Essential fatty acids in growth and development

During early pregnancy there is an increase in body fat accumulation, associated with both hyperphagia and increased lipogenesis. During late pregnancy there is an accelerated breakdown of fat depots, which plays a key role in fetal development. Besides using placental transferred fatty acids, the fetus benefits from two other products: glycerol and ketone bodies. Although glycerol crosses the placenta in small proportions, it is a preferential substrate for maternal gluconeogenesis, and maternal glucose is quantitatively the main substrate crossing the placenta. Enhanced ketogenesis under fasting conditions and the easy transfer of ketones to the fetus allow maternal ketone bodies to reach the fetus, where they can be used as fuels for oxidative metabolism as well as lipogenic substrates. Although maternal cholesterol is an important source of cholesterol for the fetus during early gestation, its importance becomes minimal during late pregnancy, owing to the high capacity of fetal tissues to synthesize cholesterol. Maternal hypertriglyceridemia is a characteristic feature during pregnancy and corresponds to an accumulation of triglycerides not only in very low-density lipoprotein but also in low- and high-density lipoprotein. Although triglycerides do not cross the placental barrier, the presence of lipoprotein receptors in the placenta, together with lipoprotein lipase, phospholipase A2, and intracellular lipase activities, allows the release to the fetus of polyunsaturated fatty acids transported as triglycerides in maternal plasma lipoproteins. Normal fetal development needs the availability of both essential fatty acids and long chain polyunsaturated fatty acids, and the nutritional status of the mother during gestation has been related to fetal growth. However, excessive intake of certain long chain fatty acids may cause both declines in arachidonic acid and enhanced lipid peroxidation, reducing antioxidant capacity.

Lipid Metabolism in Pregnancy and its Consequences in the Fetus and Newborn

Although essential fatty acids (EFA) and their longer chain, more unsaturated derivatives play a major role during pregnancy, hardly any information is available with respect to the course of the maternal EFA status during an uncomplicated pregnancy and its relationship to the neonatal EFA status. Therefore, a longitudinal study was started in which 110 pregnant women gave repeated blood samples from the 10th week of gestation until delivery. After birth a blood sample from the umbilical vein and a maternal venous blood sample were collected as well, and 6 months after delivery a final blood sample from the mother was taken. The absolute (mg/l) and relative (% total fatty acids) amounts of the fatty acids in plasma phospholipids were determined. The total amounts of fatty acids increased significantly during pregnancy. This pattern was similar for the individual fatty acids and fatty acid families. The relative amount of linoleic acid (18:2n-6) did not change during pregnancy, whereas the relative amount of arachidonic acid (20:4n-6) decreased. Despite maternal mobilization of docosahexaenoic acid (22:6n-3, DHA), suggested by a temporary increase in the DHA status until 18 weeks gestation, the DHA status steadily declined thereafter. This pattern was associated with a progressive increase in the DHA deficiency index in maternal blood throughout pregnancy and resulted in a sub-optimal neonatal DHA status. The overall maternal EFA status also declined steadily during pregnancy. Therefore, the question arises whether the mother, under the prevailing dietary conditions, is able to meet the high fetal requirement for EFA.

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Maternal essential fatty acid patterns during normal pregnancy and their relationship to the neonatal essential fatty acid status

Placental Regulation of Fatty Acid Delivery and its Effect on Fetal Growth—A Review

The essentiality of n−6 polyunsaturated fatty acids (PUFA) is described in relation to a thymus/thymocyte accretion of arachidonic acid (20∶4n−6, AA) in early development, and the high requirement of lymphoid and other cells of the immune system for AA and linoleic acid (18∶2n−6, LA) for membrane phospholipids. Low n−6 PUFA intakes enhance whereas high intakes decrease certain immune functions. Evidence from in vitro and in vivo studies for a role of AA metabolites in immune cell development and functions shows that they can limit or regulate cellular immune reactions and can induce deviation toward a T helper (Th)2-like immune response. In contrast to the effects of the oxidative metabolites of AA, the longer-chain n−6 PUFA produced by γ-linolenic acid (18∶3n−6, GLA) feeding decreases the Th2 cytokine and immunoglobulin (Ig)G1 antibody response. The n−6 PUFA, GLA, dihomo-γ-linolenic acid (20∶3n−6, DHLA) and AA, and certain oxidative metabolites of AA can also induce T-regulatory cell activity, e.g., transforming growth factor (IGF)-β-producing T cells; GLA feeding studies also demonstrate reduced proinflammatory interleukin (IL)-1 and tumor necrosis factor (TNF)-α production. Low intakes of long-chain n−3 fatty acids (fish oils) enhance certain immune functions, whereas high intakes are inhibitory on a wide range of functions, e.g., antigen presentation, adhesion molecule expression, Th1 and th2 responses, proinflammatory cytokine and eicosanoid production, and they induce lymphocyte apoptosis. Vitamin E has a demonstrable critical role in long-chain n−3 PUFA interactions with immune functions, often reversing the effects of fish oil. The effect of dietary fatty acids on animal autoimmune disease models depends on both the autoimmune model and the amount and type of fatty acids fed. Diets low in fat, essential fatty acid deficient (EFAD), or high in long-chain n−3 PUFA from fish oils increase survival and reduce disease severity in spontaneous autoantibody-mediated disease, whereas high-fat LA-rich diets increase disease severity. In experimentally induced T cell-mediated autoimmune disease, EFAD diets or diets supplemented with long-chain n−3 PUFA augment disease, whereas n−6 PUFA prevent or reduce the severity. In contrast, in both T cell- and antibody-mediated autoimmune disease, the desaturated/elongated metabolites of LA are protective. PUFA of both the n−6 and n−3 families are clinically useful in human autoimmune-inflammatory disorders, but the precise mechanisms by which these fatty acids exert their clinical effects are not well understood. Finally, the view that all n−6 PUFA are proinflammatory requires revision, in part, and their essential regulatory and developmental role in the immune system warrants appreciation.

Fatty acids, the immune response, and autoimmunity: A question of n−6 essentiality and the balance between n−6 and n−3

Placental essential fatty acid transport and prostaglandin synthesis

Cyclooxygenase inhibition reduces placental transfer: Reversal by carbacyclin

Transport and metabolism of essential fatty acids by the human placenta.

Placental blood flow is reduced in pregnancies complicated by hypertension, intrauterine growth retardation, maternal smoking, or diabetes. Umbilical-placental production of the potent vasodilator prostacyclin is also reduced in these pathologic states and this deficiency may contribute to an associated increase in the incidence of low infant birthweight by affecting a reduction in placental nutrient transfer. We have studied the effects of the prostacyclin analogue carbacyclin on diffusional transfer in the human placenta perfused in vitro. We have found that carbacyclin crosses the human placenta and can significantly increase diffusional transfer in placenta from pregnancies complicated by hypertension or maternal smoking and in the normal term placenta in which prostacyclin production has first been reduced through the administration of ibuprofen. Carbacyclin had no effect, however, in untreated placenta from normal pregnancies or in placenta from diabetic pregnancies. These results suggest that the prostacyclin-deficient perfused placenta may serve as a model for several placental insufficiency syndromes and that the possibility that prostacyclin analogues may improve deficient nutrient transfer in some pathologic pregnancies warrants further investigation.

Douglas C. Kuhn

Papers

Placental essential fatty acid transport and prostaglandin synthesis

Cyclooxygenase inhibition reduces placental transfer: Reversal by carbacyclin

Transport and metabolism of essential fatty acids by the human placenta.

A prostacyclin analogue crosses the in vitro perfused human placenta and improves transfer in some pathologic states.