BACKGROUND AND PURPOSE:

• n-3 fatty acids, such as docosahexaenoic acid (DHA), have been shown in meta-analyses to reduce the risk of early preterm birth
  • However, the required dose of DHA is unclear
• Carlson et al. (EClinicalMedicine, 2021) conducted a superiority trial comparing the standard 200 mg DHA dose, often found in prenatal supplements, vs 1000 mg

METHODS:

• Randomized, multicenter, double-blind, adaptive-design, superiority trial
  • NICHD funded
• Participants
  • Singleton pregnancies
  • 12 to 20 weeks gestation
• Intervention
  • 1000 mg DHA
  • 200 mg DHA (standard)
• Study design
  • Women were randomized by participating site in blocks of 4
  • Adaptive design: Allocation ratios that favor the better performing dose are periodically generated with the goal of saving time, study resources and may be more ethical
    • Simulations performed to determine design that optimizes time and number of patients required
  • Bayesian posterior probabilities (pp) were determined for planned efficacy and safety outcomes using intention-to-treat
  • In addition to dichotomous design, a continuous time-to-event value was also calculated
• Primary outcome
  • Early preterm birth

RESULTS:

• 1000 mg dose: 540 participants | 200 mg dose: 492 participants
• The higher DHA dose was associated with a lower rate of early preterm birth
  • 1000 mg: 1.7%
  • 200 mg: 2.4%
  • pp = 0.81
• Using continuous time-to-event value and Baysian credible intervals (CI)  
  • 1000 mg: 1.7% (95% CI, 0.8% to 2.8%)
  • 200 mg: 2.9% (95% CI, 1.6% to 4.3%)
  • pp=0.91

Note: “A pp = 0.81 or 0.91 is much larger than an indifferent probability of 0.50 but not as strong as almost certainty (e.g., > 0.99)”

• This association was especially strong if participants had a low DHA status at enrollment
  • 1000mg w/ low DHA at enrollment: 2.0%
  • 200 mg w/ low DHA at enrollment: 4.1%
  • pp = 0.93
• Participants who had high DHA levels at enrollment did not see a difference in early preterm birth rates with the different DHA doses
  • 1000 mg w/ high DHA at enrollment: 1.4%
  • 200 mg w/ high DHA at enrollment: 1.1%
  • pp = 0.57
• The higher dose of DHA was also associated with fewer serious adverse events such as (all pp>0.90)
  • Chorioamnionitis
  • Premature rupture of membranes and pyelonephritis
  • Feeding problems
  • Genitourinary and neurologic problems

CONCLUSION:

• For women with low levels of DHA, supplementing with 1000 mg of DHA confers a greater benefit for reducing early preterm birth risk vs 200 mg
• When women are able to be screened for DHA, clinicians should consider prescribing a 1000 mg dose of DHA to women with low levels
• The authors suggest the following regarding policy

Regarding policy, the National Academy of Medicine in the USA could now set a Dietary Recommended Intake for DHA in pregnancy, not possible before an amount of DHA could be linked to lower EPB

Regarding clinical practice, clinicians could consider testing DHA status and offering high dose DHA supplementation to those with low DHA status

Women with high DHA status at enrolment should be encouraged to take a prenatal with 200 mg DHA 

Learn More – Primary Sources:

Higher dose docosahexaenoic acid supplementation during pregnancy and early preterm birth: A randomised, double-blind, adaptive-design superiority trial

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