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

30 Pages Posted: 8 Feb 2021

See all articles by Susan E. Carlson

Susan E. Carlson

University of Kansas - Department of Dietetics and Nutrition

Byron J. Gajewski

University of Kansas - University of Kansas Medical Center

Christina J. Valentine

University of Cincinnati - Department of Obstetrics and Gynecology

Elizabeth H. Kerling

University of Kansas - Department of Dietetics and Nutrition

Carl P. Weiner

University of Kansas Medical Center - Department of Obstetrics and Gynecology

Michael Cackovic

Ohio State University - Department of Obstetrics and Gynecology

Catalin S. Buhimschi

University of Illinois - Department of Obstetrics and Gynecology

Lynette K. Rogers

Nationwide Children's Hospital

Scott A. Sands

University of Kansas - Department of Dietetics and Nutrition

Alexandra R. Brown

University of Kansas Medical Center - Department of Biostatistics & Data Science

Dinesh Pal Mudaranthakam

University of Kansas - Department of Biostatistics & Data Science

Sarah A. Crawford

University of Kansas - Department of Dietetics and Nutrition

Emily A. DeFranco

University of Cincinnati Medical Center - Department of Obstetrics and Gynecology

More...

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 (STUDY00003455). All participants gave written consent.

Suggested Citation

Carlson, Susan E. and Gajewski, Byron J. and Valentine, Christina J. and Kerling, Elizabeth H. and Weiner, Carl P. and Cackovic, Michael and Buhimschi, Catalin S. and Rogers, Lynette K. and Sands, Scott A. and Brown, Alexandra R. and Pal Mudaranthakam, Dinesh and Crawford, Sarah A. and DeFranco, Emily A., Higher Dose Docosahexaenoic Acid Supplementation During Pregnancy Reduces Early Preterm Birth: A Randomised, Double-Blind, Adaptive-Design Superiority Trial. Available at SSRN: https://ssrn.com/abstract=3781704 or http://dx.doi.org/10.2139/ssrn.3781704

Susan E. Carlson (Contact Author)

University of Kansas - Department of Dietetics and Nutrition ( email )

3901 Rainbow Blvd.
MS 4013
Kansas City, KS 66160
United States
1.816.820.4668 (Phone)

Byron J. Gajewski

University of Kansas - University of Kansas Medical Center ( email )

3901 Rainbow Boulevard
Kansas City, KS 66160
United States

Christina J. Valentine

University of Cincinnati - Department of Obstetrics and Gynecology ( email )

Cincinnati, OH
United States

Elizabeth H. Kerling

University of Kansas - Department of Dietetics and Nutrition ( email )

3901 Rainbow Blvd.
Kansas City, KS 66160
United States

Carl P. Weiner

University of Kansas Medical Center - Department of Obstetrics and Gynecology ( email )

3901 Rainbow Boulevard
Kansas City, KS 66160
United States

Michael Cackovic

Ohio State University - Department of Obstetrics and Gynecology ( email )

Blankenship Hall-2010
901 Woody Hayes Drive
Columbus, OH OH 43210
United States

Catalin S. Buhimschi

University of Illinois - Department of Obstetrics and Gynecology ( email )

1200 W Harrison St
Chicago, IL 60607
United States

Lynette K. Rogers

Nationwide Children's Hospital ( email )

700 Children's Dr.
Columbus, OH 43205
United States

Scott A. Sands

University of Kansas - Department of Dietetics and Nutrition

3901 Rainbow Blvd.
Kansas City, KS 66160
United States

Alexandra R. Brown

University of Kansas Medical Center - Department of Biostatistics & Data Science ( email )

3901 Rainbow Boulevard
Kansas City, KS 66160
United States

Dinesh Pal Mudaranthakam

University of Kansas - Department of Biostatistics & Data Science ( email )

Kansas City, KS
United States

Sarah A. Crawford

University of Kansas - Department of Dietetics and Nutrition ( email )

3901 Rainbow Blvd.
Kansas City, KS 66160
United States

Emily A. DeFranco

University of Cincinnati Medical Center - Department of Obstetrics and Gynecology ( email )

Cincinnati, OH
United States

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