Maternal High-Dose DHA Supplementation and Neurodevelopment at 18-22 Months of Preterm Children.

OBJECTIVES: To determine whether maternal supplementation with high-dose docosahexaenoic acid (DHA) in breastfed, very preterm neonates improves neurodevelopmental outcomes at 18 to 22 months' corrected age (CA). METHODS: Planned follow-up of a randomized, double-blind, placebo-controlled, multicenter trial to compare neurodevelopmental outcomes in breastfed, preterm neonates born before 29 weeks' gestational age (GA). Lactating mothers were randomized to receive either DHA-rich algae oil or a placebo within 72 hours of delivery until 36 weeks' postmenstrual age. Neurodevelopmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development third edition (Bayley-III) at 18 to 22 months' CA. Planned subgroup analyses were conducted for GA (<27 vs ≥27 weeks' gestation) and sex. RESULTS: Among the 528 children enrolled, 457 (86.6%) had outcomes available at 18 to 22 months' CA (DHA, N = 234, placebo, N = 223). The mean differences in Bayley-III between children in the DHA and placebo groups were -0.07 (95% confidence interval [CI] -3.23 to 3.10, P = .97) for cognitive score, 2.36 (95% CI -1.14 to 5.87, P = .19) for language score, and 1.10 (95% CI -2.01 to 4.20, P = .49) for motor score. The association between treatment and the Bayley-III language score was modified by GA at birth (interaction P = .07). Neonates born <27 weeks' gestation exposed to DHA performed better on the Bayley-III language score, compared with the placebo group (mean difference 5.06, 95% CI 0.08-10.03, P = .05). There was no interaction between treatment group and sex. CONCLUSIONS: Maternal DHA supplementation did not improve neurodevelopmental outcomes at 18 to 22 months' CA in breastfed, preterm neonates, but subgroup analyses suggested a potential benefit for language in preterm neonates born before 27 weeks' GA.

Use of SMOF lipid emulsion in very preterm infants does not affect the incidence of bronchopulmonary dysplasia-free survival.

BACKGROUND: We aim to assess whether the docosahexaenoic acid (DHA)-containing lipid emulsion (LE) SMOFlipid 20% (Fresenius Kabi Canada Ltd) is associated with bronchopulmonary dysplasia (BPD)-free survival at 36 weeks' postmenstrual age in very preterm infants. METHODS: This cohort study is nested in the MOBYDIck randomized clinical trial (NCT02371460), which investigated the effect of maternal DHA supplementation on BPD-free survival in breastfed very preterm infants born between 23 0/7 and 28 6/7 weeks' gestation in 16 Canadian neonatal intensive care units (2015-2018). Parenteral SMOF-LE was given to the infants according to the sites' routine care protocols. Relative risks (RRs) were estimated using a modified Poisson regression model with generalized estimating equations taking into account recruitment site, multiple birth, DHA supplementation, birth weight, sex, and gestational age. RESULTS: Among 528 infants (mean gestational age, 26.5 weeks [SD, 1.6]), 272 received SMOF-LE. Overall, 56.7% of the infants in the SMOF-LE group and 59.7% infants in the non-SMOF-LE group survived without BPD (adjusted RR, 0.94 [95% CI, 0.77-1.14]; P = 0.51). BPD rates were 39.3% in the SMOF-LE group vs 34.1% in the non-SMOF-LE group (adjusted RR, 1.10 [95% CI, 0.82-1.47]; P = 0.53). Severe BPD rates were 31.8% in the SMOF-LE group vs 28.8% in the non-SMOF-LE group (adjusted P = 0.59). Mortality was not significantly different between the SMOF-LE (6.7%) and non-SMOF-LE groups (9.5%; adjusted P = 0.40). CONCLUSION: In very preterm infants, intravenous DHA-containing SMOF-LE during the neonatal period was not associated with BPD-free survival.

Effect of Maternal Docosahexaenoic Acid Supplementation on Very Preterm Infant Growth: Secondary Outcome of a Randomized Clinical Trial.

INTRODUCTION: The aim of the study was to determine the effect of a maternal docosahexaenoic acid (DHA) supplementation during lactation, compared with a placebo, on the neonatal growth profile of breastfed very preterm infants. METHODS: Preterm infants' growth profile, growth velocity from birth to 36 weeks' postmenstrual age (PMA), and growth at 36 weeks' PMA were pre-specified secondary outcomes of a randomized placebo-controlled trial conducted in 16 Canadian neonatal intensive care units (2015-2018). Lactating mothers who delivered before 29 weeks' gestation were given 1.2 g of DHA daily or a placebo within 72 h of delivery and up to 36 weeks' PMA. Analyses were performed using a linear regression model with generalized estimating equations. RESULTS: 461 mothers and their 528 infants (DHA, N = 273; placebo, N = 255) were included with mean gestational age of 26.5 weeks (standard deviation [SD] = 1.6); 275 (52.1%) were males; mean birth weight was 895 g (SD = 240). DHA interaction with sex was significant on weight profile (interaction p < 0.001), weight velocity (interaction p = 0.05), and weight at 36 weeks' PMA (interaction p = 0.02). Females in the DHA group gained more weight compared to the placebo group (mean difference [MD], 52.6 g [95% confidence interval [CI]: 24.5-80.8], p < 0.001). Weight velocity was significantly higher in females of the DHA group (MD, 3.4 g/kg/day [95% CI: 0.6-6.2], p = 0.02). At 36 weeks' PMA, the weight of males in the DHA group was significantly smaller (MD, -88.9 g [95% CI: -166.2 to -11.6], p = 0.02). CONCLUSION: DHA positively affected female infants' neonatal weight profile and velocity and negatively affected male infants' weight at 36 weeks' PMA.

Effect of Maternal Docosahexaenoic Acid Supplementation on Bronchopulmonary Dysplasia-Free Survival in Breastfed Preterm Infants: A Randomized Clinical Trial.

Importance: Maternal docosahexaenoic acid (DHA) supplementation may prevent bronchopulmonary dysplasia, but evidence remains inconclusive. Objective: To determine whether maternal DHA supplementation during the neonatal period improves bronchopulmonary dysplasia-free survival in breastfed infants born before 29 weeks of gestation. Design, Setting, and Participants: Superiority, placebo-controlled randomized clinical trial at 16 Canadian neonatal intensive care units (June 2015-April 2018 with last infant follow-up in July 2018). Lactating women who delivered before 29 weeks of gestation were enrolled within 72 hours of delivery. The trial intended to enroll 800 mothers, but was stopped earlier. Interventions: There were 232 mothers (273 infants) assigned to oral capsules providing 1.2 g/d of DHA from randomization to 36 weeks' postmenstrual age and 229 mothers (255 infants) assigned to placebo capsules. Main Outcomes and Measures: The primary outcome was bronchopulmonary dysplasia-free survival in infants at 36 weeks' postmenstrual age. There were 22 secondary outcomes, including mortality and bronchopulmonary dysplasia. Results: Enrollment was stopped early due to concern for harm based on interim data from this trial and from another trial that was published during the course of this study. Among 461 mothers and their 528 infants (mean gestational age, 26.6 weeks [SD, 1.6 weeks]; 253 [47.9%] females), 375 mothers (81.3%) and 523 infants (99.1%) completed the trial. Overall, 147 of 268 infants (54.9%) in the DHA group vs 157 of 255 infants (61.6%) in the placebo group survived without bronchopulmonary dysplasia (absolute difference, -5.0% [95% CI, -11.6% to 2.6%]; relative risk, 0.91 [95% CI, 0.80 to 1.04], P = .18). Mortality occurred in 6.0% of infants in the DHA group vs 10.2% of infants in the placebo group (absolute difference, -3.9% [95% CI, -6.8% to 1.4%]; relative risk, 0.61 [95% CI, 0.33 to 1.13], P = .12). Bronchopulmonary dysplasia occurred in 41.7% of surviving infants in the DHA group vs 31.4% in the placebo group (absolute difference, 11.5% [95% CI, 2.3% to 23.2%]; relative risk, 1.36 [95% CI, 1.07 to 1.73], P = .01). Of 22 prespecified secondary outcomes, 19 were not significantly different. Conclusions and Relevance: Among breastfed preterm infants born before 29 weeks of gestation, maternal docosahexaenoic acid supplementation during the neonatal period did not significantly improve bronchopulmonary dysplasia-free survival at 36 weeks' postmenstrual age compared with placebo. Study interpretation is limited by early trial termination. Trial Registration: ClinicalTrials.gov Identifier: NCT02371460.

Association Between Vitamin D Supplementation During Pregnancy and Offspring Growth, Morbidity, and Mortality: A Systematic Review and Meta-analysis.

Importance: Whether vitamin D supplementation during pregnancy is beneficial and safe for offspring is unclear. Objective: To systematically review studies of the effects of vitamin D supplementation during pregnancy on offspring growth, morbidity, and mortality. Data Sources: Searches of Medline, Embase, and the Cochrane Database of Systematic Reviews were conducted up to October 31, 2017. Key search terms were vitamin D, pregnancy, randomized controlled trials, and offspring outcomes. Study Selection: Randomized clinical trials of vitamin D supplementation during pregnancy and offspring outcomes. Data Extraction and Synthesis: Two authors independently extracted data, and the quality of the studies was assessed. Summary risk ratio (RR), risk difference (RD) or mean difference (MD), and 95% CI were calculated using fixed-effects or random-effects meta-analysis. Main Outcomes and Measures: Main outcomes were fetal or neonatal mortality, small for gestational age (SGA), congenital malformation, admission to a neonatal intensive care unit, birth weight, Apgar scores, neonatal 25-hydroxyvitamin D (25[OH]D) and calcium concentrations, gestational age, preterm birth, infant anthropometry, and respiratory morbidity during childhood. Results: Twenty-four clinical trials involving 5405 participants met inclusion criteria. Vitamin D supplementation during pregnancy was associated with a lower risk of SGA (RR, 0.72; 95% CI, 0.52 to 0.99; RD, -5.60%; 95% CI, -0.86% to -10.34%) without risk of fetal or neonatal mortality (RR, 0.72; 95% CI, 0.47 to 1.11) or congenital abnormality (RR, 0.94; 95% CI, 0.61 to 1.43). Neonates with prenatal vitamin D supplementation had higher 25(OH)D levels (MD, 13.50 ng/mL; 95% CI, 10.12 to 16.87 ng/mL), calcium levels (MD, 0.19 mg/dL; 95% CI, 0.003 to 0.38 mg/dL), and weight at birth (MD, 75.38 g; 95% CI, 22.88 to 127.88 g), 3 months (MD, 0.21 kg; 95% CI, 0.13 to 0.28 kg), 6 months (MD, 0.46 kg; 95% CI, 0.33 to 0.58 kg), 9 months (MD, 0.50 kg; 95% CI, 0.01 to 0.99 kg), and 12 months (MD, 0.32 kg; 95% CI, 0.12 to 0.52 kg). Subgroup analysis by doses showed that low-dose vitamin D supplementation (≤2000 IU/d) was associated with a reduced risk of fetal or neonatal mortality (RR, 0.35; 95% CI, 0.15 to 0.80), but higher doses (>2000 IU/d) did not reduce this risk (RR, 0.95; 95% CI, 0.59 to 1.54). Conclusions and Relevance: Vitamin D supplementation during pregnancy is associated with a reduced risk of SGA and improved infant growth without risk of fetal or neonatal mortality or congenital abnormality. Vitamin D supplementation with doses of 2000 IU/d or lower during pregnancy may reduce the risk of fetal or neonatal mortality.

Impact of SMOFLipid on Pulmonary Alveolar Development in Newborn Guinea Pigs.

BACKGROUND: Parenteral nutrition (PN) is associated with bronchopulmonary dysplasia in premature infants. In animals, PN leads to alveolar loss following stimulation of apoptosis by oxidative stress (oxidized redox potential). Peroxides and aldehydes generated in PN can induce hypo-alveolarization. The implication of peroxides, which is reduced by light protection, is demonstrated. The implication of aldehydes from omega-6 fatty acids oxidation is expected. The hypothesis is that composition and light exposure of PN influences bronchopulmonary dysplasia development. Since SMOFLipid (SMOF) contains a lower amount of omega-6 fatty acids than Intralipid (IL), the aim was to compare, the impacts of PN compounded with SMOF or IL, photo-protected or not, on alveolar development. MATERIALS AND METHODS: Three-day-old Guinea pigs received PN, photo-protected or not, made with SMOF or IL through a jugular vein catheter. After 4 days, lungs were sampled for determinations of redox potential of glutathione, apoptosis (caspase-3, caspase-8, and caspase-9) and alveolarization index (histology: number of intercepts/mm). RESULTS: Compared with IL, SMOF induces a greater oxidation of redox potential (-200 ± 1 versus [vs] -205 ± 1 mV), apoptosis (caspase-3: 0.27 ± 0.04 vs 0.16 ± 0.02; caspase-9: 0.47 ± 0.03 vs 0.30 ± 0.03), and a lower alveolarization index (27.2 ± 0.8 vs 30.0 ± 0.9). Photo-protection prevented activation of caspase-9 and was statistically without effect on redox potential, caspase-3, and alveolarization index. CONCLUSION: In our model, SMOF is pro-oxidant and induces hypo-alveolarization following exaggerated apoptosis. These results highlight the need for further studies before introducing SMOFLipid in standard neonatal care.

Early docosahexaenoic acid supplementation of mothers during lactation leads to high plasma concentrations in very preterm infants.

Very preterm infants are vulnerable to deficiency in DHA. In a longitudinal study, 10 mothers who delivered ≤29 wk gestation and planned to breast-feed received DHA (1200 mg/d) until 36 wk after conception. The plasma DHA status was assessed in their 12 infants (including 2 pairs of twins) from birth to d 49. Fatty acid profiles were measured weekly in breast milk, and in plasma of mothers and infants at baseline and at d15 and 49. Plasma and breast milk fatty acid concentrations in the DHA-supplemented group at d 49 were compared with a reference group of very preterm infants (n = 24, including triplets) whose mothers (n = 22) did not receive DHA during lactation. The infants' plasma DHA concentration tended to be greater in the DHA group than in the reference group (P = 0.10) and was greater when expressed as a percentage of total fatty acids (P = 0.009). At d 49, maternal milk DHA in the DHA group (1.92 ± 1.10 mmol/L) was ~12 times higher than in the reference group (0.15 ± 0.27 mmol/L) (P < 0.001). The amount of DHA provided to the infants increased from wk 1 through wk 7 in the DHA group (P < 0.001). Although enteral intake at wk 7 did not differ between the DHA group [119 ± 51 mL/(kg·d)] and the reference group [113 ± 66 mL/(kg·d)], DHA group infants received 55 ± 38 mg/(kg·d) of DHA, and the reference group infants received 7 ± 11 mg/(kg·d) (P < 0.001). Early supplementation with DHA to lactating mothers with low dietary DHA intake successfully increased the plasma DHA status in very preterm infants.

Long-term impact of an antioxidant-deficient neonatal diet on lipid and glucose metabolism.

Newborn infants are at risk for oxidative stress leading to metabolic syndrome features. Oxidative stress can be induced by oxidant load such as oxygen supplementation, peroxides from intravenous nutrition, or low antioxidant defenses. We hypothesize that a modulation of antioxidant defenses during the neonatal period, without external oxidant challenge, will have a long-term influence on energy metabolism. Guinea pigs were fed between their third and their seventh day of life a regular chow leading to "mature" antioxidant defenses or a deficient chow leading to lower antioxidant defenses. Between weeks 1 and 14, the animals were fed regular chow. The hepatic oxidized redox status of glutathione associated with the deficient diet (-221 +/- 2 vs -228 +/- 1 mV, p < 0.01) was maintained until 14 weeks. At 13-14 weeks, animals fed the deficient diet presented lower plasma TG (479 +/- 57 vs 853 +/- 32 microM, p < 0.01), lower blood glucose (5.8 +/- 0.3 vs 6.9 +/- 0.3 mM, p < 0.05), and better tolerance to glucose (p < 0.05). Blood glucose correlated negatively with the redox status (r2 = 0.47, p < 0.01). Low antioxidant defenses during the neonatal period induce a better energy substrate profile associated with an oxidized redox status later in life. These findings suggest being aware of negative consequences when adopting "aggressive" antioxidant therapies in newborn infants.

Recorded maternal voice for preterm neonates undergoing heel lance.

PURPOSE: To determine if a recording of a mother's voice talking soothingly to her baby is useful in diminishing pain in newborns born between 32 and 36 weeks' gestational age (GA) during routine painful procedures. BACKGROUND: While maternal skin-to-skin contact has been proven efficacious for diminishing procedural pain in both full-term and preterm neonates, it is often not possible for mothers to be present during a painful procedure. Because auditory development occurs before the third trimester of gestation, it was hypothesized that maternal voice could substitute for maternal presence and be effective in diminishing pain response. SUBJECTS: Preterm infants between 32 and 36 weeks' GA (n = 20) in the first 10 days of life admitted to 2 urban university-affiliated neonatal intensive care units. DESIGN AND METHODS: Crossover design with random ordering of condition. Following informed consent, an audio recording of the mother talking soothingly to her baby was filtered to simulate the mother's voice traveling through amniotic fluid. A final 10-minute recording of repetition of mothers' talking was recorded with maximum peaks of 70 decibels (dB) and played at levels ranging between 60 and 70 ambient decibels (dbA), selected above recommendations of the American Academy of Pediatrics in order to be heard over high ambient noise in the settings. This was played to her infant by a portable cassette tape player 3 times daily during a 48-hour period after feedings (gavage, bottle, or breast). At the end of 48 hours when blood work was required for clinical purposes, using a crossover design, the infant underwent the heel lancing with or without the recording being played. The order of condition was randomized, and the second condition was within 10 days. The Premature Infant Pain Profile (PIPP) was used as primary outcome. This is a composite measure using heart rate, oxygen saturation, 3 facial actions, behavioral state, and gestational age. This measure has demonstrated reliability and validity indexes. RESULTS: There were no significant differences between groups on the PIPP or any of the individual components of the PIPP except a lower oxygen saturation level in the voice condition following the procedure. The second condition, regardless of whether it was voice or control, had higher heart rate scores and lower oxygen saturation scores even in the prelance baseline and warming phases. Order did not affect PIPP scores or facial actions. CONCLUSIONS: Different modalities of maternal presence would appear to be necessary to blunt pain response in infants, and recorded maternal voice alone is not sufficient. The loudness of the recording may have obliterated the infant's ability to discern the mother's voice and may even have been aversive, reflected in decreased oxygen saturation levels in the voice condition. Preterm neonates of 32 to 36 weeks' gestation may become sensitized to painful experiences and show anticipatory physiological response.