A Gene Variant That May Explain Who Benefits From Extra Omega-3 in Pregnancy

A fresh look at the ADORE trial asks whether a simple genetic test could one day guide the DHA dose offered in pregnancy

Omega-3 supplements taken in pregnancy modestly lower the chance of a baby arriving too early, but the effect has been inconsistent: some studies found a clear benefit and others none. Researchers have now re-examined a completed American trial of two DHA doses and found that a common variation in a single gene seemed to predict how the higher dose affected the very earliest births and the length of pregnancy. Among women carrying this gene variant, the higher dose was linked to fewer early births; among women without it, the higher dose was instead linked to more pregnancies lasting to 40 weeks or beyond.

This is an early, exploratory finding resting on small numbers, not a new rule for care, but it points to a simple idea: the right dose may not be the same for everybody.

Why preventing early birth is so hard

Complications of being born too soon are the biggest cause of death in children under five worldwide, accounting for 17.7% of the 5.30 million such deaths estimated for 2019 [1]. "Preterm" means birth before 37 completed weeks of pregnancy; "early preterm" means before 34 weeks, and those earliest births carry the highest risk of problems for the baby [2]. Doctors have few tools to prevent it, and those they have help only particular groups. A hormone treatment called vaginal progesterone helps women whose cervix — the neck of the womb — is unusually short on a mid-pregnancy scan, and is recommended when it measures 20 mm or less [3]. But when tested more broadly it did not help: in a trial of 1,228 women considered at risk it made no significant difference to loss of the baby or birth before 34 weeks [4], and across 39 maternity hospitals in Australia, New Zealand and Canada, among 787 women who had already had an early birth, the rates were almost identical with and without treatment [5].

Omega-3 fats offered a different route. These are the fats found in oily fish; the one that matters most here is docosahexaenoic acid, or DHA, which many prenatal vitamins already contain in small amounts. The idea had a basis in biology — in sheep, omega-3 fats delayed artificially triggered early labour [6] — and an early trial in Kansas City, in which 350 women took either 600 mg of DHA a day or a dummy capsule, found pregnancies lasting almost three days longer and fewer births before 34 weeks [7]. When researchers pooled 70 trials involving 19,927 women in 2018, the picture was positive: birth before 37 weeks fell from 13.4% to 11.9%, and birth before 34 weeks from 4.6% to 2.7%. The review also noted a trade-off — pregnancies past 42 weeks became slightly more common — and called for studies of the best dose and of which women respond [8].

A large Australian trial known as ORIP, which tested fish-oil omega-3 supplements in 5,544 pregnancies across six centres, found no reduction in early birth [9]. Yet a closer look found benefit in women who began pregnancy with low blood omega-3 levels, while those who already had high levels had more early births when given supplements [10]. In other words, the same supplement may help one woman and do nothing — or possibly the opposite — for another. But blood omega-3 tests still lack standard methods and cut-offs [11]; a one-off test of something that never changes would be more practical. That is where genes come in.

The trial, and the gene variant at the centre of it

The trial is called ADORE, short for Assessment of DHA on Reducing Early Preterm Birth. It was run at three university hospitals in Ohio and Kansas, USA: The University of Kansas Medical Center in Kansas City, the University of Cincinnati Medical Center, and Ohio State University in Columbus. Women aged 18 or over, expecting one baby, joined between 12 and 20 weeks of pregnancy and were randomly assigned capsules containing extra DHA or identical-looking capsules containing none, on top of an ordinary prenatal supplement with 200 mg of DHA — 1,000 mg a day against 200 mg a day until birth, with neither the women nor their care team knowing which was which [2]. Recruitment ran from June 2016 to March 2020, and 1,032 of the 1,100 women enrolled had birth information for the main result, which was modest: early birth before 34 weeks occurred in 1.7% of those on the higher dose against 2.4% on the standard dose, with a clearer benefit among women whose DHA levels started low, and no extra safety problems [12].

The gene variant is a small piece of DNA — 22 letters long — either present or absent in a region controlling how efficiently the body builds a fat called arachidonic acid, or ARA, from simpler building blocks. Scientists call the two versions I (insertion) and D (deletion); everyone has two copies, so a person can be D/D, I/D or I/I, and the more I copies someone carries, the more ARA their body makes [13][14]. This matters because ARA is the raw material for prostaglandins — hormone-like signals that help start labour and soften the cervix. One of the two most important in human labour, and probably the main one for getting labour started, is prostaglandin E2 [15]; a manufactured version is used in hospitals to induce labour [16]. The theory is straightforward: women who naturally make more ARA may be primed towards earlier labour, and extra DHA may counterbalance that. There was already a hint: in a bowel-polyp prevention trial analysed by a team in Leeds, United Kingdom, an omega-3 supplement was linked to fewer polyps in people carrying at least one I copy, though not across everyone in the trial [17].

The researchers tested stored blood samples from 761 ADORE participants who had agreed to optional genetic research, with the laboratory unaware of how each pregnancy had ended until testing was finished [18]. Of these women, 342 were D/D, 313 were I/D and 106 were I/I, and age, previous early births and starting DHA levels were similar across the genotype groups.

What the results showed

Across all 761 pregnancies, 74 babies (9.7%) were born before 37 weeks and 17 (2.2%) before 34 weeks [18]. The key comparison, which keeps the strength of the original random assignment, is the higher dose against the standard dose within each genetic group. Among women carrying at least one I copy, 19 of 205 babies on the higher dose were born preterm (9.3%) against 31 of 214 on the standard dose (14.5%); for the earliest births, before 34 weeks, the difference looked larger, 2 of 205 versus 9 of 214. Most of this came from women with one I copy and one D copy; the 106 women with two I copies showed no real difference between doses in births before 37 weeks.

D/D women, whose bodies make the least ARA, showed a different picture. Their preterm-birth rates were already low (11 of 191 on the higher dose, 13 of 151 on the standard dose), and the higher dose was instead linked to more pregnancies reaching 40 weeks or later: 49 of 191 women, or 25.7%, compared with 23 of 151, or 15.3% [18]. Note that 40 weeks is full term, not overdue — "post-term" usually means 42 weeks or more, which this study did not report separately. A possible rise in very early births among D/D women on the higher dose rested on five cases against one, far too few to conclude from.

Among the 156 Black participants, 133 — about 85% — carried at least one I copy, compared with roughly 47% of the 605 others, and their preterm-birth rate was about twice as high (16.1% versus 8.1%). This needs careful reading. Race is a social category, not a biological one, and researchers have proposed that where people are able to live, the schools and jobs available to them, and discrimination may be large contributors to differences in early birth rates in the United States [19]. A gene variant more common in one group cannot explain away those realities, and the researchers stress that their genetic comparisons were not randomly assigned.

How much confidence to place in this

ADORE was not designed to answer this question, as the authors acknowledge. Only 17 babies in the study were born before 34 weeks, and in some gene-and-dose combinations the findings depend on one to three births. The researchers tested how easily their conclusions could be upset, and found the result for birth before 37 weeks fragile — shifting three or four cases would have weakened it — while the finding for the earliest births stood up better. Cervical length in mid-pregnancy was similar in the two dose groups, and very few women had a short cervix [18].

There is a precedent. In bowel cancer, two drugs turned out to work only in patients whose tumours lacked a particular gene change, a discovery made by looking back at finished trials that went on to shape how the drugs are used [20][21][18]. Still, the authors say a single-trial finding like theirs needs repeating in other omega-3 trials; that is the stage it is at.

What this means for families now, and what comes next

If you are pregnant or planning a pregnancy, nothing here changes what to do, and there is no routine clinical test for this variant. Current international guidance recommends that women get at least 250 mg a day of omega-3 (DHA and a related omega-3 fat, EPA) and, in pregnancy, at least 100–200 mg of DHA a day on top of that, and roughly 600–1,000 mg a day for women whose intake or blood levels are low, from the second trimester to around 37 weeks or until birth if earlier [11]. The practical point this analysis reinforces is that stopping rule: because higher-dose DHA was linked to longer pregnancies in some women, and because nobody's genotype is known in ordinary care, the researchers suggest stopping DHA supplements at 37 weeks [18]. If you take a high-dose supplement, that is worth raising with your midwife or obstetrician.

The next step is the trial this study calls for: one that measures the gene variant first, then randomly assigns women within each genetic group to a higher or standard DHA dose, following enough pregnancies to settle both the benefit and the possible downside. It would also compare the gene test against the blood measurement. In[Neo]Sight has covered related questions, including DHA and arachidonic acid given to extremely preterm babies after birth and cervical length screening with progesterone. For now, the value of this work is a shift in the question — from whether omega-3 prevents early birth to for whom, and at what dose — precisely what the authors of that review of 70 trials asked the field to find out [8].

References

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