Pregnant women who received omega-3 (n-3) long-chain polyunsaturated fatty acid supplements did not have a lower risk of early preterm delivery (prior to 34 weeks gestation), according to a new phase 3 trial.
Maria Makrides, PhD, with the South Australian Health and Medical Research Institute, Women’s and Children’s Hospital, North Adelaide, Australia, and colleagues reported their findings in the September 12, 2019 issue of The New England Journal of Medicine.
The World Health Organization (WHO) estimates 15 million babies are born preterm (prior to completing 37 weeks gestation), over 10% of births worldwide. Preterm birth is associated with increased rates of disability and is the leading cause of death in children under five.
Omega-6 (n-6) fatty acids are precursors of several mediators of inflammation, such as prostaglandins. Prostaglandin E2 and prostaglandin F2α have been shown to initiate labor by inducing cervical ripening and uterine contractions. The n-3 fatty acids, on the other hand, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors of several anti-inflammatory mediators. They are inefficiently produced in mammals and often require dietary sources, such as fish, flaxseed, some vegetables, or supplements containing DHA or EPA, to maintain proper levels. The typical western diet, relatively low in n-3 fatty acids and high in n-6 fatty acids, shifts production to more pro-inflammatory mediators and, as a result, may influence preterm delivery.
Several epidemiological studies have shown an association between lower dietary fish intake and increased rates of preterm delivery, leading to the WHO recommendation that pregnant women take 300 mg of n-3 long-chain polyunsaturated fatty acids daily. A 2018 birth cohort study in Denmark corroborated this by showing a correlation between low plasma concentrations of EPA and DHA in pregnancy with an increased rate of early preterm birth.
A previous randomized controlled study, called DOMInO (DHA to Optimise Mother Infant Outcome), showed that while DHA had no effect on postpartum depression or infant brain development, a secondary analysis showed a decreased incidence in early preterm delivery compared with control. Thus, it is unclear whether supplementation with n-3 long-chain polyunsaturated fatty acids results in a lower rate of early preterm delivery.
This trial, called ORIP (Omega-3 to Reduce the Incidence of Preterm Birth), enrolled 5517 women, with a total of 5544 pregnancies, less than 20 weeks gestation, and taking no more than 150 mg of n-3 long-chain polyunsaturated fatty acid supplementation daily. 2770 pregnancies in 2766 women were randomly assigned to receive three 500-mg fish-oil capsules per day, containing approximately 800 mg of DHA and 100 mg of EPA daily until 34 weeks gestation or delivery, whichever occurred first. A control group included 2774 pregnancies in 2765 women randomly assigned to receive three 500-mg capsules of an isocaloric vegetable-oil blend, containing approximately 15 mg of DHA and 4 mg of EPA per day for the same duration. 5486 pregnancies (2734 in the n-3 group and 2752 in the control group) were included in the final analysis. The incidence of early preterm delivery was compared between groups.
Early preterm delivery occurred in 2.2% of the n-3 group and 2.0% of the control group (relative risk 1.13; 95% confidence interval [CI], 0.79 to 1.63; P=0.50).
There was no significant difference in the rate of serious adverse outcomes (5.0% in the n-3 group and 4.0% in the control group). There were more gastrointestinal side effects reported in the n-3 group, including burping, diarrhea, and constipation.
This study showed that DHA and EPA supplementation did not reduce the incidence of early preterm delivery, and does not confirm the result of the secondary outcome analysis in the DOMInO trial. The authors suggest that further studies are needed to evaluate subgroups that may show a benefit, for example, those with low levels of n-3 fatty acids.
The study was funded by the Australian National Health and Medical Research Council and the Thyne Reid Foundation.
Makrides, M, PhD, et al. A Randomized Trial of Prenatal n-3 Fatty Acid Supplementation and Preterm Delivery. N Engl J Med. 2019; 381:1035-45.