A maternal erythrocyte DHA content of approximately 6 g% is the DHA status at which intrauterine DHA biomagnifications turns into bioattenuation and postnatal infant DHA equilibrium is reached

The higher RBC-AA contents in Maasai (low fish), compared to Pare (intermediate fish) and Sengerema (high fish) mothers (Fig. 1a), are likely to be caused by their higher intakes of AA from meat and their low intakes of DHA from fish. Biomagnification [13] of AA is consistent with data from many others studying plasma PL [14, 29] or RBC [30‐32]. Higher infant compared to maternal RBC-AA at delivery was previously found by us in Dominica [33] and by others in the Netherlands [32], and the data of those 2 studies fitted well within those of the present study (Dominica: mean maternal RBC-AA 12.4 g%, infant 16.6 g%; Netherlands: mean maternal RBC-AA 10.0 g%, infant 14.2 g% AA). The uniformly high infant RBC-AA at delivery occurred despite between-tribe differences in maternal RBC-AA and DHA (Fig. 1a, b), and in the absence of a relationship between maternal and infant RBC-AA (Fig. 2a).

Although we observed no consistent changes in maternal RBC-AA during pregnancy, maternal RBC-AA was consistently higher after 3 months of exclusive lactation as compared to delivery, which coincided with a drop of infant RBC-AA. The decreasing maternal AA status during pregnancy found by Al et al. [14] and the well-known postnatal drop of infant RBC-AA [34] suggests that the fetus accretes AA at the expense of maternal AA status. However, no clear relationship between maternal and infant RBC-AA could be demonstrated in our data, which may question the causality of these opposing changes. The increasing maternal AA status after delivery may derive from the discontinued utilization of AA by the placenta or discontinued AA transport to the fetus [35, 36]. Secondly, the postpartum increasing maternal AA status may result from decreasing maternal adipose tissue lipolysis and decreasing de novo lipogenesis (DNL), secondary to the changing hormonal milieu after delivery, notably the restoration of the state of diminished insulin sensitivity/compensatory hyperinsulinemia in the end of pregnancy. Discontinuation of the influx of these sources of saturated fatty acids (SAFA), monosaturated fatty acids (MUFA), and PUFA (i.e., notably linoleic acid) leads to less dilution of LCP [35, 36]. The decrease in infant RBC-AA may have been caused by postpartum changing infant RBC-PL species [37] and the interrupted transplacental AA transport [35, 36]. It can additionally be explained by a lower conversion of LA to AA, since the infant’s capacity to synthesize LC-PUFA decreases drastically after delivery [38]. This lower conversion might result from lower activities of the delta-5 and delta-6 desaturase enzymes, secondary to the changing hormonal milieu after delivery. Finally, LA intakes correlate inversely with RBC-AA [39]. Consequently, the high LA content of human milk (Kuipers, unpublished) and the ensuing postnatal surge in the infant LA status [35] suggest that the infant’s RBC-AA decrease may also be a result of the high LA intake from breast milk. At 3 months of age, infant RBC-AA in Pare (intermediate fish) and Sengerema (high fish) was comparable to that of their mothers, indicating a rapid postnatal adaptation of RBC-AA to adult levels. Taken together, AA biomagnification seems to aim at a uniform, high infant AA status during pregnancy, most likely to sustain neurodevelopment and infant growth [40].

As expected [41], maternal DHA status, and thereby infant RBC-DHA status, appeared highly sensitive to maternal fish intake. The virtually constant maternal RBC-DHA levels during pregnancy are in accordance with earlier data for plasma PL [14, 42].

At delivery, infant RBC-DHA appeared higher than maternal RBC-DHA, but this “‘biomagnification” occurred only up to about 5.6 g% maternal RBC-DHA. Beyond this point of maternal–fetal equilibrium, infant RBC-DHA was mostly lower than maternal RBC-DHA, suggesting “bioattenuation”, rather than biomagnification (Fig. 2b). The mean RBC-DHA data for a Dutch population [32] (with low fish intakes) and a Dominican population [33] (Caribbean Sea; with local high fish intakes) are consistent with the switch from biomagnification to bioattenuation at a higher maternal RBC-DHA status (Dominica: mean maternal RBC-DHA 7.6 g%, infants 6.5 g%; Netherlands: mean maternal 3.9 g%, infants 4.7 g%). In other words, biomagnification might be confined to populations with low maternal DHA status, such as typically encountered in most Western countries, but also the currently studied Pare (intermediate fish) and Maasai (no fish), who, in contrast to the high fish consuming Sengerema women, exhibited tendencies of increasing RBC-DHA during pregnancy (Fig. 1b). Increasing amounts of DHA in the maternal circulation during pregnancy [43, 44] might derive from an insulin-induced augmented elongation/desaturation of ALA in the maternal liver, secondary to the state of reduced insulin sensitivity/compensatory hyperinsulinism that is characteristic for the third trimester [35]. This maternal DHA increase is unlikely to occur at high fish intakes such as in the women from Sengerema, because of the negative feedback of dietary DHA on delta-5 and delta-6 desaturase activity (Fig. 1b). The DHA increase in the maternal circulation might be a driving force in biomagnification that is further supported by selective transport to the fetal circulation [45]. Fetal albumin has been regarded as a major contributor to LCP biomagnification because of its ability to bind placentally transferred free LC-PUFA, while fetal albumin concentrations at term are also 10–20% higher, and albumin’s free fatty acid saturation is four times lower, in the fetal circulation compared to the maternal circulation. A role of the uniquely present alpha fetoprotein (AFP) with similar free fatty acid loading capacity in the fetal circulation was dismissed because of its 1,000 times lower concentration compared to albumin in the fetus [46]. AFP, however, has high preference for AA and DHA and is preferentially to albumin taken up by immature tissues, suggesting that, rather than concentrations, notably fluxes of LC-PUFA trapping proteins might be important for biomagnification. Another suggested mechanism for the trapping of LC-PUFA is the incorporation of free LC-PUFA from the fetal circulation into phospholipids in the liver or other organs [46].

Higher maternal compared to infant RBC-DHA contents were previously noted after daily supplementation of pregnant women from 20 weeks of gestation until delivery with a high fish oil supplement containing 2.24 g DHA and 1.12 g EPA [47]. In this study, a maternal–fetal equilibrium was found at an RBC-DHA of 8.87 g%, named “saturation point”. A possible explanation for the equilibrium at higher maternal RBC-DHA than the current about 6 g% is that fish oil was supplemented during the 3rd trimester of pregnancy, which is characterized by reduced insulin sensitivity and continuous adipose tissue mobilization [48]. Therefore, the supplemental DHA might have been abundantly available for incorporation into circulating lipids, and to a lesser extent to adipose tissue stores, which might have resulted in an overestimation of the genuine whole body DHA status during this non-steady state condition characterized by preferential nutrient transfer to the rapidly growing infant. In our study, circulating DHA derived from lifelong stable fish intakes that probably caused a steady state DHA supply of the infant from both the diet and adipose tissue stores.

Data from our populations with stable high intakes of fish suggest that DHA bioattenuation aims at the inhibition of abundant transplacental passage, possibly to prevent undesired competition of DHA with AA in competition-sensitive fetal organs. Consistent with this notion, we have shown that at high DHA status, DHA seems to lower AA, at least in postnatal RBC, but that in umbilical vessels, DHA does not seem to exceed certain levels, possibly to avoid competition with AA [49]. Prevention of DHA competition with AA in the fetal period seems important, since fetal AA is implicated in development and growth [10, 50].

The consistent decrease in maternal RBC-DHA during lactation suggests that a lactating woman loses large quantities of DHA to her infant via the milk. This postpartum mother-to-infant DHA “surge” [51] may represent a genuine form of “postnatal DHA biomagnification”, since it clearly occurs at the expense of the mother. This surge coincides with a more rapid postnatal accretion of DHA in the infant brain compared with AA [52] and may therefore illustrate the increasing importance of DHA for retinal and neurodevelopment [52, 53] after delivery.

The mother-to-infant DHA surge via the milk seemed unable to prevent a RBC-DHA drop in the Maasai (low fish) infants, prevented a decrease in the Pare (intermediate fish) infants, but did enable a postpartum RBC-DHA increase in the infants of the Sengerema (high fish) women (Fig. 1b). A state of postpartum infant DHA equilibrium might therefore be reached at lifelong DHA intakes that are somewhat below the intakes by the Sengerema (high fish) women, who reported to eat fish 4–5 times/week on average. Using the joint data of all mothers and infants, we estimated that mothers with an RBC-DHA status of about 6 g% in early pregnancy will exhibit an RBC-DHA of about 6 g% at delivery and will give birth to infants with about 6 g% RBC-DHA. Whether this maternal RBC-DHA of 6 g% constitutes an appropriate target for the DHA status of the mother is questionable, since a maternal RBC-DHA of 6 g% is unable to prevent a drop in maternal RBC-DHA during lactation. We [51] recently showed that maternal postpartum DHA equilibrium is reached at a maternal RBC-DHA content of 8 g% DHA, which is even higher than the mean DHA status of the pregnant women in Sengerema and coincides with an increase in infant RBC-DHA from 7 g% at delivery to adult levels of 8 g% at 3 months.

We recently estimated that our hunter-gatherer ancestors living in a water–land ecosystem had daily intakes of gram amounts of AA, EPA, and DHA [5], which are substantially higher than the current daily intakes of about 200 mg AA and 275 mg DHA (men) from a typically Western diet [8, 54]. There is also good evidence showing that daily intakes above the recommended 450 mg DHA + EPA might be beneficial for the lowering of heart rate, blood pressure, and triglycerides and to reach maximum antithrombotic effects [55]. It has been proposed that optimal protection from cardiovascular disease occurs from 8 g% RBC EPA + DHA [56, 57], while an RBC-DHA of 7 g% [i.e., RBC-(EPA + DHA) ≥ 8 g%], as found in healthy subjects in Japan, might be an appropriate target to minimize major depressive disorders and bipolar depression [56]. The above-mentioned maternal postpartum equilibrium of 8 g% [51] is in line with these suggested targets for adequate DHA status and also the observation that antagonism between EPA + DHA and AA occurs at RBC-(EPA + DHA) contents above 8 g% [49].

Pregnant women in Western countries with low intakes of fish have RBC-DHA contents well below 8 g%. For example, non-supplemented Dutch pregnant women had RBC-DHA contents of 4.41 g% at 36 weeks [19], while after 12 weeks of exclusive lactation, their infants had an RBC-DHA content of 4.73 g%. Supplementation of 220 mg DHA or 220 mg DHA + 220 mg AA during pregnancy resulted in a maternal RBC-DHA contents of 5.51 and 5.57 g% at 36 weeks gestation, respectively [19], while their exclusively breastfed infants had RBC-DHA of 5.50 and 4.95 g%, respectively, at 12 weeks postpartum. The mean daily intake of EPA + DHA by Dutch women amounted to 84 mg in 2003 [58]. In another study, daily supplementation of 1.3 g DHA during 3 months of lactation resulted in a maternal RBC-DHA of 7.9 g% [59] that coincided with an infant RBC-DHA content of 9.1 g% [60]. Taken together, these data suggest that the presently advised intake of 200–300 mg DHA daily during pregnancy and lactation [61] will be insufficient to reach the maternal RBC-DHA target of 6 g% (i.e., postpartum infant equilibrium) and will be even more insufficient to reach the target of 8 g% RBC-DHA (i.e., postpartum maternal equilibrium and infant increase) [51].