Higher Dose Docosahexaenoic Acid Supplementation During Pregnancy and Early Preterm Birth: A Randomised, Double-Blind, Adaptive-Design Superiority Trial

Abstract

Background: Several meta analyses have concluded n-3 fatty acids, including docosahexaenoic acid (DHA), reduce early preterm birth (<34 weeks), however, the amount of DHA required is unclear. We hypothesized that 1000 mg DHA per day would be superior to 200 mg, the amount in most prenatal supplements. Methods: This randomised, multicentre, double-blind, adaptive-design, superiority trial was conducted in three USA medical centres. Women with singleton pregnancies and 12 to 20 weeks gestation were eligible. Randomisation was generated in SAS® by site in blocks of 4. The planned adaptive design periodically generated allocation ratios favoring the better performing dose. Managing study personnel were blind to treatment until 30 days after the last birth. The primary outcome was early preterm birth by dose and by enrollment DHA status (low/high). Bayesian posterior probabilities (pp) were determined for planned efficacy and safety outcomes using intention-to-treat. Findings: Eleven hundred participants (1000 mg, n=576; 200 mg, n=524) were enrolled between June 8, 2016 and March 13, 2020. 1032 (n=540 and n=492) were included in the primary analyses. The higher dose was superior for prevention of early preterm birth [1.7% (9/540) vs 2.4% (12/492), pp=0.81]. Participants with low enrollment DHA status had half the rate of early preterm birth with 1000 compared to 200 mg [2.0% (5/249) vs 4.1%, (9/219), pp=0.93]. Participants with high enrollment DHA status did not realize a dose effect [1000 mg: 1.4% (4/289); 200 mg: 1.1% (3/271), pp=0.57]. The higher dose was associated with fewer serious adverse events (maternal: chorioamnionitis, premature rupture of membranes and pyelonephritis; neonatal: feeding, genitourinary and neurologic problems, all pp>0.90). Interpretation: Physicians should consider prescribing 1000 mg DHA daily during pregnancy to reduce early preterm birth, particularly in women entering pregnancy with low DHA status. Trial Registration: The study is registered with ClinicalTrials.gov (NCT02626299) and closed to enrollment. Funding Statement: National Institutes of Health Child Health and Human Development (NICHD) R01HD083292. Declaration of Interests: SEC has received honorariums for presentations about DHA in infancy and pregnancy. CJV is an employee of RB Nutrition, which produces infant formulas and supplements, however, RB had no involvement in the study execution or analysis. She conducted this study through her role as an Adjunct Professor at The University of Cincinnati. The other authors have no competing interests. Ethics Approval Statement: The University of Kansas Medical Center granted approval under a central IRB with reliance by the other institutions (STUD3455). All participants gave written consent.