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

Pierre Julien, Pascal M Lavoie, Faiza Khurshid, Chelsea Ruth, Cecilia de Cabo, Bodil Larsen, Gustavo Pelligra, Kamran Yusuf, Zenon Cieslak, Lannae Strueby, Thérèse Perreault, Michel Lucas, Anne Synnes, Mosarrat Qureshi, Georges Caouette, Brigitte Lemyre, Jehier Afifi, Benoît Mâsse, William Fraser, Thierry Lacaze-Masmonteil, Bruno Piedboeuf, Isabelle Marc, Anne Monique Nuyt, Edith Massé, Ibrahim Mohamed, Julie Bartholomew

Journal: JAMA 2020;324(2):157-167

PMID: 32662862

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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 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.

Address: Department of Pediatrics, Faculty of Medicine, Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, Quebec, Canada.; Department of Pediatrics, Cumming School of Medicine, University of Calgary, Foothills Medical Centre, Calgary, Alberta, Canada.; Department of Obstetrics and Gynecology, Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada.; School of Public Health, Université de Montréal, Montreal, Quebec, Canada.; Department of Pediatrics, Université de Montréal, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada.; Division of Neonatology, Royal Alexandra Hospital, Edmonton, Alberta, Canada.; Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.; Division of Neonatology, Children's Hospital of Eastern Ontario, Ottawa, Canada.; Department of Neonatology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.; Department of Endocrinology and Nephrology, Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, Quebec, Canada.; Department of Pediatrics, Division of Neonatology, University of British Columbia, Vancouver, Canada.; Department of Social and Preventive Medicine, Centre Hospitalier Universitaire de Québec-Université Laval, Hôpital du Saint-Sacrement, Quebec City, Quebec, Canada.; Division of Neonatology, Montréal Children's Hospital, McGill University, Montreal, Quebec, Canada.; Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada.; Department of Pediatrics, Royal Columbian Hospital, New Westminster, British Columbia, Canada.; Department of Pediatrics, Section of Neonatology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.; Department of Maternity Care and Pediatrics, Victoria General Hospital, Island Health, Victoria, British Columbia, Canada.; Department of Pediatrics, Université de Sherbrooke, Hôpital Fleurimont, Sherbrooke, Quebec, Canada.; Faculty of Agricultural, Life, and Environmental Sciences, University of Alberta, Edmonton, Canada.; Department of Pediatrics and Child Health, Max Rady School of Medicine, University of Manitoba, Winnipeg, Canada.; Department of Pediatrics, Queen's University, Kingston, Ontario, Canada.

DOI: 10.1001/jama.2020.8896

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MeSH Terms: Adult, Bronchopulmonary Dysplasia, Dietary Supplements, Docosahexaenoic Acids, Equivalence Trials as Topic, Female, Gestational Age, Humans, Infant, Extremely Premature, Infant, Newborn, Lactation, Patient Compliance, Sample Size