Birth Outcomes

Several studies showed that the maternal intake of n-3 LCPUFA during pregnancy resulted in a slightly longer gestation period and somewhat higher birth weight (Table 1). The sample size is critical for identifying differences in these variables, and large studies such as DOMINO⁽Reference Makrides, Gibson, McPhee, Yelland, Quinlivan and Ryan³⁴⁾, POSGRAD⁽Reference Ramakrishnan, Stein, Parra-Cabrera, Wang, Imhoff-Kunsch, Juarez-Marquez, Rivera and Martorell³⁵⁾, or the Danish Cohort⁽Reference Olsen, Sorensen, Secher, Hedegaard, Henriksen, Hansen and Grant³⁶⁾ found differences in birth outcomes as a result of n-3 supplementation during pregnancy (Table 1). It is important to consider that the higher birth weight reported for n-3 LCPUFA supplementation during pregnancy was probably due to the greater length of these pregnancies, since the differences in birth weight disappeared when using the gestational age as covariable⁽Reference Makrides, Gibson, McPhee, Yelland, Quinlivan and Ryan³⁴⁾. Helland et al ⁽Reference Helland, Saugstad, Smith, Saarem, Solvoll, Ganes and Drevon³⁷⁾ did not find differences in the duration of gestation or birth weight in 341 subjects (148 subjects receiving cod liver with 1·18 g DHA+0·8 g EPA vs. 137 subjects receiving corn oil); nevertheless, when they compared the quartile with the highest concentration of DHA in umbilical plasma phospholipids with the quartile with the lowest concentration of DHA, they found a longer gestational period in the group of babies with higher DHA cord concentration. In addition, Knudsen et al.⁽Reference Knudsen, Hansen, Osterdal, Mikkelsen, Mu and Olsen³⁸⁾ suggested that the effect of n-3 LCPUFA on the length of gestation could be a “quick-acting” effect, since they did not find any association between the intake of n-3 LCPUFA or α-linolenic acid and the timing of spontaneous delivery in their study in which a large proportion of the women stopped taking the capsules before they delivered. For smaller studies, limitations in their statistical power for such variables could explain the lack of differences for these parameters⁽Reference Innis and Friesen^21, Reference Bergmann, Haschke-Becher, Klassen-Wigger, Bergmann, Richter, Dudenhausen, Grathwohl and Haschke^22, Reference Krauss-Etschmann, Shadid and Campoy^27, Reference Smuts, Huang, Mundy, Plasse, Major and Carlson³⁹⁾.

The results on higher birth weight and length of gestation were also confirmed in different meta-analyses about the effects of n-3 LCPUFA supplementation during pregnancy⁽Reference Makrides, Duley and Olsen^40–Reference Salvig and Lamont⁴²⁾. Szajewska et al ⁽Reference Szajewska, Horvath and Koletzko⁴¹⁾ reported that n-3 LCPUFA supplementation during pregnancy (1278 infants from 6 randomized controlled trials) enhanced the duration of the pregnancy by an average of 1·6 days, and head circumference was also 0·26 cm greater in the supplemented group. In the Cochrane review⁽Reference Makrides, Duley and Olsen⁴⁰⁾, covering 6 trials involving 2783 women, marine oil supplementation during pregnancy resulted in a mean gestation that was 2·6 days longer for these subjects than for women allocated to placebo or no treatment, and the birth weight was slightly higher (weight mean difference 47 g, 95 % CI 1-93 g; 3 trials, 2440 women). Recently, Salvig & Lamont⁽Reference Salvig and Lamont⁴²⁾ also reported higher birth weight (71 g) in women who received n-3 fatty acids during pregnancy compared with a placebo (3 RCT involving 1187 women), and a longer gestational period (4·5 days). However, its effect on the rate of preterm birth is controversial; only Salvig et al.⁽Reference Salvig and Lamont⁴²⁾ reported a significant reduction of preterm births ( < 37 weeks) while the reduction of early preterm birth ( < 34 weeks) was found to be significant in two of these meta-analyses⁽Reference Makrides, Duley and Olsen^40, Reference Salvig and Lamont⁴²⁾. However, the rate of low birth weight ( < 2500 g) was not statistically different in any of the 3 meta-analyses⁽Reference Makrides, Duley and Olsen^40–Reference Salvig and Lamont⁴²⁾.

Although the effect of n-3 LCPUFA supplementation in high risk pregnancies is not mainly addressed in this systematic review, the results in this respect are controversial. In a European Multicenter Trial⁽Reference Olsen, Secher, Tabor, Weber, Walker and Gluud⁴³⁾ involving women with a preterm delivery history, those randomly assigned to receive an n-3 LCPUFA supplement (0·9 g DHA+1·3 g EPA) had significantly lower rate of recurrent preterm delivery before 37 weeks (mean difference 0·54 %, 95 % CI 0·30-0·98) and before 34 weeks. Moreover, in a prospective cohort study in Denmark with 8729 pregnant women, the low consumption of fish was a strong risk factor for preterm delivery and low birth weight⁽Reference Olsen and Secher⁴⁴⁾. However, recently, Harper et al ⁽Reference Harper, Thom and Klebanoff⁴⁵⁾ did not report changes in gestational length, birth weight or length in pregnant women receiving 17-α-hydroxyprogesterone caproate plus 800 mg/d DHA+1·2 g EPA to prevent recurrent preterm birth. In addition, the daily intake of either 3 g EPA or placebo did not prevent the recurrence of intrauterine growth retardation or pregnancy induced hypertension in 63 subjects with high risk pregnancies. The results of the meta-analyses showed no clear difference in the relative risk of birth before 37 completed weeks in high risk pregnancies⁽Reference Makrides, Duley and Olsen^40, Reference Horvath, Koletzko and Szajewska⁴⁶⁾. Thus, using n-3 LCPUFA supplements to reduce the risk of preterm birth, low birth weight or small-for-gestational age is still controversial, although a slight effect remains a possibility.

Effects on visual and cognitive functions

To date, no meta-analyses on the effect of the maternal intake of n-3 fatty acids during pregnancy on the visual or cognitive functions of the offspring have been published. Two Cochrane reviews are available on the effects of infant formulas supplemented with n-3 LCPUFA after birth in term and preterm babies but this is beyond our scope⁽Reference Simmer, Patole and Rao^47, Reference Schulzke, Patole and Simmer⁴⁸⁾.

The available results of the present systematic review suggest some association between early DHA status and cognitive function in infancy and early childhood (Table 2). Helland et al.⁽Reference Helland, Saugstad, Smith, Saarem, Solvoll, Ganes and Drevon³⁷⁾ reported that 1·18 g of DHA supplementation during pregnancy did not change electroencephalogram tests on the second day of life or the results of the Fagan test of intelligence at 27 and 39 weeks of age; however, neonates with mature electroencephalography scores had a higher concentration of DHA in umbilical plasma phospholipids. The Fagan test of infant cognitive function is predictive for IQ at an older age, and is comparable to the Bayley test⁽Reference Fagan and Shephard⁴⁹⁾. Since it is more difficult to detect small differences in neurodevelopment early in life with these tests than later on when children are older, these authors are engaged in following up this cohort of children. In fact, at 4 years of age, these authors reported improved results in the Kaufmann ABC test of cognitive development in children from mothers receiving DHA supplements⁽Reference Helland, Smith, Saarem, Saugstad and Drevon⁵⁰⁾, and significant correlations for IQ in the sequential processing at 7 years of age with maternal DHA proportions⁽Reference Helland, Smith, Blomen, Saarem, Saugstad and Drevon⁵¹⁾.

Rudimentary forms of various attentional functions are present at birth, but each of the functions exhibits different and apparently dissociable periods of postnatal change during the first years of life.⁽Reference Colombo⁵²⁾. Malcolm et al. demonstrated an association between DHA status of term infants and retinal sensitivity within the first week of life⁽Reference Malcolm, Hamilton, McCulloch, Montgomery and Weaver⁵³⁾, as well as visual evoked potential (VEPs) at 1 year old (50 weeks), and 66 weeks post-conceptional age⁽Reference Malcolm, McCulloch, Montgomery, Shepherd and Weaver³⁰⁾, although no differences between supplemented and placebo groups were reported. Other studies also reported improved visual acuity (Teller cards) at 4 months but not at 6 months⁽Reference Judge, Harel and Lammi-Keefe⁵⁴⁾, and even improved eye-hand co-ordination at the age of 2·5 years⁽Reference Dunstan, Simmer, Dixon and Prescott⁵⁵⁾. In this line, Judge et al. pointed to a benefit for problem-solving skills but not for recognition memory at 9 months of age⁽Reference Judge, Harel and Lammi-Keefe⁵⁶⁾. Problem solving requires that an infant both remember that a toy is hidden and be able to pay sufficient attention to execute a series of steps to achieve a goal. This result complemented the report of improved mental processing at 4 years⁽Reference Helland, Smith, Saarem, Saugstad and Drevon⁵⁰⁾. Some authors did not find improvements of neurodevelopmental tests as a result of HA supplementation versus placebo during gestation⁽Reference Colombo, Kannass, Shaddy, Kundurthi, Maikranz, Anderson, Blaga and Carlson^57, Reference Tofail, Kabir, Hamadani, Chowdhury, Yesmin, Mehreen and Huda⁵⁸⁾, but regression analyses showed maternal DHA percentages positively related to measurements of central nervous system development in these studies. In the DOMINO study, no effect of DHA treatment during pregnancy on early childhood cognitive or language scores was reported; fewer children in the DHA treated group had delayed cognitive development compared with the control group, and girls exposed to higher-dose DHA in utero had lower language scores than girls from the control group⁽Reference Makrides, Gibson, McPhee, Yelland, Quinlivan and Ryan³⁴⁾, pointing to an interaction with the sex of the children. It has been suggested that the effects of n-3 fatty acids on neurodevelopment might meet a saturation point, above which no further effect of LCPUFA n-3 could be detected⁽Reference Innis and Friesen²¹⁾.

Observational longitudinal studies have also supported a relationship between DHA status and infant development; in Inuits from Arctic Quebec, cord DHA levels were associated with greater visual, cognitive and motor development during the first year of life⁽Reference Jacobson, Jacobson, Muckle, Kaplan-Estrin, Ayotte and Dewailly⁵⁹⁾, as well as shorter latencies of VEP in school-age children⁽Reference Jacques, Levy, Muckle, Jacobson, Bastien, Dewailly, Ayotte, Jacobson and Saint-Amour⁶⁰⁾. Further support for the importance of DHA availability in early life comes from the positive associations between maternal fish consumption during pregnancy and cognitive performance of the offspring, observed in large birth cohorts such as ALSPAC⁽Reference Hibbeln, Davis, Steer, Emmett, Rogers, Williams and Golding⁶¹⁾, VIVA⁽Reference Oken, Wright, Kleinman, Bellinger, Amarasiriwardena, Hu, Rich-Edwards and Gillman⁶²⁾ and the Danish National Birth Cohort⁽Reference Oken, Osterdal, Gillman, Knudsen, Halldorsson, Strom, Bellinger, Hadders-Algra, Michaelsen and Olsen⁶³⁾. However, these results should be interpreted with caution, considering the limitations of observational studies which often cannot fully adjust for all confounding variables.

A novel approach has been proposed to check whether a poor DHA status sufficient to delay infant development occurs among pregnant women. In this sense, an increased risk of low visual acuity scores among infants at 2 months of age born to mothers following their usual diet was reported compared with infants of women considered at low risk of inadequate DHA due to DHA supplementation⁽Reference Innis and Friesen²¹⁾. Some pregnant women seem to be DHA-deficient and further studies should addressed to ascertain the dietary n-3 LCPUFA requirements during pregnancy, identificatying the asymptote in functions above which no further benefits occurs.

Effects on maternal depression and infant immunity

The effect of DHA supplementation during pregnancy on maternal depression has been addressed in very few studies, most of them with a small sample size, possibly non-specific and without placebo comparison. No clear benefit was observed in these studies. Four of these studies did not find significant effect of DHA supplementation taken for 6 or 8 weeks during pregnancy in subjects with diagnosed major depression in studies involving a small number of participants⁽Reference Freeman, Hibbeln, Wisner, Brumbach, Watchman and Gelenberg^64–Reference Rees, Austin and Parker⁶⁷⁾. Only Su et al.⁽Reference Su, Huang, Chiu, Huang, Huang, Chang and Pariante⁶⁸⁾ with 36 depressed subjects receiving 1·2 g DHA+2·2 g EPA found reduced depression scores, although no placebo group was included in this study.

In healthy pregnant women, no effect on postpartum maternal depression was found in a study with a small number of subjects⁽Reference Doornbos, van Goor, jck-Brouwer, Schaafsma, Korf and Muskiet⁶⁹⁾, or in a large study (DOMINO study) involving more than 2000 participants⁽Reference Makrides, Gibson, McPhee, Yelland, Quinlivan and Ryan³⁴⁾. Recently, Jans et al.⁽Reference Jans, Giltay and Van der Does⁷⁰⁾ performed a meta-analysis including 7 randomized controlled trials, in which a total of 309 women taken n-3 fatty acid supplementation were compared with 303 women following a placebo treatment, and no significant effect was found on post-treatment maternal depression (95 % CI - 0·18, 0·13; P = 0·76). The quality of research in this area needs to be improved.

Concerning the effect of n-3 LCPUFA supplementation in healthy pregnancies and on the immunological function, positive effects were reported concerning a reduction in food allergy risk and Ig E associated eczema in infants during the first year of life⁽Reference Furuhjelm, Warstedt, Larsson, Fredriksson, Bottcher, Falth-Magnusson and Duchen⁷¹⁾, and reduced proinflammatory cytokines and Th2 promoting prostaglandin E2 in the mother⁽Reference Warstedt, Furuhjelm, Duchen, Falth-Magnusson and Fageras⁷²⁾. These results were also supported by Krauss-Etschmann et al.⁽Reference Krauss-Etschmann, Hartl and Rzehak⁷³⁾, who observed reduced Th2 inflammatory cytokines in cord blood during the NUHEAL study. From the Danish cohort, a lower rate of allergic asthma was observed in 16 year old children born to mothers receiving supplementation with fish oil compared with olive oil⁽Reference Olsen, Osterdal, Salvig, Mortensen, Rytter, Secher and Henriksen⁷⁴⁾. For infants with a family history of allergic disease, maternal n-3 LCPUFA supplementation during pregnancy also decreased the risk of food allergy and Ig E eczema during the first year of life⁽Reference Furuhjelm, Warstedt, Larsson, Fredriksson, Bottcher, Falth-Magnusson and Duchen^71, Reference Furuhjelm, Warstedt, Fageras, Falth-Magnusson, Larsson, Fredriksson and Duchen⁷⁵⁾ and improved the cord blood cytokine pattern⁽Reference Dunstan, Mori, Barden, Beilin, Taylor, Holt and Prescott^76, Reference Dunstan, Mori, Barden, Beilin, Taylor, Holt and Prescott⁷⁷⁾.

In conclusion, n-3 LCPUFA supplementation during pregnancy has a moderate effect on higher length of gestation and birth weight, but not enough for general recommendation in order to avoid preterm deliveries. Most of the papers found significant differences in some visual or cognitive tests in the offspring or, at least, positive associations between DHA status in the neonate and pregnant mother and neurodevelopmental outcomes. LCPUFA supplementation, in addition to an already adequate omnivorous diet, may not yield any measurable benefit, but very low LC-PUFA intakes could result in loss of function that could even be of major importance in prematurely born babies. The effect of n-3 LCPUFA supplementation during pregnancy on depressive symptoms has been evaluated in studies with too many limitations to achieve a final conclusion, although no effect was observed in these preliminary studies. In contrast, its effects on reducing allergic biomarkers in children seem very promising.