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Essential Fatty Acid Deficiency in Preterm versus Full Term Infants

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The essential fatty acid status of the neonate has been shown to be related to gestational age (15). Marginal EFA status in preterm infants compared to full term infants has been documented (16). Alpha-linolenic acid availability may be insufficient to support functional development of the eye and brain of preterm infants fully (17). In full term newborns, n-3 FA accretion rates in brain tissue are reported to show a lag phase, suggesting that desaturation of parent EFA may be limited (17–19). This increases premature infant EFAD risk, since they have reduced intrauterine EFA accre tion time and possible limited desaturase activity after birth (17). Therefore, n-3 LCPUFA supplementation may be essential for maximal neural development. Commercial formula for both preterm and term infants provides only LA and LnA, whereas breast milk usually contains a range of EFA and chain-elongation and desaturation products and includes γ-linolenic acid (18:3n-6), dihomo-γ-linolenic acid (20:3n-6), AA, EPA, and DHA (20). Docosahexaenoic acid in erythrocyte membrane phospholipids in both term and preterm infants is lower in formula-fed infants than in breast-fed infants (20,21). Supplementation with n-3 LCPUFA has been shown to increase membrane phospholipid DHA and to improve visual function through retinal and occipital cortex development (17,22). Low level supplementation with DHA (presumably balanced with AA levels) improves growth in preterm infants (23). In summary, two major factors contribute to EFA deficiency in preterm infants: lack of EFA accretion during the last trimester of gestation, and possibly limited desaturase activity in the immature liver. Maternal EFA status during gestation may be critical for optimal fetal neural development and may play a role in the maintenance of normal pregnancy through LCPUFA metabolism to eicosanoids. Prostaglandin Biosynthesis Prostaglandins (PG) are eicosanoids synthesized from phospholipid-derived arachidonic acid by prostaglandin H synthase (PGHS or cyclooxygenase, COX). The common intermediate of PG biosynthesis, PGH2, gives rise to a variety of prostaglandins, such as PGE2 and PGF2α. Two forms of cyclooxygenase occur in tissues, COX-1 the constitutive enzyme and COX-2 the inducible form (24). The inducible COX-2 expression may be important in sustaining conversion of AA to PG, since rapid autoinactivation of the cyclooxygenase pathway occurs as PGH2 is formed. Cyclooxygenase-2 expression in rat uterus has been shown to increase approximately fourfold by the onset of parturition, while COX-1 expression remained constant (24). Membrane phospholipid AA (20:4n-6) gives rise to the 2-series PG, whereas n-3 fatty acids, such as EPA, can give rise to the 3-series PG when present in sufficient amounts in phospholipids. In addition, n-3 fatty acids depress the synthesis of 2-series PG, presumably by competition at the level of PGHS or by incorporation into membrane precursor pools. Prostaglandins in Gestation and Parturition Prostaglandins and other eicosanoids play important physiological roles in gestation length and parturition. Numerous studies, primarily in animals, suggest that eicosanoids regulate gestational length and parturition (25–30). The role of prostaglandins in labor initiation is well accepted, although the exact mechanism of action remains unclear. Arachidonic acid concentrations are elevated in the amniotic fluid of women during labor, and intra-amniotic injections of AA stimulate labor. Lev els of PGE2, PGF2α, leukotriene (LT)C4, and LTB4 are elevated in the maternal circulation prior to the onset of spontaneous labor (14,25), exogenous administration of either PGE2 or PGF2α induces cervical ripening, uterine contractions, and emptying in both full term and preterm labor, while inhibitors of cyclooxygenase inhibit labor (25,28). Examinations of amniotic fluid during pregnancy found concentrations of primary prostaglandins to be lower in early and mid-pregnancy than near term (29,30). Studies in animal intrauterine tissues demonstrated increased PGHS activity during the third trimester with rapid increases close to term. In the rabbit amnion, a 10- to 38-fold increase in PG synthesis occurs from day 20–30 (term = 31 days), with the sharpest increases reported on days 29 and 30 (31,32). Both primary PG, PGE2 and PGF2α, and the major metabolite of PGF2α (15-keto-13, 14-dihydro-PGF2α), are increased in the amniotic fluid during labor. Primary prostaglandin metabolites increase in the peripheral circulation during labor, adding evidence that increased PG synthesis occurs during parturition at term (33–35). Additionally, thromboxane and prostacyclin may exert effects on myometrial contractility, although the effects are not as well established (36). Tissue-sample homogenates (amnion, chorion, placental arteries, placenta, and myometrium) extracted both before and after labor, all demonstrated capability to convert labeled AA into one or more PG (37). Prostaglandin H synthase has been localized in the amnion epithelium and the cytoplasm of fibroblast-like cells in the subepithelial connective tissue. It has also been identified in the villous and chorionic cytotrophoblast, villus syncytotrophoblasts, and decidualized stroma (38,39). PGE2 has been identified in all gestational tissues, and PGF2α is measurable in all but the amnion. The PGI2 metabolite, 6-keto-PGF1α, has been found in the myometrium, placental arteries, and only sporadically in the amnion and chorion (37). Although thromboxane (TX) has been found in the placenta, placental arteries, and myometrium, it is unclear whether these tissues synthesize TX or whether this represents contribution by blood platelets. Comparisons of relative PG biosynthetic ability have shown that the myometrium demonstrated the greatest overall rate of AA to PG conversion, the placenta demonstrated the lowest, while the amnion showed the highest capacity for PGE2 synthesis.

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