Abstract
Background: Several meta analyses have concluded n-3 fatty acids, including docosahexaenoic acid (DHA), reduce early preterm birth (EPB, < 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. randomization 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 EPB by dose and by enrolment DHA status (low/high). Bayesian posterior probabilities (pp) were determined for planned efficacy and safety outcomes using intention-to-treat. The study is registered with ClinicalTrials.gov (NCT02626299) and closed to enrolment. Findings: Eleven hundred participants (1000 mg, n = 576; 200 mg, n = 524) were enrolled between June 8, 2016 and March 13, 2020 with the last birth September 5, 2020. 1032 (n = 540 and n = 492) were included in the primary analyses. The higher dose had a lower EPB rate [1.7% (9/540) vs 2.4% (12/492), pp=0.81] especially if participants had low DHA status at enrolment [2.0% (5/249) vs 4.1%, (9/219), pp=0.93]. Participants with high enrolment 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: Clinicians could consider prescribing 1000 mg DHA daily during pregnancy to reduce EPB in women with low DHA status if they are able to screen for DHA. Funding: The National Institutes of Health Child Health and Human Development (NICHD) funded the study. Life's DHA™-S oil, DSM Nutritional Products LLC, Switzerland provided all capsules.
Original language | English |
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Article number | 100905 |
Journal | EClinicalMedicine |
Volume | 36 |
DOIs | |
State | Published - Jun 2021 |
Bibliographical note
Publisher Copyright:© 2021 The Author(s)
Funding
SEC reports grants from NICHD R01HD083292 during the conduct of the study and non-financial support from DSM (donated capsules) and personal fees from DSM and Mead Johnson Nutrition outside the submitted work. CPW reports he is an inventor on EU Patent No.2646554 and US patent pending No. 15/991,735 that describe an early pregnancy screening test for subsequent preterm birth that was not involved in the submitted study. BJG reports grant support for the conduct of the study (NICHD R01HD083292. CJV is an employee of RB Nutrition, which produces infant formulas and supplements, however, RB was not involved in the study execution or analysis. She conducted this study through her role as an Adjunct Professor at The University of Cincinnati. EHK and SAC report grants from NICHD R01HD083292 during the conduct of the study and non-financial support from DSM for capsules. The other authors have no competing interests. We are willing to share deidentified data from the study including data from individual participants with a signed data access agreement that includes the study principal investigators and is contingent on their approval of the planned use of the data. As the data are entered into an electronic system, a specific request to SEC ([email protected]) or BJG ([email protected]) would be needed to generate a data output for other investigators. Our study protocol has been published [9] and the protocol update as well as statistical analysis plan are available from SEC or BJG. We plan to publish the secondary results of the trial and cannot share some data until then, however, we are willing to consider requests for data any time after the primary results are published. We are grateful for the support of numerous study personnel who were responsible for recruiting participants at all three sites, communicating with them monthly, and collecting the data critical for the study. They did so with diligence and care and this study would not have been possible without them or the nurses at each medical center who took on the additional work of obtaining blood samples and informing staff of their availability. We are very grateful as well to our DSMB, excellently chaired by Prof Daniel Robinson MD of Lurie Children's Hospital in Chicago, IL (USA), Prof Arthur Evans MD of the University of Cincinnati, Cincinnati, OH; Dr. Ian Griffin MD of the Biomedical Research Institute of New Jersey, Cedar Knolls, NJ, and Prof Ardythe Morrow PhD of the University of Cincinnati, Cincinnati, OH. As a group, they were all engaged and invaluable in helping us refine our system for reporting adverse events. We are also grateful to the 1100 women who enrolled in the study. SEC reports grants from NICHD R01HD083292 during the conduct of the study and non-financial support from DSM (donated capsules) and personal fees from DSM and Mead Johnson Nutrition outside the submitted work. CPW reports he is an inventor on EU Patent No.2646554 and US patent pending No. 15/991,735 that describe an early pregnancy screening test for subsequent preterm birth that was not involved in the submitted study. BJG reports grant support for the conduct of the study (NICHD R01HD083292. CJV is an employee of RB Nutrition, which produces infant formulas and supplements, however, RB was not involved in the study execution or analysis. She conducted this study through her role as an Adjunct Professor at The University of Cincinnati. EHK and SAC report grants from NICHD R01HD083292 during the conduct of the study and non-financial support from DSM for capsules. The other authors have no competing interests.
Funders | Funder number |
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Biomedical Research Institute of New Jersey | |
University of Cincinnati University Research Council | |
Eunice Kennedy Shriver National Institute of Child Health and Human Development | R01HD083292 |
Eunice Kennedy Shriver National Institute of Child Health and Human Development | |
DSM Biomedical | 15/991,735, 2646554 |
DSM Biomedical |
Keywords
- Docosahexaenoic acid (DHA) amount
- Early preterm birth
- Gestation less than 34 weeks
- Pregnancy
ASJC Scopus subject areas
- General Medicine