Patricia Mena

Long Chain Polyunsaturated Fatty Acid Formation in Neonates: Effect of Gestational Age and Intrauterine Growth

The present study was designed to evaluate the effect of gestational age and intrauterine growth on the long chain polyunsaturated fatty acid (LCP) synthesis from dietary precursors in neonates as reflected by plasma pools. These have been considered conditionally essential nutrients for normal growth, sensory maturation, and neurodevelopment. In vivo elongation/desaturation of deuterated d5-linoleic acid (d5-LA) to form arachidonic acid (AA), and d5-α-linolenic acid (d5-LNA) to form docosahexaenoic acid (DHA), was studied in 19 preterm appropriate-for-gestational-age (AGA) infants, 11 AGA term, and 11 intrauterine growth-retarded (IUGR) infants. They received a dose of 50 mg/kg body weight of d5-LA and d5-LNA enterally during the first days of life; d5-labeled derivatized fatty acids were determined in blood samples obtained at 24, 48, and 96 h after dosing. Lipids were extracted and fatty acids analyzed by gas chromatography and negative ion mass spectrometry. Mean concentrations, μg/mL, and d5/d0 for n-3 and n-6 precursor and products were computed at various times and were also integrated over the complete study period. Significantly higher time-integrated concentration of d5-AA and d5-DHA were observed in preterm infants relative to the other two groups. Time-integrated enrichment of DHA relative to LNA was 100-fold lower in preterms, 410-fold lower in term, and 27-fold lower in IUGR infants. Similar significant declines in product to precursor enrichments were noted for the n-6 series. A significant negative correlation of AA and DHA formation based on time-integrated d5/d0 ratios with gestational age was noted; product/precursor enrichment versus gas chromatography for the n-6 series had an r of −0.5, p = 0.001, and for the n-3 series had an r of −0.6, p = 0.0001. Birth weight or weight adequacy did not add further strength to the relationship. We conclude that LCP formation from deuterated precursors occurs as early as 26 wk gestation, and in fact is more active at earlier gestational ages; growth retardation appears to slow down or diminish LCP formation. No quantitative estimates of LCP synthesis or nutritional sufficiency can be derived from these data.

Essential fatty acids in early life: structural and functional role.

Essential fatty acids (EFA) are structural components of all tissues and are indispensable for cell membrane synthesis; the brain, retina and other neural tissues are particularly rich in long-chain polyunsaturated fatty acids (LCPUFA). These fatty acids serve as specific precursors for eicosanoids that regulate numerous cell and organ functions. Results from animal and recent human studies support the essential nature of n-3 EFA in addition to the well-established role of n-6 EFA for human subjects, particularly in early life. The most significant effects relate to neural development and maturation of sensory systems. Recent studies using stable-isotope-labelled tracers demonstrate that even preterm infants are able to form arachidonic acid (AA) and docosahexaenoic acid (DHA), but that synthesis is extremely low. Intracellular fatty acids or their metabolites regulate transcriptional activation of gene expression during adipocyte differentiation, and retinal and nervous system development. Regulation of gene expression by LCPUFA occurs at the transcriptional level and is mediated by nuclear transcription factors activated by fatty acids. These nuclear receptors are part of the steroid hormone receptor family. Two types of polyunsaturated fatty acid responsive transcription factors have been characterized, the peroxisome proliferator-activated receptor (PPAR) and the hepatic nuclear factor 4alpha. DHA also has significant effects on photoreceptor membranes involved in the signal transduction process, rhodopsin activation, and rod and cone development. Comprehensive clinical studies have shown that dietary supplementation with marine oil or single-cell oils, sources of LCPUFA, results in increased blood levels of DHA and AA, as well as an associated improvement in visual function in formula-fed premature infants to match that of human milk-fed infant. Recent clinical trials convincingly support LCPUFA supplementation of preterm infant formulations and possibly term formula to mimic human milk composition.

ROLE OF ESSENTIAL FATTY ACIDS IN THE FUNCTION OF THE DEVELOPING NERVOUS SYSTEM

The basis for n-3 fatty acid essentiality in humans includes not only biochemical evidence but functional measures associated with n-3 deficiency in human and nonhuman primates. Functional development of the retina and the occipital cortex are affected by α-linolenic acid deficiency and by a lack of docosahexaenoic acid (DHA) in preterm infant formulas and, as reported more recently, in term diets. Functional effects of n-3 supply on sleep-wake cycles and heart rate rhythms support the need for dietary n-3 fatty acids during early development. Our results indicate that n-3 long-chain polyunsaturated fatty acids should be considered provisionally essential for infant nutrition. DHA may also be required by individuals with inherited metabolic defects in elongation and desaturation activity, such as patients with peroxisomal disorders and some forms of retinitis pigmentosa.

Growth and Development of Premature Infants Fed Predominantly Human Milk, Predominantly Premature Infant Formula, or a Combination of Human Milk and Premature Formula

Background In a recent meta-analysis, human milk feeding of low birth-weight (LBW) infants was associated with a 5.2 point improvement in IQ tests. However, in the studies in this meta-analysis, feeding regimens were used (unfortified human milk, term formula) that no longer represent recommended practice. Objective To compare the growth, in-hospital feeding tolerance, morbidity, and development (cognitive, motor, visual, and language) of LBW infants fed different amounts of human milk until term chronologic age (CA) with those of LBW infants fed nutrient-enriched formulas from first enteral feeding. Methods The data in this study were collected in a previous randomized controlled trial assessing the benefit of supplementing nutrient-enriched formulas for LBW infants with arachidonic acid and docosahexaenoic acid. Infants (n = 463, birth weight, 750–1,800 g) were enrolled from nurseries located in Chile, the United Kingdom, and the United States. If human milk was fed before hospital discharge, it was fortified (3,050–3,300 kJ/L, 22–24 kcal/oz). As infants were weaned from human milk, they were fed nutrient-enriched formula with or without arachidonic and docosahexaenoic acids (3,300 kJ/L before term, 3,050 kJ/L thereafter) until 12 months CA. Formula fed infants were given nutrient-enriched formula with or without added arachidonic and docosahexaenoic acids (3,300 kJ/L to term, 3,050 kJ/L thereafter) until 12 months CA. For the purposes of this evaluation, infants were categorized into four mutually exclusive feeding groups: 1) predominantly human milk fed until term CA (PHM-T, n = 43); 2) ≥ 50% energy from human milk before hospital discharge (≥ 50% HM, n = 98); 3) < 50% of energy from human milk before hospital discharge (< 50% HM, n = 203); or 4) predominantly formula fed until term CA (PFF-T, n = 119). Results PFF-T infants weighed approximately 500 g more at term CA than did PHM-T infants. This absolute difference persisted until 6 months CA. PFF-T infants were also longer (1.0–1.5 cm) and had larger head circumferences (0.3–1.1 cm) than both PHM-T and ≥ 50% HM infants at term CA. There was a positive association between duration of human milk feeding and the Bayley Mental Index at 12 months CA (P = 0.032 full and P = 0.073 reduced, statistical models) after controlling for the confounding variables of home environment and maternal intelligence. Infants with chronic lung disease fed ≥ 50% HM until term CA (n = 22) had a mean Bayley Motor Index about 11 points higher at 12 months CA compared with infants PFF-T (n = 24, P = 0.033 full model). Conclusion Our data suggest that, despite a slower early growth rate, human milk fed LBW infants have development at least comparable to that of infants fed nutrient-enriched formula. Exploratory analysis suggests that some subgroups of human milk fed LBW infants may have enhanced development, although this needs to be confirmed in future studies.

Essential fatty acids as determinants of lipid requirements in infants, children and adults

Essential fatty acids (EFA) are the indispensable component of the lipid supply beyond the provision of energy as a fuel for oxidation. They serve as dietary precursors for the formation of prostanoids and other eicosanoids thus are of great significance in health and modulation of disease conditions. Eicosanoids are powerful autocrine and paracrine regulators of cell and tissue functions: thrombocyte aggregation, inflammatory reactions and leukocyte functions, vasoconstriction and vasodilatation, blood pressure, bronchial constriction, and uterine contraction. Recent attention has focused on the effect of n-3 and n-6 long chain EFAs in normal fetal development. Results from human infant studies suggest that n-3 fatty acids are needed for optimal development of visual and brain function. Human milk is the best and only time proven source of fat and dietary essential fatty acids for infant feeding. International recommendations for n-3 and n-6 EFA dietary intake are reviewed and suggested intakes for long chain EFAs are provided.

Compartmental analyses of 2H5-α-linolenic acid and C-U-eicosapentaenoic acid toward synthesis of plasma labeled 22:6n−3 in newborn term infants

BACKGROUND During early postnatal development, the nervous system accretes docosahexaenoic acid (DHA; 22:6n-3), a highly unsaturated n-3 (omega-3) fatty acid (FA) used in the formation of neural cell membranes. DHA, which is present in human breast milk, may also be biosynthesized from n-3 FAs such as 18:3n-3 [alpha-linolenic acid (ALA)] or 20:5n-3 [eicosapentaenoic acid (EPA)]. An important concern is to what extent these precursors can supply DHA to the developing infant. OBJECTIVE We analyzed measurements of fractional percentages of plasma (2)H(5)-ALA and (13)C-U-EPA directed toward the synthesis of labeled 22:6n-3 in 11 newborn infants by using compartmental modeling procedures. DESIGN One-week-old infants received doses of (2)H(5)-ALA and (13)C-U-EPA ethyl esters enterally. We drew blood from the infants periodically and analyzed the plasma for endogenous and labeled n-3 FAs. From the time-course concentrations of the labeled FAs, we determined rate constant coefficients, fractional synthetic rates, and plasma turnover rates of n-3 FAs. RESULTS In infants, approximately 0.04% of the (2)H(5)-ALA dose converted to plasma (2)H(5)-EPA. Plasma (2)H(5)-EPA and (2)H(5)-22:5n-3 [docosapentaenoic acid (DPA)] efficiently converted to (2)H(5)-DPA and (2)H(5)-DHA, respectively. The percentage of plasma (13)C-U-EPA directed toward the synthesis of (13)C-DHA was lower than the percentage of plasma (2)H(5)-EPA that originated from (2)H(5)-ALA. CONCLUSIONS Endogenously synthesized EPA was efficiently converted to DHA. In comparison, preformed EPA was less efficiently used for DHA biosynthesis, which suggests a differential metabolism of endogenous EPA compared with exogenous EPA. However, on a per mole basis, preformed EPA was 3.6 times more effective toward DHA synthesis than was ALA. Newborns required an intake of approximately 5 mg preformed DHA. kg(-1) x d(-1) to maintain plasma DHA homeostasis.

Iron status in low-birth-weight infants small and appropriate for gestational age. A follow-up study.

Iron nutrition was measured in 84 low‐birth‐weight infants. At birth, they were assigned to three groups: preterm infants appropriate for gestational age (n= 29); preterm infants small for gestational age (n= 17); and full‐term infants* small for gestational age (n= 38). A sub‐sample of infants was supplemented with iron 3 mg/kg from two to four months of age. At birth, preterm appropriate‐for‐gestational‐age infants had a lower hemoglobin concentration than full‐term small‐for‐gestational‐age infants (p < 0.01) and a higher serum ferritin than preterm small‐for‐gestational‐age infants (p < 0.05). In the non‐supplemented group, full‐term small‐for‐gestational‐age infants had significantly higher hemoglobin concentrations at four months of age. At this age, iron‐supplemented preterm infants appropriate or small for gestational age had significantly higher hemoglobin levels than non‐supplemented subjects, while iron supplementation did not have an effect on final hemoglobin concentration in full‐term small‐for‐gestational‐age infants. We conclude that preterm infants, irrespective of their adequacy for gestational age, show evidence of iron deficiency before four months of age. Full‐term infants do not develop iron deficiency up to this age.

Infants with intrauterine growth restriction have impaired formation of docosahexaenoic acid in early neonatal life: a stable isotope study.

This study evaluated the arachidonic acid (AA) and docosahexaenoic acid (DHA) formation from d5-labeled linoleic acid (d5-LA) and α-linolenic acid (d5-LNA) precursors in infants with intrauterine growth restriction (IUGR) compared with control groups matched by gestational age (GA) or birth weight. We compared DHA and AA formation from deuterated precursors d5-LA and d5-LNA in 11 infants with IUGR with 13 and 25 control subjects who were appropriate for GA and matched by GA and by birth weight, respectively. After an enteral administration of d5-LA and d5-LNA, we determined unlabeled and d5-labeled fatty acids at 24, 48, and 96 h in plasma. Absolute concentrations and area under the curve (AUC) over the 96-h study were used for analysis. Absolute concentration of d5-DHA and the product/precursor ratio of the d5-labeled AUCs indicated a less active DHA formation from LNA in infants with IUGR compared with their GA-matched (2-fold) and birth weight–matched (3-fold) control subjects. The ratios of eicosapentaenoic and n-3 docosapentaenoic acid to DHA were also affected. Similar evaluation for the n-6 series was not significant. DHA metabolism is affected in infants with IUGR; the restricted DPA to DHA conversion step seems to be principally responsible for this finding.

Effect of maternal administration of thyrotropin releasing hormone on the preterm fetal pituitary-thyroid axis

We evaluated the response of preterm fetuses to maternal intravenous injection of 400 micrograms of thyrotropin releasing hormone (TRH) between 30 minutes and 5 hours before delivery (n = 12). An additional seven mothers received saline solution and served as control subjects. There were no statistically significant differences in gestational age, birth weight, or Apgar scores between groups. At delivery, concentrations of maternal thyrotropin were elevated in the TRH group compared with the control group (12.0 +/- 1.6 vs 5.6 +/- 0.5 mU/L; p less than 0.005); however, maternal triiodothyronine (T3) values remained unchanged. Significant elevations of fetal thyrotropin and T3 were observed after maternal administration of TRH compared with control subjects (45.8 +/- 7.7 vs 8.4 +/- 0.9 mU/L (p less than 0.002) and 1.3 +/- 0.07 vs 0.7 +/- 0.04 nmol/L or 87 +/- 5 vs 49 +/- 3 ng/dl (p less than 0.001), respectively). Fetal thyroxine (T4) and prolactin values were also elevated after exposure to TRH (135 +/- 5 vs 86 +/- 10 nmol/L or 10.5 +/- 0.4 vs 6.7 +/- 0.8 micrograms/dl (p less than 0.001) and 212 +/- 31 vs 105 +/- 28 micrograms/L (p less than 0.05), respectively). Two hours after birth, a significant increase in T3 but not T4 levels was observed in both groups of infants. These data indicate that fetal exposure to a single dose of TRH via maternal administration of this hormone results in marked stimulation of the preterm fetal pituitary-thyroid axis, as in the fetus at term, and that this treatment does not inhibit the early postnatal surge of T3.

Compartmental Analyses of Plasma 13C- and 2H-Labeled n-6 Fatty Acids Arising from Oral Administrations of 13C-U-18:2n-6 and 2H5-20:3n-6 in Newborn Infants

Efficacy of 13C-U-18:2n-6 and 2H5-20:3n-6 toward synthesis of labeled-20:4n-6 was studied in newborn infants utilizing compartmental models of plasma labeled n-6 fatty acids (FA). Ten infants received oral doses of 13C-U-18:2n-6 and 2H5-20:3n-6 ethyl esters (100 and 2 mg/kg, respectively). Rate constant coefficients and half-lives (t½) of n-6 FA were determined from the time-course concentrations of labeled-FA. Plasma n-6 FA values approximated steady state concentrations. Synthetic and utilization rates were calculated. Eight percent (range, 2–21%) of plasma 13C-U-18:2n-6 was used for synthesis of 13C-18:3n-6, -20:2n-6, and -20:3n-6. Seventy percent of 13C-20:3n-6 (mean, CV: 0.26) was available for synthesis of 13C-20:4n-6. The percentage of 2H5-20:3n-6 converted to 2H5-20:4n-6 was lower (mean: 26%, p < 0.02) than the 13C-labeled analogue. Turnover of 18:2n-6 in subjects and of 20:4n-6 in plasma was 4.2 g/kg/d (CV: 0.58) and 4.3 mg/kg/d (CV: 0.81), respectively. Intake of 18:2n-6 and 20:4n-6 were estimated to be 3.0 g/kg/d (±1.7) and 2.8 mg/kg/d (± 2.2), respectively. Infants required additional 18:2n-6 and 20:4n-6 (mean: 1.2 g and 1.5 mg/kg/d) above predicted intake amounts to maintain plasma concentrations of 18:2n-6 and 20:4n-6, in order to spare FA from fat stores.