One Gene Variant May Decide Whether Omega-3 Protects Pregnancies From Early Preterm Birth

A single stretch of DNA that many people carry may determine whether a daily omega-3 supplement shortens or extends a pregnancy, according to a new secondary analysis of a large randomized trial published in PLOS Medicine. The study, led by Yan Ning Li of the University of Texas at Austin together with Kumar S. D. Kothapalli, Susan E. Carlson, Byron J. Gajewski, Emily A. DeFranco, and J. Thomas Brenna, examined data from the Assessment of DHA on Reducing Early Preterm Birth (ADORE) trial and found that the effect of docosahexaenoic acid, or DHA, on gestational length depended strongly on a participant’s genotype at a polymorphism known as the FADS Indel. The finding, if confirmed prospectively, points toward a precision-medicine approach to one of obstetrics’ most stubborn problems: spontaneous early preterm birth, defined as delivery before 34 weeks of gestation, which remains a leading contributor to newborn illness and death worldwide.

The biological logic behind the study begins with an enzyme called fatty acid desaturase 1, or FADS1, which sits at a critical junction in the metabolism of dietary polyunsaturated fatty acids. FADS1 helps convert precursor fatty acids into longer-chain, more unsaturated products, including arachidonic acid, the raw material from which the body manufactures prostaglandins. Prostaglandins are the parturifacient molecules that soften the cervix and drive the contractions of labor, so the amount of arachidonic acid circulating in a pregnant woman’s blood can plausibly influence when labor begins. The FADS Indel, catalogued as rs66698963, is an insertion-deletion polymorphism located within the FADS gene cluster. People carrying the insertion allele, abbreviated I, tend to have higher FADS1 expression and greater capacity to synthesize arachidonic acid, whereas people homozygous for the deletion allele, abbreviated D/D, have lower expression. DHA, meanwhile, is known to inhibit the prostaglandin pathway, which is precisely why omega-3 supplementation has long been investigated as a strategy to delay preterm delivery.

What made the ADORE trial an ideal testing ground was its design. Between June 8, 2016, and March 13, 2020, the researchers screened 10,497 women for eligibility across three US medical centers, ultimately enrolling 1,032 participants who completed the trial. Women between 12 and 20 weeks of gestation were randomly assigned to receive either a low dose of 200 milligrams of DHA per day or a high dose of 1,000 milligrams per day, and the trial’s primary aim was to test whether the higher dose reduced early preterm birth. Crucially for the new analysis, participants had consented to genetic analysis, and the FADS Indel was the only genetic variant measured. It was selected on mechanistic grounds rather than through an untargeted search, and genotyping was performed blind to pregnancy outcomes, which reduces the risk that the genetic findings were shaped by knowledge of the results.

For the secondary analysis, the team restricted the sample to the 761 participants who consented to genetic testing, of whom 396 had received the 1,000-milligram dose and 365 had received the 200-milligram dose. Participants were grouped by genotype into I-allele carriers, meaning those with either I/I or I/D genotypes, and D/D homozygotes. The primary outcomes were early preterm birth before 34 weeks and preterm birth before 37 weeks, analyzed using treatment-specific Bayesian binomial models. This statistical framework yields credible intervals and posterior probabilities, which express how strongly the data support a difference between groups, rather than the conventional frequentist p-values. Cervical length, an established predictor of preterm delivery, was also assessed in 574 participants, adding a clinical dimension to the genetic analysis.

The results revealed a striking genotype-dependent pattern. Among I-allele carriers who received the low 200-milligram dose of DHA, 4.3 percent delivered before 34 weeks, or 9 of 214 women, with a 95 percent credible interval of 2.0 to 7.3 percent. Among D/D women on the same low dose, only 0.8 percent delivered that early, or 1 of 151, with a credible interval of 0.04 to 2.7 percent, and the posterior probability supporting the difference was 0.99. A similar pattern appeared for preterm birth before 37 weeks: 14.5 percent among I-carriers on low dose, or 31 of 214, versus 8.7 percent among D/D women, or 13 of 151, with a posterior probability of 0.96. In other words, women genetically predisposed to produce more arachidonic acid fared worse on the low dose, exactly as the prostaglandin mechanism would predict.

When the dose was raised to 1,000 milligrams per day, the picture flipped for the I-allele group. Early preterm birth fell to 1.1 percent, or 2 of 205 women, with a credible interval of 0.2 to 2.8 percent and a posterior probability of 0.99, and preterm birth before 37 weeks fell to 9.3 percent, or 19 of 205, with a posterior probability of 0.95. The high dose had little effect on early delivery in the D/D group, whose baseline risk was already low. Meanwhile, a different kind of risk emerged at the other end of the pregnancy timeline: birth at 40 weeks or later was more frequent among D/D women receiving the high dose, suggesting that for this genotype, extra DHA may have tipped the prostaglandin balance too far toward prolonging gestation. The genotype-by-dose interaction was credibly different for early preterm birth and prolonged gestation, with posterior probabilities of 0.99 and 0.98 respectively.

The analysis also carried significant implications for health equity. Black women in the trial had higher rates of both preterm and early preterm birth, and they also carry the I allele at higher frequencies, consistent with known ancestry-related variation in the FADS Indel. Because of this overlap, Black women stood to benefit most from the 1,000-milligram dose, since the high dose specifically reduced early delivery among I-allele carriers. This convergence of genetic risk, ancestry, and treatment response offers a concrete explanation for why one-size-fits-all omega-3 recommendations have produced inconsistent results across populations, and it suggests that genotype-informed dosing could help direct the strongest intervention to the women who need it most. Notably, both genotypes appeared to share a modest benefit of high-dose DHA for overall preterm birth before 37 weeks, with a posterior probability of only 0.56 that the benefit differed between groups, meaning the genotype mattered most for the earliest and most dangerous deliveries and for prolonged gestation.

Perhaps the most clinically suggestive result concerned what happens when genotype and dose are deliberately matched. The researchers found that retrospectively pairing the high 1,000-milligram dose with I-carrier genotype and the low 200-milligram dose with D/D genotype was associated with the highest proportion of births occurring in the ideal 37-to-40-week window. That is, the combination that matched supplement dose to each woman’s fatty acid metabolism produced the most pregnancies ending at term but not beyond it. This is precisely the pattern a predictive biomarker would be expected to produce, and it is what distinguishes the FADS Indel from the many genetic variants that have failed to translate into clinical utility. Because the polymorphism is functional, mechanistically grounded in prostaglandin biochemistry, and variable across racial and ethnic groups, it satisfies several of the criteria that precision-medicine advocates look for in a usable genetic test.

The authors are careful to frame the caveats. This was a post hoc analysis, and although genetic analysis had been anticipated and genotyping was completed blind to outcomes, the genotype-by-dose comparison was not a prespecified aim of the original trial. Some subgroups contained few early preterm or preterm birth events, so the estimates, particularly for overall preterm birth, should be interpreted cautiously and confirmed in prospective studies designed specifically to test genotype-guided dosing. The Bayesian credible intervals, while supportive, cannot substitute for a trial in which women are randomized to doses according to their genotype from the outset. Still, the consistency of the mechanistic story, the large sample size, the blinded genotyping, and the dose-response alignment all strengthen the case that the finding is more than statistical noise.

If prospective trials bear out these results, the implications for prenatal care could be substantial. A simple genotyping test early in pregnancy, performed alongside the routine bloodwork already collected at 12 to 20 weeks, could identify I-allele carriers who would benefit from 1,000 milligrams of DHA daily and D/D women for whom the lower dose may be safer, reducing both early preterm birth and excessively prolonged gestation. Given that early preterm birth before 34 weeks drives the majority of newborn deaths and long-term disability among preterm infants, and that preventive measures currently available are limited, a cheap, mechanistically rational, genotype-guided supplement strategy would represent a meaningful advance. The ADORE secondary analysis, registered under ClinicalTrials.gov identifier NCT02626299, provides the strongest evidence yet that the era of personalized omega-3 dosing in pregnancy may be within reach, pending the confirmatory studies that the authors themselves call for.

Subject of Research: Genotype-informed DHA dosing based on the FADS Indel polymorphism to reduce preterm and prolonged gestation in pregnancy

Article Title: Genotype-informed docosahexaenoic acid dosing based on the FADS Indel to reduce preterm and prolonged gestation: A secondary analysis of the ADORE randomized trial

Article References: Li, Y. N., Kothapalli, K. S. D., Carlson, S. E., Gajewski, B. J., DeFranco, E. A., & Brenna, J. T. (2026). Genotype-informed docosahexaenoic acid dosing based on the FADS Indel to reduce preterm and prolonged gestation: A secondary analysis of the ADORE randomized trial. PLOS Medicine, 23(10), e1005274. https://doi.org/10.1371/journal.pmed.1005274

Image Credits: AI Generated

DOI: 10.1371/journal.pmed.1005274

Keywords: DHA, omega-3 fatty acids, FADS Indel, preterm birth, pregnancy, precision medicine, prostaglandins, ADORE trial, genotype, gestational length, arachidonic acid, Bayesian analysis