Fish consumption and marine omega-3 fatty acid supplementation in pregnancy

INTRODUCTION — Maternal consumption of fish and marine omega-3 fatty acid supplements, such as omega-3-acid ethyl esters (fish oil), is an active area of investigation because of potential favorable effects on pregnancy and offspring outcome. This topic will discuss these potential benefits as well as the risks of maternal fish and fish oil consumption during pregnancy.

Issues related to the health effects of fish and these supplements in the general population are reviewed separately (see "Fish oil: Physiologic effects and administration"). Omega-3 fatty acid supplementation for breast- and formula-fed infants is also reviewed separately. (See "Long-chain polyunsaturated fatty acids (LCPUFA) for preterm and term infants".)

BACKGROUND

●Terminology – The two major categories of polyunsaturated fatty acids (PUFAs) are the omega-3 (also called n-3) and omega-6 (n-6) fatty acids, based on the location of the first double bond in the fatty acid chain. The three major dietary omega-3s are eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA). EPA and DHA are long-chain omega-3 PUFAs present in fish, shellfish, and (in much lower amounts) some other animal foods. They are the major components of fish oil supplements. ALA is an intermediate-chain omega-3 PUFA present in certain plants and their oils, such as flaxseed and walnuts. When referring to EPA and DHA, common terms include "long-chain omega-3 fatty acids," "seafood-derived omega-3 fatty acids," and "marine omega-3 fatty acids." In this topic, all omega-3 fatty acids are assumed to be long-chain unless otherwise specified.

●Biology and biologic effects – Marine omega-3 fatty acids have a variety of biologic effects, including specific effects related to pregnancy. DHA and EPA are important because they are components of the phospholipids that form the structures of cell membranes (especially retina and brain). In addition, high concentrations of EPA and DHA tip the eicosanoid balance toward less inflammatory activity. Although the body can convert ALA to the more biologically active DHA and EPA, the conversion rate is very low (<1 percent for DHA, <10 percent for EPA). Therefore, consumption of marine omega-3 fatty acids is the most efficient means for individuals to increase their DHA and EPA levels.

The fetus depends on transplacental transfer of DHA for optimal visual and cognitive development [1-4]. EPA appears to facilitate transfer and uptake of DHA in fetal cells [5,6]. DHA is preferentially incorporated into the rapidly developing fetal brain during the last trimester of pregnancy, concentrating in the gray matter and retinal membranes [1,4]. Autopsy analysis estimates that the fetus accumulates 50 to 60 mg/day of DHA during the third trimester [7]. Rapid accumulation of DHA into the central nervous system continues during the first 24 months of life, with ongoing accrual throughout childhood.

Marine omega-3 fatty acids may have other maternal and fetal benefits. Because of the role DHA and EPA play in anti-inflammatory eicosanoid/docosanoid synthesis, signaling events, gene expression, and cytokine expression, it has been hypothesized that ensuring appropriate maternal marine omega-3 fatty acid intake during pregnancy might reduce inflammation-mediated disorders, such as preterm birth, preeclampsia, and allergic/atopic disease in offspring. (See 'Reduction in preterm birth' below and 'Possible reduction in allergy and atopic disease' below and 'Possible reduction in preeclampsia' below.)

●Fish as a source of DHA and EPA – Fish, including finfish and shellfish, is a healthful food that is low in saturated fat; high in protein and micronutrients, including vitamin D and iodine; and the primary dietary source of DHA and EPA. Early observational studies linked fish intake during pregnancy with gestational age at delivery and neurodevelopment in offspring. Based on these data (discussed below), expert groups consistently recommend that pregnant people consume two to three servings of fish weekly. Because fish consumption also exposes the fetus to methylmercury and other environmental contaminants in fish, guidelines for fish consumption in pregnancy emphasize choosing fish species high in DHA and low in mercury. (See 'Fish consumption' below.)

It is well-established that many pregnant individuals do not consume fish at the level required to achieve the DHA intake recommended by expert groups. For this reason, maternal consumption of marine omega-3 fatty acid supplements (eg, fish oil or derived from algae) or marine omega-3 fatty acid-fortified foods has been proposed. Although these products are alternative sources of DHA and EPA for individuals who cannot or choose not to consume fish, they may not have identical effects. This is an active area of investigation. (See 'Marine omega-3 fatty acid supplements and fortified foods' below.)

POTENTIAL BENEFITS — Conflicting evidence suggests that fish and marine omega-3 fatty acid intake during pregnancy has favorable effects on neurodevelopment and preterm birth rates and possibly on reduction of allergy/atopic disease in offspring.

Effects on offspring neurodevelopment — In most prospective cohort and retrospective studies, higher maternal fish consumption during pregnancy was associated with modest improvements in neurodevelopment of offspring [8-18]. However, a 2018 Cochrane meta-analysis of randomized trials comparing marine omega-3 fatty acid intervention (food, supplements) with placebo or no marine omega-3 fatty acid intervention during pregnancy found insignificant differences between groups for childhood development (cognition, attention, behavior, vision, language, hearing, motor) [19].

The findings from the observational studies are not necessarily discordant with those from the meta-analysis because only three trials in the meta-analysis involved fish intake rather than marine omega-3 fatty acid supplements and these trials did not evaluate neurodevelopmental outcomes. Furthermore, the supplement trials, which did evaluate this outcome, were of very low or low quality, so the possibility of a benefit cannot be confidently excluded. Additionally, fish consumption habits are likely to be consistent before and during pregnancy, whereas supplement trials have typically initiated treatment during the second or third trimester of pregnancy and thus cannot evaluate effects of preconceptional or first-trimester exposure.

However, observational studies reporting the benefits of fish consumption are limited by multiple factors. For example, prospective studies have relatively high rates of drop-out and loss to follow-up; retrospective studies have difficulties in accurately measuring the type and quantity of fish consumed. Confounding is a key issue as seafood intake may be a marker of a healthy lifestyle or socioeconomic resources. Fish consumption may replace consumption of foods that are harmful, or fish may have nutrients other than marine omega-3 fatty acids that account for the observed benefits. Thus, it is possible that high prenatal fish consumption is only an indirect marker of other factors associated with a good offspring neurodevelopmental outcome.

Reduction in preterm birth — Marine omega-3 fatty acids appear to reduce the risk for preterm birth and lengthen gestation. In the 2018 Cochrane meta-analysis of randomized trials discussed above, compared with placebo or no marine omega-3 fatty acid intervention, marine omega-3 fatty acid supplementation during pregnancy resulted in the following [19]:

●Reduction in preterm birth <37 weeks (11.9 versus 13.4 percent, risk ratio [RR] 0.89, 95% CI 0.81-0.97, 26 trials, n>10,300) and <34 weeks (2.7 versus 4.6 percent, RR 0.58, 95% CI 0.44-0.77, 9 trials, n>5200), with a corresponding trend in reduction in perinatal death (RR 0.75, 95% CI 0.54-1.03, 10 trials, n>7400).

Few trials evaluated major neonatal morbidities (eg, retinopathy of prematurity, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage); no clear difference between groups was found for these outcomes.

The analysis did not distinguish between spontaneous and medically/obstetrically indicated preterm birth.

●Reduction in low birth weight (14 versus 15.6 percent, RR 0.90, 95% CI 0.82-0.99, 15 trials, n>8400).

●Increase in mean gestational length by 1.67 days (95% CI 0.95-2.39, 41 trials, n>12,500).

●Increase in postterm gestation >42 weeks (2.6 versus 1.6 percent, RR 1.61, 95% CI 1.11-2.33, 6 trials, n>5100), which was not associated with a clear increase in postterm induction (RR 0.82, 95% CI 0.22-2.98, 2 trials, n>2800).

These findings were derived from trials of supplements containing docosahexaenoic acid (DHA)/largely DHA, mixed eicosapentaenoic acid (EPA)/DHA, or mixed EPA/DHA/other at various doses; the three trials in the analysis involving fish intake did not evaluate the outcome of preterm birth [20-22]. The dose subgroup analysis did not identify a clear difference in birth outcomes based on dose (low [<500 mg/day] versus mid [500 mg to 1 gram/day] versus high [>1 gram/day] dose) or type of supplement (DHA versus mixed DHA/EPA), suggesting a low level of intake is sufficient [19]. Most of the trials were conducted in upper middle or high income countries, and many included participants at increased risk for adverse pregnancy outcomes.

Design limitations included an unclear risk of selective reporting, unclear or high attrition bias, and baseline imbalances in some of the smaller trials despite randomization. The largest trial (n = 2400) in the meta-analysis observed a relatively small number of preterm births, and preterm birth was a post hoc endpoint [23]. The trial with the most preterm birth events was performed in high-risk individuals, and the upper limit of the confidence interval crossed 1.0 for both births <37 and <34 weeks [24]. The overall meta-analysis's finding of a large reduction in early preterm birth, which is the common endpoint of widely different etiologies, and with any dose/combination of DHA/EPA, may not be biologically plausible.

In 2019, a large multicenter randomized trial in Australia (5544 pregnancies) comparing daily supplementation with fish oil capsules (intervention) versus vegetable oil capsules (control) from 14 to 34 weeks of gestation found that the intervention did not reduce the primary endpoint preterm birth <34 weeks (2.2 versus 2.0 percent, RR 1.13, 95% CI 0.79-1.63) but showed a trend toward reduction of preterm birth <37 weeks (7.7 versus 8.9 percent, RR 0.86, 95% CI 0.72-1.03); maternal and neonatal outcomes were generally similar for both groups [25]. The analysis did not distinguish between spontaneous and medically/obstetrically indicated preterm birth, but there was no reduction in preterm spontaneous labor. In contrast to previous trials, participants represented the general obstetric population and were excluded only if taking daily supplements containing more than 150 mg of marine omega-3 fatty acids, they were unwilling to discontinue daily supplements containing ≤150 mg of marine omega-3 fatty acids, had a coagulopathy, were receiving anticoagulants, had a known history of substance abuse, or had a fetus with a known congenital abnormality. An updated meta-analysis including the results of this trial needs to be done. However, the population in this trial had higher baseline marine omega-3 fatty acid levels (approximately 30 percent higher) compared with participants in prior trials that showed a benefit, which may have contributed to the lack of benefit if the benefit mostly accrues to those who have poor baseline intake. If a meta-analysis including the new trial does not show a benefit, it could indicate that periconception and first-trimester intake is important for a beneficial effect and starting supplementation after the first trimester is not, or less, effective.

The effect of fish consumption on preterm birth has also been studied. In a meta-analysis of 21 observational studies with a total of nearly 600,000 participants, a 45 g/day increment in seafood consumption was associated with a reduced risk of low birth weight (OR 0.65, 95% CI 0.47-0.90) and small for gestational age newborns (OR 0.84, 95% CI 0.71-0.98), and a nonlinear dose-response relationship between maternal seafood consumption and the risk of preterm birth was observed, with no further benefit with intake above 45 g/day [26]. These data are subject to the usual limitations of observational studies, as discussed above. (See 'Effects on offspring neurodevelopment' above.)

Possible reduction in allergy and atopic disease — Supplementation with marine omega-3 fatty acids started during pregnancy has at most a weak association with reduction in allergic outcomes. In a 2019 meta-analysis of randomized trials (10 trials, over 3600 children), pooled estimates showed a reduction in childhood sensitization to egg (RR 0.54, 95% CI 0.32-0.90) and sensitization to peanut (RR 0.62, 95% CI 0.40-0.96), but no statistical differences for other allergic outcomes (eg, eczema, asthma/wheeze) [27]. The findings are inconclusive due to heterogeneity in individuals (eg, prenatal versus both prenatal and postnatal), duration and dose of supplementation, reported outcomes, and duration of follow-up (1 to 24 years); moderate to high risk of bias overall; and high loss to follow-up in half of the trials.

One of the larger trials included in the meta-analysis was a double-blind placebo-controlled randomized trial of third-trimester supplementation with high-dose (2.4 g/day) marine omega-3 fatty acids (fish oil) [28]. In this trial, the intervention resulted in a 7 percent absolute reduction in the risk of persistent wheeze or asthma in offspring followed to ages three to five years (16.9 versus 23.7 percent, hazard ratio [HR] 0.69, 95% CI 0.49-0.97), as well as a reduction in lower respiratory tract infections, but no difference in rates of asthma exacerbations, eczema, or allergic sensitization between groups. The reduction in wheeze/asthma was driven by the impact of treatment of individuals with EPA and DHA blood levels in the lowest third at baseline or with a FADS genotype associated with low EPA and DHA blood levels (low baseline EPA and DHA: persistent wheeze or asthma in offspring 17.5 versus 34.1 percent, HR 0.46, 95% CI 0.25-0.83). The estimated combined EPA and DHA intake of these individuals was below 321 mg/day before the intervention. Although including the specific subset of individuals with lower EPA/DHA levels in this study in the meta-analysis only modestly changed the overall estimate for asthma (from RR 0.87, 95% CI 0.70-1.07 to RR 0.83, 95% CI 0.64-1.08), other studies did not specifically stratify by low baseline fatty acid status.

Subsequent trials should address whether similar effects will be observed in other populations, whether the beneficial effects persist, and whether lower marine omega-3 fatty acid doses are effective. It would be essentially impossible to achieve a comparable marine omega-3 fatty acid dose from fish consumption since the dose was 20-fold higher than the average intake from fish consumption in the United States, and, as an example, 10 3.5 oz (100 gram) portions of Atlantic salmon would need to be consumed each day.

The effect of fish consumption on allergy outcomes has also been studied. In a meta-analysis of 31 observational studies, increased maternal fish intake was associated a lower risk of wheeze, eczema and food allergy in offspring, but no significant association with risk of asthma, allergic rhinitis, and inhalant allergy [29]. These data are subject to the usual limitations of observational studies.

Possible reduction in preeclampsia — In the 2018 Cochrane systematic review and meta-analysis of randomized trials discussed above, compared with placebo or no marine omega-3 fatty acid intervention, marine omega-3 fatty acid supplementation (food, supplements) during pregnancy showed a trend toward a reduction in preeclampsia (RR 0.84, 95% CI 0.69-1.01, 20 trials, n>8300 women), but the evidence was low quality [19]. When only trials at low risk of bias were analyzed, the trend disappeared (RR 1.00, 95% CI 0.81-1.25).

In another review [30], only three trials of marine omega-3 fatty acid supplementation in individuals with singleton gestations at high risk of preeclampsia or growth restriction were considered well-designed, and none reported a reduction in these outcomes [24,31,32].

POTENTIAL HARMS

Methylmercury in fish — Fish consumption is the primary source of nonoccupational maternal methylmercury exposure. Some mercury exposure is inevitable if fish are consumed since it is present in all fish tissues, cannot be cooked out of the fish, and over 95 percent is absorbed from the gastrointestinal tract. This risk has resulted in reluctance of many pregnant people to eat fish [33].

The fetal brain is considered the tissue most sensitive to the harms of mercury. Exposure to methylmercury in fetal life can cause diffuse and widespread neurologic damage [34], best illustrated by episodes of community-wide mercury poisoning in Japan (Minamata disease) and Iraq [35,36]. Pregnant people exposed to high levels of methylmercury in these communities did not necessarily develop symptoms themselves, but many of their children had delayed attainment of developmental milestones and, in some cases, devastating neurologic handicaps, including blindness, deafness, and cerebral palsy. (See "Mercury toxicity" and "Overview of occupational and environmental risks to reproduction in females".)

Chronic, low-level maternal mercury exposure from habitual fish consumption may also have toxic fetal effects, prompting recommendations to limit fish consumption in pregnancy. However, the relationship between maternal fish intake and toxic fetal effects from mercury is not well-established. Concerns are based, in part, on longitudinal prospective cohort studies in New Zealand and the Faroe Islands that reported that higher prenatal methylmercury exposure from high seafood consumption was associated with decrements in attention, language, verbal memory, motor speed, and visuospatial function in offspring [37-39]. However, a similar cohort study in the Seychelles Islands (Seychelles Child Development Study) found no harmful effect of prenatal methylmercury exposure through age 19 years [40-42]. Subsequent publications from cohorts with lower mercury exposures have not shown harmful associations of prenatal mercury exposure with infant development [43-45], cognition at 6 to 10 years [46], or behavior through 11 years [47].

Safe level of mercury intake — The United States Environmental Protection Agency's reference dose of methylmercury is 0.10 mcg/kg body weight/day [48]. The reference dose is an estimate (with uncertainty spanning approximately an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.

Other regulatory agencies have made different recommendations regarding intake limits for methylmercury, and these limits are two- to threefold higher than that of the Environmental Protection Agency. The United States Agency for Toxic Substances and Disease Registry derived a Minimal Risk Level of 0.30 mcg methylmercury/kg body weight/day [49], the World Health Organization's Joint Expert Committee on Food Additives and Contaminants derived a Provisional Tolerable Intake of 0.23 mcg/kg/day [50], and the Canadian Bureau of Chemical Safety recommended a Provisional Tolerable Intake of 0.20 mcg/kg/day [51].

Mercury content by type of fish — Reference levels for mercury in commercial fish and shellfish are available online from data collected 1990 to 2012 by the US Food and Drug Administration, although estimates may be based on as few as three fish samples. More comprehensive information on mercury levels in commercial fish in the United States is available in a database generated in 2012 by Stony Brook University, based on a much larger foundation of data aggregated from government monitoring programs and the scientific literature [52].

A limitation of all of these estimates is the variability in the mercury content of fish of the same species. For example, the mean concentration of mercury in canned light tuna is 0.128 ppm (mcg/g), with a range from 0 to 0.889 ppm. Thus, a 60 kg individual consuming 4 oz of canned light tuna per week would on average get 0.03 mcg mercury/kg body weight/week (30 percent of the reference dose) but could get none (0 percent of the reference dose) or could get as much as 0.25 mcg/kg/week (250 percent of the reference dose).

Screening for mercury toxicity — Routine screening for mercury toxicity in the general population, including people planning pregnancy or currently pregnant, is not recommended.

Testing is reasonable if the individual is at risk because of suggestive neurologic symptoms and frequent consumption of fish likely to have higher mercury contamination. The most useful biomarker of methylmercury exposure in clinical practice is the level in whole blood, measured in a reliable laboratory [53]. Individuals who are found to have elevated mercury levels should be advised to avoid intake of mercury-containing fish. In a case series of high consumers of fish, mercury levels declined rapidly in the first three weeks after advice to reduce fish intake [54]. (See "Mercury toxicity".)

The reference level of methylmercury in blood, set by the United States Environmental Protection Agency, is 5.8 mcg/L, which is thought to define the average long-term level of mercury in blood that is without appreciable risk. However, some research suggests a level of 3.5 mcg/L would be a better threshold. In the United States National Health and Nutrition Examination Survey (NHANES) 1999 to 2010, 10.8 percent of females of childbearing age in the Northeast had mercury concentrations ≥3.5 mcg/L, and 3.3 percent had concentrations ≥5.8 mcg/L [55]. Southern females were much less likely to have elevated mercury levels, and elevated levels were rare among females living in the West. High blood mercury levels were associated with greater frequency of seafood consumption and living in coastal regions.

Fish oil supplements — Harmful effects have not been reported from omega-3-acid ethyl esters (fish oil) supplementation during pregnancy. Bleeding diathesis is the most serious potential complication from high doses, but excessive bleeding after delivery has not been observed [19]. General safety issues (eg, bleeding, contaminants, cancer) are discussed in more detail separately. (See "Fish oil: Physiologic effects and administration", section on 'Safety'.)

Fish oil supplements contain no or minimal mercury because fish oil is generally derived from small pelagic fish used for fish feed or from formulations produced by algae [56,57]. Furthermore, most fish oil supplements have been purified to reduce environmental toxins to negligible amounts [56].

However, supplements can cause bothersome side effects. The most common are gastrointestinal disturbances such as nausea, which occurred in approximately 4 percent of individuals at doses below 3 grams/day and in approximately 20 percent of individuals at doses of ≥4 grams/day in a pooled analysis [58]. Fish oil supplements may also cause a "fishy taste" following eructation (burping), bad breath, heartburn, and odoriferous sweat [59].

In addition, the quality of fish oil supplements varies, and they are not well-monitored by regulatory agencies to ensure the product contains the amounts of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) stated on the label [60,61].

RECOMMENDATIONS FOR PEOPLE WHO ARE PREGNANT, PLANNING PREGNANCY, AND BREASTFEEDING — The benefits of consumption of fish, fish oil, and marine omega-3 fatty acid-fortified foods during pregnancy remain controversial. However, randomized trials have established that encouraging pregnant people to increase fish consumption or consume marine omega-3 fatty acid supplements or fortified foods increases both maternal and fetal docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) levels [62-64].

Fish consumption — For people who may become pregnant, are currently pregnant, or are breastfeeding, expert panels worldwide suggest a minimum DHA intake of 200 to 300 mg/day [65-69]. The Food and Nutrition Board of the Institute of Medicine (IOM; now called the National Academy of Medicine) considers 1.4 grams the adequate intake for alpha-linolenic acid (ALA) in pregnancy and 1.1 grams the adequate intake for females of reproductive age; they did not establish specific intake recommendations for EPA or DHA [70].

Two to three weekly servings of fish high in DHA and low in mercury is the optimal method for obtaining DHA because no other food contains naturally occurring marine omega-3 fatty acids in abundance and fish and other seafood also provide potentially beneficial protein, vitamins, and selenium [71]. The DHA and mercury content of fish vary independently, and several options are available that are both high in DHA and low in mercury. These include anchovies, Atlantic herring, Atlantic mackerel, mussels, oysters, farmed and wild salmon, sardines, snapper, and trout [72,73]. Of note, the most commonly consumed fish in the United States that are low in mercury (shrimp, farmed salmon, pollock, tilapia, cod, and catfish) vary considerably in their DHA content (table 1), and weekly consumption of 12 oz of some of these fish may not provide adequate amounts of DHA [74].

In the United States, a US Food and Drug Administration and Environmental Protection Agency advisory recommends consumption of two to three weekly servings of a variety of types of seafood high in marine omega-3 fatty acids and low in mercury and other contaminants and completely avoiding consumption of fish high in mercury; an online table to help consumers is available. The 2020-2025 Dietary Guidelines for Americans also include the same advice [75]. The Environmental Protection Agency further recommends consulting local advisories about the safety of consuming fish caught in local lakes, rivers, and coastal areas. If no advisory is available, they suggest restricting intake of these fish to up to 6 oz (one average meal) per week and not consuming any other fish during that week.

Marine omega-3 fatty acid supplements and fortified foods — Most pregnant people do not consume fish several times per week, or they consume fish that will not achieve the recommended level of DHA intake [65,76-79]. For those who are not able or willing to consume fish of adequate DHA content, we suggest consumption of supplements or fortified foods to achieve DHA intake of at least 200 to 300 mg/day [65-69]. In an analysis of data from women of childbearing age in the United States National Health and Nutrition Examination Survey (NHANES) cycles 2001 to 2002 through 2013 to 2014, the mean usual intake of seafood was 0.44±0.02 oz equivalent per day, and 100 percent of the population was below the current Dietary Guidelines for Americans (DGA) recommendation [79]. Mean usual intakes of EPA, DHA, and combined EPA and DHA from foods and dietary supplements combined were 26.8±1.4, 62.2±1.9, and 88.1±3.0 mg per day, respectively. Over 95 percent of the sample did not meet the daily intakes of 250 mg EPA and DHA. Similar results were observed for pregnant people.

Supplements containing either omega-3-acid ethyl esters (fish oil) or DHA synthesized by algae are available in a variety of doses and include formulations marketed for pregnant people. Some prenatal vitamins and nonprescription marine omega-3 fatty acid supplements commonly available at major drug or health food stores contain DHA and EPA: the amount is on the label and varies among products [80]. These products also contain other marine omega-3 fatty acids, monounsaturated fats, saturated fats, and gelatin or glycerin; DHA and EPA typically account for ≤500 mg of a 1000 mg fish oil capsule [81,82]. Cod liver oil contains high concentrations of EPA and DHA but is less desirable than other fish oils because it also contains vitamin A, which is teratogenic at high doses. If a fish oil supplement causes a fishy taste, freezing it, switching to a different formulation, consumption with meals, or intake at a different time of day may minimize this symptom in some people.

A number of foods fortified with DHA are also available, including yogurt, milk, eggs, and cereals. However, many fortified foods contain the plant-based omega-3 fatty acids (ALA), rather than marine omega-3 fatty acids, and these cannot be considered a replacement for DHA and EPA because of low rates of conversion [83].

Very few trials have directly compared the effects of various doses or types of marine omega-3 fatty acid supplements, timing of initiation, or duration of use, or compared outcomes based on baseline characteristics of the study participants. As discussed above, a dose subgroup analysis in a Cochrane meta-analysis of marine omega-3 fatty acid supplements during pregnancy did not identify a clear difference in birth outcomes based on dose (low [<500 mg/day] versus mid [500 mg to 1 gram/day] versus high [>1 gram/day] dose) or type of supplement (DHA versus mixed DHA/EPA) [19]. (See 'Reduction in preterm birth' above.)

The US Food and Drug Administration recommends that marine omega-3 fatty acid supplement labeling not recommend or suggest daily intake of more than 2 grams EPA and DHA [84], which is well above the amount recommended for pregnant people, females planning pregnancy, and breastfeeding people. Fish oil doses of 2.4 and 3.7 grams/day have been consumed in pregnancy without evidence of adverse effects [28,85]. In the general population, a total intake up to 3 grams/day of EPA and DHA is Generally Recognized As Safe (GRAS) [86] to "safeguard against the possible adverse effects of fatty acids on increased bleeding time."

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nutrition and supplements in pregnancy".)

SUMMARY AND RECOMMENDATIONS

●EPA and DHA – The two major categories of polyunsaturated fatty acids (PUFAs) are the omega-3 (also called n-3) and omega-6 (n-6) fatty acids. The three major dietary omega-3s are eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA). EPA and DHA are long-chain omega-3 PUFAs present in fish, shellfish, and (in much lower amounts) some other animal foods. They are the major components of omega-3-acid ethyl esters (fish oil) supplements. Marine omega-3 fatty acids have a variety of biologic effects, including specific effects related to pregnancy. (See 'Introduction' above and 'Background' above.)

●Fish intake – Fish, including finfish and shellfish, is a healthful food that is low in saturated fat, high in protein and many vitamins, and is the primary dietary source of DHA and EPA. Individuals who may become pregnant, are currently pregnant, or are breastfeeding are generally advised to consume two or three weekly servings of a variety of the types of fish high in marine omega-3 fatty acids and low in mercury. This means not eating shark, swordfish, king mackerel, marlin, orange roughy, bigeye tuna, or tilefish because they can contain relatively high levels of mercury, which can cause neurotoxicity. Online tables are available for mercury levels in fish and to help consumers make good choices. (See 'Fish consumption' above and 'Methylmercury in fish' above.)

●DHA fortified foods – A number of foods fortified with DHA are available, including yogurt, milk, and eggs. Supplements containing either fish oil or DHA synthesized by algae are also available. Prenatal vitamins may also contain DHA. (See 'Marine omega-3 fatty acid supplements and fortified foods' above.)

●Recommendations for DHA intake during pregnancy – We suggest that pregnant people consume fish or, if this is not possible, consume a supplement or fortified food source of marine omega-3 fatty acids to achieve an intake of at least 200 to 300 mg/day DHA (Grade 2B). This level of fish intake/supplementation should ideally be started preconception or as early as possible in pregnancy. Oily fish contain more DHA than non-oily fish (table 1). (See 'Recommendations for people who are pregnant, planning pregnancy, and breastfeeding' above.)

This recommendation is based on evidence from some randomized trials showing a lower risk for preterm birth, a lower risk of persistent wheeze or asthma in offspring, and no evidence of harm associated with marine omega-3 fatty acids as supplements or as dietary additions. It also acknowledges the observation that DHA is preferentially incorporated into the rapidly developing brain and retina during the last trimester and plays a role in various physiologic processes, although there is no clear evidence that marine omega-3 fatty acid supplements during pregnancy improve offspring neurodevelopment. (See 'Effects on offspring neurodevelopment' above and 'Reduction in preterm birth' above and 'Possible reduction in allergy and atopic disease' above.)