EBNEO Commentary: Maternal high-dose DHA supplementation and neurodevelopment in infants born before 29 weeks’ gestation

February 01, 2023

MANUSCRIPT CITATION

Guillot M, Synnes A, Pronovost E, Qureshi M, Daboval T, Caouette G, Olivier F, Bartholomew J, Mohamed I, Massé E, Afifi J, Hendson L, Lemyre B, Luu TM, Strueby L, Cieslak Z, Yusuf K, Pelligra G, Ducruet T, Ndiaye ABKT, Angoa G, Sériès T, Piedboeuf B, Nuyt AM, Fraser W, Mâsse B, Lacaze-Masmonteil T, Lavoie PM, Marc I. Maternal High-Dose DHA Supplementation and Neurodevelopment at 18-22 Months of Preterm Children. Pediatrics. 2022 Jul 1;150(1):e2021055819. PMID: 35652296. 

REVIEWED BY

Dr Deeva Vather
Paediatric Registrar
South Australia Paediatric Network, Adelaide, South Australia, Australia
deeva.vather@sa.gov.au

Associate Professor Amy Keir
Head of Unit MedSTAR Kids and Consultant Neonatologist
SAAS MedSTAR Kids, Adelaide, South Australia
Department of Neonatal Medicine, Women’s and Children’s Hospital, North Adelaide, South Australia
Healthy Mothers, Babies and Children Theme, South Australian Health and Medical Institute, North Adelaide, South Australia
Robinson Research Institute and the Adelaide Medical School, the University of Adelaide, Adelaide, South Australia
amy.keir@adelaide.edu.au

TYPE OF INVESTIGATION

Prevention

QUESTION

Among breastfed infants born before 29 weeks’ gestational age (P) does maternal supplementation with high-dose docosahexaenoic acid (DHA) in the neonatal period (I) compared to placebo (C) improve neurodevelopmental outcomes (O) at 18 to 22 months’ corrected age (T)? 

METHODS

  • Design:
    • This was a planned follow-up study of the multicentre, randomised, double-blind, placebo-controlled superiority trial Maternal Omega-3 Supplementation to Reduce Bronchopulmonary Dysplasia in Very Preterm Infants (MOBYDIck), where the primary outcome was bronchopulmonary dysplasia-free survival in infants at 36 weeks’ postmenstrual age.
    • Randomisation: Mothers were randomised within 72 hours of the birth of their infant.
    • Random sequence was computer generated in a 1:1 ratio using variable permuted block sizes of 4 and 6, with a separate list for each centre.
    • Participants, researchers, and clinicians were blinded throughout the trial.
  • Allocation: Site pharmacists were given a blinded randomisation list of identification numbers unique to each infant, and dispensed treatment bottles identical in appearance. DHA and placebo capsules were identical in appearance and taste.
  • Follow-up period: 18 to 22 months’ corrected age.
  • Setting: 16 Canadian neonatal intensive care units. Enrollment occurred between June 2015 and April 2018.
  • Patients: 461 mothers (528 infants) were randomised
    • Inclusion criteria:
      • Mothers who delivered prematurely between 23+0/40 and 28+6/40 weeks of gestation.
      • Aged 16 years or older.
      • Did not present contraindications for breastfeeding.
      • Intended to provide their own breast milk to their infant.
      • Were within 72 hours of delivery at the time of randomisation.
    • Exclusion criteria:
      • Mothers taking supplements containing >250 mg per day of DHA in the 3 months before birth.
      • Mothers with neonates who had a major congenital or chromosomal anomaly.
    • Intervention/Comparison: Mothers were allocated to receive high dose DHA (1.2 g daily to achieve 1% of DHA in breast milk) or placebo capsules (a mix of corn and soy oils) within 72 hours of delivery until 36 weeks’ postmenstrual age.
    • Outcomes:
      • Primary outcome of this follow-up study at 18 to 22 months’ corrected age: neurodevelopmental performance in preterm children who survived at 18 to 22 months’ corrected age.
        • This was assessed with the Bayley-III cognitive, language, and motor composite scores.
        • Children who were untestable because of severe disability were assigned a score of 3 standard deviations below the mean.
      • Secondary outcomes:
        • Death or significant neurodevelopmental impairment.
          • Deaths from any causes between randomisation and 18 to 22 months’ corrected age.
        • Significant neurodevelopmental impairment defined as 1 or more of the following:
          • Bayley-III cognitive, language, or motor composite score <70.
          • Cerebral palsy with Gross Motor Function Classification System level ³
          • Hearing impairment with hearing aid or cochlear implant.
          • Bilateral visual impairment with no functional vision.
        • Bayley-III in category for each component (cognitive, language and motor).
          • Scores <85 – at least mild impairment.
          • Scores <70 – significant impairment.
        • Analysis:
          • The treatment effect on the primary outcome was measured using mixed linear models.
          • The treatment effect for secondary outcomes was measured using log-binomial regression in generalized estimating equation models.
          • Analyses were adjusted for study site and clustering of children because of multiple birth, and no imputation was performed for missing data.
          • A P value of £ .05 was defined as statistically significant.
          • As grade 3 or 4 intraventricular haemorrhage (IVH) occurred more frequently in the placebo group compared to the treatment group (17% versus 8.5%), post hoc sensitivity analysis excluding participants with grade 3 or 4 IVH was conducted.
        • Sample size:
          • The MOBYDIck trial aimed to enrol 450 infants per group to detect an absolute difference of 10% in bronchopulmonary dysplasia–free survival in infants. The estimated rate of bronchopulmonary dysplasia at 36 weeks’ postmenstrual age was 45% and the estimated rate of mortality was 10%.
          • At the interim analysis of the MOBYDIck trial, the data and safety monitoring board recommended that recruitment be terminated. This was due to concern that DHA was associated with bronchopulmonary dysplasia.
            • Bronchopulmonary dysplasia-free survival at 36 weeks’ postmenstrual age was found to be 147/268 (54.9%) in the treatment group and 157/225 (61.6%) in the placebo group (relative risk 0.91 [95% CI, 0.80 to 1.04; P = .18])
            • Level of severity:
              • Severe bronchopulmonary dysplasia – 88/252 (34.9%) in the treatment group and 58/229 (25.3%) in the placebo group (relative risk 1.41 [95% CI, 1.07 to 1.86; P = .02])
              • Moderate bronchopulmonary dysplasia – 16/252 (6.4%) in the treatment group and 13/229 (5.7%) in the placebo group (relative risk 1.12 [95% CI, 0.55 to 2.27; P = .75])
              • Mild bronchopulmonary dysplasia – 70/252 (27.8%) in the treatment group and 78/229 (34.1%) in the placebo group (relative risk 0.81 [95% CI, 0.62 to 1.04; P = .10])
            • Death before 36 weeks’ postmenstrual age was found to be 16/268 (6.0%) in the treatment group and 26/255 (10.2%) in the placebo group (relative risk 0.61 [95% CI, 0.33 to 1.13; P = .12])
          • 461 mothers (and 528 infants) were randomised in total.
          • 457 infants (399 mothers) had ³1 outcome of interest available at 18-22 months’ corrected age.
        • Patient follow-up: Less than 15% of infants were lost to follow-up, with comparable numbers between each group.

MAIN RESULTS

  • Baseline characteristics:
    • Of note, the groups had the following baseline characteristics:
      • Mother’s age at randomisation in years, mean – 30.9 in the treatment group and 31.5 in the placebo group
      • Mother’s number of years of schooling completed at randomisation, mean – 15.1 in the treatment group and 14.9 in the placebo group
      • Magnesium sulfate during labour – 67.8% of mothers in the treatment group and 73.5% of mothers in the placebo group
      • Caesarean delivery – 69.5% of mothers in the treatment group and 54.5% of mothers in the placebo group
      • Gestational age at birth in weeks, mean – 26.7 in the treatment group and 26.4 in the placebo group
      • Infants born at <27 weeks’ gestational age – 52.1% in the treatment group and 58.3% in the placebo group
      • Birth weight in grams, mean – 897.8 in the treatment group and 884.6 in the placebo group
      • Apgar score <7 at 5 min after birth – 44% in the treatment group and 48% in the placebo group
      • Infants with bronchopulmonary dysplasia-free survival at 36 weeks’ postmenstrual age – 56.4% in the treatment group and 61.9% in the placebo group. In the MOBYDIck trial, the difference between the groups was not found to be statistically significant.
      • Infants with severe bronchopulmonary dysplasia – 30.3% in the treatment group and 21.5% in the placebo group
      • Grade 3 or 4 intraventricular haemorrhage – 8.5% in the treatment group and 17% in the placebo group
    • Primary outcome: Maternal supplementation with high-dose DHA compared to placebo in the neonatal period did not affect neurodevelopmental outcomes at 18 to 22 months’ corrected age.
      • Bayley-III Cognitive Composite Score mean difference -0.07 (95% CI, -3.23 to 3.10; P = .97).
      • Bayley-III Language Composite Score mean difference 2.36 (95% CI, -1.14 to 5.87; P = .19)
      • Bayley-III Motor Composite Score mean difference 1.10 (95% CI, -2.01 to 4.20; P = .49)
    • Secondary outcomes: There were no statistically significant differences found between treatment groups in rates of the following:
      • Death before 18–22 months’ corrected age was 21/234 (9%) in the treatment group and 28/223 (12.6%) in the placebo group (relative risk 0.75 [95% CI, 0.43 to 1.29; P = .30])
      • Significant neurodevelopmental impairment at 18–22 months’ corrected age was 30/184 (16.3%) in the treatment group and 32/168 (19.1%) in the placebo group (relative risk 0.91 [95% CI, 0.57 to 1.46; P = .70])
      • Bayley-III Cognitive Composite Score
        • Significant impairment, <70, was 12/198 (6.1%) in the treatment group and 7/180 (3.9%) in the placebo group (relative risk 1.73 [95% CI, 0.65 to 4.59; P = .27])
        • At least mild impairment, <85, was 26/198 (13.1%) in the treatment group and 24/180 (13.3%) in the placebo group (relative risk 1.00 [95% CI, 0.59 to 1.70; P = 1.00])
      • Bayley-III Language Composite Score
        • Significant impairment, <70, was 24/190 (12.6%) in the treatment group and 29/176 (16.5%) in the placebo group (relative risk 0.84 [95% CI, 0.50 to 1.41; P = .51])
        • At least mild impairment, <85, was 60/190 (31.6%) in the treatment group and 68/176 (38.6%) in the placebo group (relative risk 0.81 [95% CI, 0.61 to 1.09; P = .16])
      • Bayley-III Motor Composite Score
        • Significant impairment, <70, was 17/189 (9.0%) in the treatment group and 11/167 (6.6%) in the placebo group (relative risk 1.41 [95% CI, 0.65 to 3.02; P = .38])
        • At least mild impairment, <85, was 34/189 (18.0%) in the treatment group and 42/167 (25.2%) in the placebo group (relative risk 0.72 [95% CI, 0.48 to 1.09; P = .12])
      • Cerebral palsy with Gross Motor Function Classification System level 3 or higher was 2/212 (0.9%) in the treatment group and 1/191 (0.5%) in the placebo group (relative risk 1.91 [95% CI, 0.17 to 20.93; P = .60])
      • Hearing loss requiring aid or cochlear implant was 5/207 (2.4%) in the treatment group and 3/184 (1.6%) in the placebo group (relative risk 1.61 [95% CI, 0.39 to 6.64; P = .51])
      • Bilateral visual impairment was 1/184 (0.5%) in the treatment group and 0/172 in the placebo group (0.0) (relative risk and 95% CI not presented)
    • Subgroup Analysis: This was stratified by sex and gestational age at birth for the primary and major secondary outcomes.
      • For neonates born <27 weeks’ gestation, those exposed to DHA had higher language scores compared with the placebo group (mean difference 5.06 [95 % CI, 0.08 to 10.03; P = .05]).
    • Post hoc sensitivity analysis: Primary and major secondary neurodevelopment outcomes at 18 to 22 months’ corrected age when excluding participants with grade 3 or 4 intraventricular haemorrhage.
      • Primary neurodevelopment outcomes
        • Bayley-III Cognitive Composite Score mean difference 0.41 (95% CI, -2.93 to 3.76; P = .81)
        • Bayley-III Language Composite Score mean difference 2.45 (95% CI, -1.29 to 6.18; P = .20)
        • Bayley-III Motor Composite Score mean difference 1.55 (95% CI, -1.71 to 4.81; P = .35)
      • Major secondary neurodevelopment outcomes
        • Death before 18–22 months’ corrected age was 13/214 (6.1%) in the treatment group and 12/185 (6.5%) in the placebo group (relative risk 0.95 [95% CI, 0.44 to 2.03; P = .89])
        • Significant neurodevelopmental impairment at 18–22 months’ corrected age was 27/175 (15.4%) in the treatment group and 28/148 (18.9%) in the placebo group (relative risk 0.85 [95% CI, 0.52 to 1.40; P = .53])

CONCLUSION

Among breastfed infants born before 29 weeks’ gestational age maternal supplementation with high-dose DHA compared to placebo in the neonatal period did not improve neurodevelopmental outcomes at 18 to 22 months’ corrected age.

COMMENTARY

This was a planned follow-up study of the Canadian multicentre, randomised, double-blind, placebo-controlled superiority trial, Maternal Omega-3 Supplementation to Reduce Bronchopulmonary Dysplasia in Very Preterm Infants (MOBYDIck). Enrolment in the primary study occurred from 2015 to 2018. Four hundred and fifty-seven infants were included in the final analysis.1,2 At 18-22 months’ corrected age, neurodevelopmental outcomes as assessed by Bayley-III cognitive, language, and motor composite scores were not statistically significant between the treatment and placebo groups.1 The rates of death before 18–22 months’ corrected age, cerebral palsy, hearing impairment and visual impairment were also not statistically significant between the two groups.1

Some aspects may bias study results toward the null. Firstly, approximately half the infants in both groups received intravenous DHA. This was on average for 21-23 days, in the form of DHA-rich lipids. Secondly, there may have been additional enteral DHA supplementation in both groups. At 6 weeks postmenstrual age, infants received a median of 130-133ml/kg/day of expressed breast milk.1 This suggests that many infants at this age were receiving supplemental nutrition, such as donor breast milk or formula. Formula frequently contains DHA.3 The use of fortifier, which also contains DHA, wasn’t commented on.4

The total fatty acid levels in breast milk at 14 days post-delivery were, on average, similar between the groups. In the treatment group DHA composed on average 0.97% of total fatty acids in breast milk at 14 days post-delivery, and in the placebo group, 0.35%.1 The authors note the hypothesis that sole DHA supplementation may cause an imbalance between the long-chain polyunsaturated fatty acids (LCPUFAs), potentially negating the benefits of high-dose DHA supplementation.1 Indeed, expert consensus statements recommend that preterm infants are supplemented with multiple LCPUFAs, such as DHA and arachidonic acid.4,5

Due to the lower frequency of severe intraventricular haemorrhage (IVH) in the DHA group, a post hoc sensitivity analysis excluding participants with severe IVH was completed. This did not change the primary findings. Subgroup analysis found that for neonates born <27 weeks’ gestation, those in the treatment group had a higher language score (mean difference 5.06, 95% CI 0.08–10.03; P = .05). This analysis was not adjusted for the imbalance in frequency of IVH.1

Further study limitations are well-documented by authors. This includes a suboptimal sample size limiting study interpretation, as enrolment for the MOBYDIck trial was terminated early due to concern that DHA was associated with bronchopulmonary dysplasia.1 Additionally, the sample size was chosen for the primary outcome of the MOBYDIck trial, and therefore has limited ability to detect differences in the primary outcome of this study.

Despite the theoretical benefit of LCPUFA supplementation for preterm infants, several randomised controlled trials and a Cochrane systematic review have found little, if any, clinical neurodevelopmental effect.4,6,7,8,9 This study is important as there is limited data on very preterm and extremely preterm infants. Based on this trial, maternal supplementation with high-dose DHA in breastfed infants born before 29 weeks’ gestational age does not improve neurodevelopmental outcomes at 18 to 22 months’ corrected age.

REFERENCES

  1. Guillot M, Synnes A, Pronovost E, Qureshi M, Daboval T, Caouette G, et al. Maternal High-Dose DHA Supplementation and Neurodevelopment at 18-22 Months of Preterm Children. Pediatrics. 2022;150(1):e2021055819.

  2. Marc I, Piedboeuf B, Lacaze-Masmonteil T, Fraser W, Mâsse B, Mohamed I, et al. Effect of Maternal Docosahexaenoic Acid Supplementation on Bronchopulmonary Dysplasia-Free Survival in Breastfed Preterm Infants: A Randomized Clinical Trial. JAMA. 2020;324(2):157-167.

  3. Alberta Health Services. Infant Formulas for Healthy Term Infants Compendium [Internet]. Alberta (CA): Alberta Health Services; 2018 [cited 2023 Jan 4]. Available from: https://www.albertahealthservices.ca/assets/info/nutrition/if-nfs-ng-healthy-infants-infant-formula-compendium.pdf

  4. Abrams SA. Long-chain polyunsaturated fatty acids (LCPUFA) for preterm and term infants. In: Motil KJ, Martin R, editors. UpToDate. [Internet]. Waltham (MA): UpToDate Inc; 2022. [updated 2022 Jul 21; cited 2022 Aug 19]. Available from: https://www.uptodate.com/contents/long-chain-polyunsaturated-fatty-acids-lcpufa-for-preterm-and-term-infants

  5. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. ESPGHAN Committee on Nutrition. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2010;50(1):85-91.

  6. Moon K, Rao SC, Schulzke SM, Patole SK, Simmer K. Longchain polyunsaturated fatty acid supplementation in preterm infants. Cochrane Database Syst Rev. 2016;12(12):CD000375.

  7. Makrides M, Gibson RA, McPhee AJ, Collins CT, Davis PG, Doyle LW, et al. Neurodevelopmental outcomes of preterm infants fed high-dose docosahexaenoic acid: a randomized controlled trial. JAMA. 2009;301(2):175-82.

  8. Henriksen C, Haugholt K, Lindgren M, Aurvåg AK, Rønnestad A, Grønn M, et al. Improved cognitive development among preterm infants attributable to early supplementation of human milk with docosahexaenoic acid and arachidonic acid. Pediatrics. 2008;121(6):1137-45.

  9. Isaacs EB, Ross S, Kennedy K, Weaver LT, Lucas A, Fewtrell MS. 10-year cognition in preterms after random assignment to fatty acid supplementation in infancy. Pediatrics. 2011;128(4):890-8.

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