregnancies. CONCLUSIONS: The correlation between neonatal outcomes of twins varies considerably between outcomes and may be lower than expected. Our ICC estimates can be used for designing and analysing RCTs that recruit women with twin pregnancies and for performing meta-analyses that include such RCTs. Researchers are encouraged to report ICCs for neonatal outcomes in twins in their own RCTs. TWEETABLE ABSTRACT: Correlation between neonatal outcomes of twins depends on the outcome and may be lower than expected.

Predicting the effect of maternal docosahexaenoic acid (DHA) supplementation to reduce early preterm birth in Australia and the United States using results of within country randomized controlled trials.

The DHA to Optimize Mother Infant Outcome (DOMInO) and Kansas DHA Outcomes Study (KUDOS) were randomized controlled trials that supplemented mothers with 800 and 600mg DHA/day, respectively, or a placebo during pregnancy. DOMInO was conducted in Australia and KUDOS in the United States. Both trials found an unanticipated and statistically significant reduction in early preterm birth (ePTB; i.e., birth before 34 weeks gestation). However, in each trial, the number of ePTBs were small. We used a novel Bayesian approach to estimate statistically derived low, moderate or high risk for ePTB, and to test for differences between the DHA and placebo groups. In both trials, the model predicted DHA would significantly reduce the expected proportion of deliveries in the high risk group under the trial conditions of the parent studies. Among the next 300,000 births in Australia we estimated that 1112 ePTB (95% credible interval 51-2189) could be avoided by providing DHA. And in the USA we estimated that 106,030 ePTB (95% credible interval 6400 to 175,700) could be avoided with DHA.

Maternal characteristics influence response to DHA during pregnancy.

We explored the degree to which maternal and offspring outcomes resulting from consuming prenatal docosahexaenoic acid (DHA, 800mg/day) in a clinical trial were influenced by maternal characteristics. Among non-smokers, women who received DHA had heavier babies (adjusted mean difference (MD)=99g 95% CI 45-153, p<0.01; interaction p=0.01) and fewer low birth weight babies than control women (adjusted relative risk=0.43 95% CI 0.25-0.74, p<0.01; interaction p=0.01). From women who had not completed further education, children in the DHA group had higher cognitive scores at 18 months compared with control children (adjusted MD=3.15 95% CI 0.93-5.37, p=0.01; interaction p<0.01). Conversely, the children of women who completed further education in the DHA group had lower language scores than control children (adjusted MD -2.82 95% CI -4.90 to -0.73, p=0.01; interaction p=0.04). Our results support the notion that responsiveness to prenatal DHA may depend on the characteristics of specific population subgroups.

Antenatal dietary and lifestyle advice for women who are overweight or obese and the effect on fetal growth and adiposity: the LIMIT randomised trial.

OBJECTIVE: To report the influence of maternal overweight and obesity on fetal growth and adiposity and effects of an antenatal dietary and lifestyle intervention among these women on measures of fetal growth and adiposity as secondary outcomes of the LIMIT Trial. DESIGN: Randomised controlled trial. SETTING: Public maternity hospitals in metropolitan Adelaide, South Australia. POPULATION: Pregnant women with a body mass index ≥ 25 kg/m(2), and singleton gestation between 10(+0) and 20(+0) weeks. METHODS: Women were randomised to Lifestyle Advice or continued Standard Care and offered two research ultrasound scans at 28 and 36 weeks of gestation. MAIN OUTCOME MEASURES: Ultrasound measures of fetal growth and adiposity. RESULTS: For each fetal body composition parameter, mean Z-scores were substantially higher when compared with population standards. Fetuses of women receiving Lifestyle Advice demonstrated significantly greater mean mid-thigh fat mass, when compared with fetuses of women receiving Standard Care (adjusted difference in means 0.17; 95% CI 0.02-0.32; P = 0.0245). While subscapular fat mass increased between 28 and 36 weeks of gestation in fetuses in both treatment groups, the rate of adipose tissue deposition slowed among fetuses of women receiving Lifestyle Advice, when compared with fetuses of women receiving Standard Care (P = 0.0160). No other significant differences were observed. CONCLUSIONS: These findings provide the first evidence of changes to fetal growth following an antenatal dietary and lifestyle intervention among women who are overweight or obese.

The effect of antenatal lifestyle advice for women who are overweight or obese on secondary measures of neonatal body composition: the LIMIT randomised trial.

OBJECTIVE: To evaluate the effect of providing antenatal dietary and lifestyle advice on neonatal anthropometry, and to determine the inter-observer variability in obtaining anthropometric measurements. DESIGN: Randomised controlled trial. SETTING: Public maternity hospitals across metropolitan Adelaide, South Australia. POPULATION: Pregnant women with a singleton gestation between 10(+0) and 20(+0) weeks, and body mass index (BMI) ≥25 kg/m(2). METHODS: Women were randomised to either Lifestyle Advice (comprehensive dietary and lifestyle intervention over the course of pregnancy including dietary, exercise and behavioural strategies, delivered by a research dietician and research assistants) or continued Standard Care. Analyses were conducted using intention-to-treat principles. MAIN OUTCOME MEASURES: Secondary outcome measures for the trial included assessment of infant body composition using body circumference and skinfold thickness measurements (SFTM), percentage body fat, and bio-impedance analysis of fat-free mass. RESULTS: Anthropometric measurements were obtained from 970 neonates (488 Lifestyle Advice Group, and 482 Standard Care Group). In 394 of these neonates (215 Lifestyle Advice Group, and 179 Standard Care Group) bio-impedance analysis was also obtained. There were no statistically significant differences identified between those neonates born to women receiving Lifestyle Advice and those receiving Standard Care, in terms of body circumference measures, SFTM, percentage body fat, fat mass, or fat-free mass. The intra-class correlation coefficient for SFTM was moderate to excellent (0.55-0.88). CONCLUSIONS: Among neonates born to women who are overweight or obese, anthropometric measures of body composition were not modified by an antenatal dietary and lifestyle intervention.

Heterogeneity in cord blood DHA concentration: towards an explanation.

This paper aimed to identify the dietary and non-dietary determinants of docosahexaenoic acid (DHA) levels in umbilical cord blood at delivery. DHA was measured in cord blood plasma phospholipids of 1571 participants from the DOMInO (DHA to Optimize Mother Infant Outcome) randomized controlled trial. Socioeconomic, lifestyle and clinical data relating to the mother and current pregnancy were obtained from all women and their relationships with cord blood DHA assessed. DHA concentrations in the cord plasma phospholipids at delivery covered a 3-4 fold range in both control and DHA groups. The total number of DHA-rich intervention supplement capsules consumed over the course of pregnancy and gestational age at delivery individually explained 21% and 16% respectively of the variation in DHA abundance in the cord blood plasma phospholipids at delivery, but no other clinical or life-style factors explored in this study could account for >2% of the variation. Indeed, more than 65% of the variation remained unaccounted for even when all factors were included in the analysis. These data suggest that factors other than maternal DHA intake have an important role in determining cord blood DHA concentrations at delivery, and may at least partially explain the variation in the response of infants to maternal DHA supplementation reported in published trials.

Maternal adverse effects with different loading infusion rates of antenatal magnesium sulphate for preterm fetal neuroprotection: the IRIS randomised trial.

OBJECTIVE: To evaluate a slower (compared with a standard) infusion rate of the loading dose of magnesium sulphate for preterm fetal neuroprotection as a strategy to reduce maternal adverse effects. DESIGN: Randomised controlled trial. SETTING: South Australian maternity hospital. POPULATION: Fifty-one women at <30 weeks of gestation, where birth was planned or expected within 24 hours. METHODS: Women received a loading infusion of 4 g of magnesium sulphate over either 60 or 20 minutes (followed by maintenance of 1 g/hour until birth, or for up to 24 hours). MAIN OUTCOME MEASURES: Any maternal adverse effects associated with the infusion. RESULTS: Overall, 71% of women experienced adverse effects during the first hour of their infusion; the difference between groups was not significant [15/25 (60%) 60-minute loading; 21/26 (81%) 20-minute loading; risk ratio (RR) 0.74; 95% confidence interval (95% CI) 0.51-1.08]. Although no serious maternal complications occurred, adverse effects led to three women ceasing the loading treatment (1/25 in the 60-minute loading group; 2/26 in the 20-minute loading group; RR 0.52; 95% CI 0.05-5.38). Women in the 60-minute loading group experienced significantly less warmth and flushing at 20 minutes into the infusion (7/25 in the 60-minute loading group; 15/26 in the 20-minute loading group; RR 0.49; 95% CI 0.24-0.99). No other differences between groups for maternally reported and clinical adverse effects were shown. CONCLUSIONS: A slower rate of administering the loading dose of magnesium sulphate did not reduce the occurrence of maternal adverse effects overall. Flushing and warmth at 20 minutes into the infusion was reduced with a slower infusion.

Correlations between blood and tissue omega-3 LCPUFA status following dietary ALA intervention in rats.

The aim of this study was to assess relationships between the fatty acid contents of plasma and erythrocyte phospholipids and those in liver, heart, brain, kidney and quadriceps muscle in rats. To obtain a wide range of tissue omega-3 (n-3) long chain polyunsaturated fatty acids (LCPUFA) we subjected weanling rats to dietary treatment with the n-3 LCPUFA precursor, alpha linolenic acid (ALA, 18:3 n-3) for 3 weeks. With the exception of the brain, we found strong and consistent correlations between the total n-3 LCPUFA fatty acid content of both plasma and erythrocyte phospholipids with fatty acid levels in all tissues. The relationships between eicosapentaenoic acid (EPA, 20:5 n-3) and docosapentaenoic acid (DPA, 22:5 n-3) content in both blood fractions with levels in liver, kidney, heart and quadriceps muscle phospholipids were stronger than those for docosahexaenoic acid (DHA, 22:6 n-3). The strong correlations between the EPA+DHA (the Omega-3 Index), total n-3 LCPUFA and total n-3 PUFA contents in both plasma and erythrocyte phospholipids and tissues investigated in this study suggest that, under a wide range of n-3 LCPUFA values, plasma and erythrocyte n-3 fatty acid content reflect not only dietary PUFA intakes but also accumulation of endogenously synthesised n-3 LCPUFA, and thus can be used as a reliable surrogate for assessing n-3 status in key peripheral tissues.