At the Global Organization for EPA and DHA Omega-3s (GOED) Exchange, held in Fort Lauderdale, FL in February, researchers specializing in fish oil and omega-3 fatty acids discussed studies they led, which will shape trends in future human clinical research.

Maria Makrides, PhD, FAA, deputy director of the South Australian Heath and Medical Research Institute, spoke about investigations she and her team conducted on the role that maternal consumption of omega-3 fatty acids plays in reducing the risk of preterm births, including early preterm births.

Richard Bazinet, PhD, Canada research chair in brain lipid metabolism at the University of Toronto, discussed some of the recent insights he and his team uncovered regarding the synthesis and metabolic pathways of EPA and DHA in the brain, which are predominantly included in a review he co-authored, appearing in Progress in Lipid Research.

Preterm Birth
Makrides has been involved in the latest, yet-to-be-published Cochrane Review on the role that omega-3 fatty acids might play in preterm birth, an important prenatal concern that she says is often overlooked in favor of the role these acids play in neurocognitive development.

“Fifteen million babies are born preterm every year, and these births are responsible for about 85% of all perinatal complications; and it is a leading cause of death for children under the age of 5 in high-income countries,” Makrides said. She noted that hypotheses about the possible protective role of EPA and DHA against preterm birth first began circulating in the 1980s. Its origins were based on comparisons between populations of countries that consumed high amounts of fish, and those with low fish intake, which illustrated associations of high fish intake to preterm birth prevention.

“A number of early randomized controlled studies were designed in attempts to reduce the risk of preterm birth, particularly in high-risk pregnancies,” Makrides said. “Eventually, the research world got more preoccupied with neurodevelopmental outcomes and allergy prevention, but all of those studies also had the opportunity to provide data on pregnancy outcomes. There’s been a range of Cochrane Reviews trying to synthesize these data over the years.”

After several trials which were inconclusive, a yet-to-be-published Cochrane Review conducted in 2021 has three-times the participants as a review conducted in 2018, to include now more than 80 randomized clinical trials involving 31,500 pregnant women.

The pending results of the study found unique and significant protective effects of omega-3s against both preterm birth and early preterm birth, the latter of which is defined as birth earlier than 34 weeks’ gestation. Across 36 trials, women who consumed omega-3s saw on average a 12% risk reduction of preterm birth compared to placebo, and in 12 trials, which followed 16,782 women, omega-3 supplementation resulted in a 35% risk reduction of early preterm birth as defined by researchers.

The present review’s subgroup analysis didn’t find any significant interactions which indicated significant differences across dose, type, or timing, Makrides said, however, starting supplementation before 20 weeks’ gestation was more effective on both preterm and early preterm birth. Dosages needed to be between 500 and 1,000 mg to confer statistically significant benefits, but dosages of greater than 1,000 mg were linked to the best outcomes for early preterm birth. While these clues could inform future research, she said that more needs to be done to distinguish data surrounding EPA versus DHA, as the two were used too frequently in combination across the portfolio of studies included in the review.

Omega-3 status at baseline, of course, is an important risk factor to consider, but data on individual participants was too limited to make a conclusion on the role that baseline status has in supplementation studies, Makrides said.

The single largest trial in the Cochrane Review is important to understand, she added. “A primary interest to convince a change in practice is that the single largest trial actually gives the same result. In cases where they don’t give the same result, some consider the systematic review to be more important, but many others consider the single largest trial to be more important than the aggregation of data because people find it easy to criticize.” This trial, known as the ORIP trial, includes singleton and multiple pregnancies, and it was a test of a “blanket, universal approach to supplementation as a policy to determine an effect on preterm birth,” according to Makrides.

While supplementing with 800 mg DHA and 100 mg EPA showed no significant effect on preterm birth, “there were quite a number of subgroup analyses which we used to understand the variation,” Makrides said. There was a reduction in preterm birth among singleton pregnancies, but not in the multiple births. Furthermore, baseline omega-3 fatty acid status was shown to have a significant effect in modifying the outcome of premature birth rates—responses to supplementation were much stronger among those who had a low omega-3 status at baseline, in relation to preterm birth prevention, suggesting that baseline status was a significant predictor.

Insights into Synthesis
Using carbon tracer molecules, Bazinet and a team of researchers at the University of Toronto uncovered some of the kinetic activities of the two omega-3 fatty acids, EPAs’ conversion to DHA, and DHA’s possible retro-conversion to EPA.

To keep things simple, EPA eventually converts to DHA in the human body through a pathway in which it first becomes DPA, then TPA, then THA, and, finally, DHA, according to Bazinet. According to his research, the approximate amount of DHA in a human brain is approximately 4 grams, based on chromatography conducted on a uniform solution created from a brain itself. “This matters, because now we can talk about how much DHA we need to eat to get 4 grams in the brain and how much is needed to sustain that,” he said.

Based on carbon isotope ratio analysis, a highly-specialized measurement of carbon dioxide’s presence in fatty acids which offers high levels of tracer precision, Bazinet’s team reached a number of conclusions about the synthesis pathways of EPA and DHA in the human brain.

Firstly, dietary studies suggest that DHA retro-converts to EPA at a rate of about 11%; however, carbon isotope ratio analysis suggests that this retro-conversion is happening at a much lower rate. This runs contrary to the paradigm that much DHA is lost to retro-conversion in humans, he said.

There are alternative reasons why increases in EPA that researchers previously considered to be DHA retro-conversion could be going on, Bazinet said. “It could be retro-conversion, an increased flux from ALA, or a decreased rate at which DHA goes to EPA, leading to an accumulation of EPA.”

Furthermore, his research concluded that DHA levels can increase EPA concentration, but not because of retro-conversion. Signs point, rather, to the presence of DHA playing a role in slowing down EPA’s conversion. So, EPA converts more readily to DHA than previously thought, Bazinet said, however, it is not likely to increase the amount of brain DHA. This means that intake of higher concentrations of DHA is much more likely to increase the amount of DHA which crosses the blood-brain barrier.

Carbon isotope ratio analysis may also be a useful tool in determining the sources of DHA, based on the weight of the DHA molecule. This has important implications in areas such as determining how farmed fish were fed, he noted.