Isabelle Marc1, Bruno Piedboeuf1, Thierry Lacaze-Masmonteil2, William Fraser3, Benoît Mâsse4,5, Ibrahim Mohamed5, Mosarrat Qureshi6, Jehier Afifi7, Brigitte Lemyre8, Georges Caouette1, Julie Bartholomew9, Anne Monique Nuyt5, Pierre Julien10, Anne Synnes11, Michel Lucas12, Thérèse Perreault13, Lannae Strueby14, Zenon Cieslak15, Kamran Yusuf16, Gustavo Pelligra17, Edith Massé18, Bodil Larsen19, Cecilia de Cabo20, Chelsea Ruth20, Faiza Khurshid21, Pascal M Lavoie11. 1. Department of Pediatrics, Faculty of Medicine, Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, Quebec, Canada. 2. Department of Pediatrics, Cumming School of Medicine, University of Calgary, Foothills Medical Centre, Calgary, Alberta, Canada. 3. Department of Obstetrics and Gynecology, Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada. 4. School of Public Health, Université de Montréal, Montreal, Quebec, Canada. 5. Department of Pediatrics, Université de Montréal, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada. 6. Division of Neonatology, Royal Alexandra Hospital, Edmonton, Alberta, Canada. 7. Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada. 8. Division of Neonatology, Children's Hospital of Eastern Ontario, Ottawa, Canada. 9. Department of Neonatology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada. 10. Department of Endocrinology and Nephrology, Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, Quebec, Canada. 11. Department of Pediatrics, Division of Neonatology, University of British Columbia, Vancouver, Canada. 12. Department of Social and Preventive Medicine, Centre Hospitalier Universitaire de Québec-Université Laval, Hôpital du Saint-Sacrement, Quebec City, Quebec, Canada. 13. Division of Neonatology, Montréal Children's Hospital, McGill University, Montreal, Quebec, Canada. 14. Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada. 15. Department of Pediatrics, Royal Columbian Hospital, New Westminster, British Columbia, Canada. 16. Department of Pediatrics, Section of Neonatology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 17. Department of Maternity Care and Pediatrics, Victoria General Hospital, Island Health, Victoria, British Columbia, Canada. 18. Department of Pediatrics, Université de Sherbrooke, Hôpital Fleurimont, Sherbrooke, Quebec, Canada. 19. Faculty of Agricultural, Life, and Environmental Sciences, University of Alberta, Edmonton, Canada. 20. Department of Pediatrics and Child Health, Max Rady School of Medicine, University of Manitoba, Winnipeg, Canada. 21. Department of Pediatrics, Queen's University, Kingston, Ontario, Canada.
Abstract
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 toplacebo 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, maternaldocosahexaenoic 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.
RCT Entities:
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.
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