Elvira Larqué

Perinatal supply and metabolism of long-chain polyunsaturated fatty acids: importance for the early development of the nervous system

Abstract: The long‐chain polyunsaturated fatty acids, arachidonic (AA) and docosahexaenoic acid (DHA), are essential structural lipid components of biomembranes. During pregnancy, long‐chain polyunsaturated fatty acids (LC‐PUFA) are preferentially transferred from mother to fetus across the placenta. This placental transfer is mediated by specific fatty acid binding and transfer proteins. After birth, preterm and full‐term babies are capable of converting linoleic and α‐linolenic acids into AA and DHA, respectively, as demonstrated by studies using stable isotopes, but the activity of this endogenous LC‐PUFA synthesis is very low. Breast milk provides preformed LC‐PUFA, and breast‐fed infants have higher LC‐PUFA levels in plasma and tissue phospholipids than infants fed conventional formulas. Supplementation of formulas with different sources of LC‐PUFA can normalize LC‐PUFA status in the recipient infants relative to reference groups fed human milk. Some, but not all, randomized, double‐masked placebo‐controlled clinical trials in preterm and healthy full‐term infants demonstrated benefits of formula supplementation with DHA and AA for development of visual acuity up to 1 year of age and of complex neural and cognitive functions. From the available data, we conclude that LC‐PUFA are conditionally essential substrates during early life that are related to the quality of growth and development. Therefore, a dietary supply during pregnancy, lactation, and early childhood that avoids the occurrence of LC‐PUFA depletion is desirable, as was recently recommended by an expert consensus workshop of the Child Health Foundation.

Dietary trans fatty acids in early life: a review

Trans fatty acids are unsaturated fatty acids with at least a double trans configuration, resulting in a more rigid molecule close to a saturated fatty acid. These appear in dairy fat because of ruminal activity, and in hydrogenated oils; margarines, shortenings and baked goods contain relatively high levels of trans fatty acids. These fatty acids can be incorporated into both fetal and adult tissues, although the transfer rate through the placenta continues to be a contradictory subject. In preterm infants and healthy term babies, trans isomers have been inversely correlated to infantile birth weight. However, in multigenerational studies using animals, there is no correlation between birth weight, growth, and dietary trans fatty acids. Maternal milk reflects precisely the daily dietary intake of trans fatty acids, from 2% to 5% of the total fatty acids in human milk. The level of linoleic acid in human milk is increased by a high trans diet, but long-chain polyunsaturated fatty acids remain mostly unaffected. Likewise, infant tissues incorporate trans fatty acids from maternal milk, raising the level of linoleic acid and relatively decreasing arachidonic and docosahexaenoic acids. This suggests an inhibitory effect of trans fatty acid on liver Delta-6 fatty-acid desaturase activity. As opposed to blood and liver, the brain appears to be protected from the trans fatty-acid accumulation in experimental animals, but no data have yet been reported for human newborns. Further investigations in humans are needed to definitively establish the potential physiological consequences of trans fatty-acid intake during the neonatal period.

Dietary fructooligosaccharides and potential benefits on health

Fructooligosaccharides (FOS) are oligosaccharides that occur naturally in plants such as onion, chicory, garlic, asparagus, banana, artichoke, among many others. They are composed of linear chains of fructose units, linked by β (2-1) bonds. The number of fructose units ranges from 2 to 60 and often terminate in a glucose unit. Dietary FOS are not hydrolyzed by small intestinal glycosidases and reach the cecum structurally unchanged. There, they are metabolized by the intestinal microflora to form short-chain carboxylic acids, L -lactate, CO2, hydrogen and other metabolites. FOS have a number of interesting properties, including a low sweetness intensity; they are also calorie free, non-cariogenic and are considered as soluble dietary fibre. Furthermore, FOS have important beneficial physiological effects such as low carcinogenicity, a prebiotic effect, improved mineral absorption and decreased levels of serum cholesterol, triacylglycerols and phospholipids. Currently FOS are increasingly included in food products and infant formulas due to their prebiotic effect stimulate the growth of nonpathogenic intestinal microflora. Their consumption increases fecal bolus and the frequency of depositions, while a dose of 4–15 g/day given to healthy subjects will reduce constipation, considered one of the growing problems of modern society, and newborns during the first months of life.

Long-chain polyunsaturated fatty acid (LC-PUFA) transfer across the placenta

Fetal long-chain polyunsaturated fatty acid (LC-PUFA) supply during pregnancy is of major importance, particularly with respect to docosahexaenoic acid (DHA) that is an important component of the nervous system cell membranes. Growing evidence points to direct effects of DHA status on visual and cognitive outcomes in the offspring. Furthermore, DHA supply in pregnancy reduces the risk of preterm delivery. Because of limited fetal capacity to synthesize LC-PUFA, the fetus depends on LC-PUFA transfer across the placenta. Molecular mechanisms of placental LC-PUFA uptake and transport are not fully understood, but it has been clearly demonstrated that there is a preferential DHA transfer. Thus, the placenta is of pivotal importance for the selective channeling of DHA from maternal diet and body stores to the fetus. Several studies have associated various fatty acid transport and binding proteins (FATP) with the preferential DHA transfer, but also the importance of the different lipolytic enzymes has been shown. Although the exact mechanisms and the interaction of these factors remains elusive, recent studies have shed more light on the processes involved, and this review summarizes the current understanding of molecular mechanisms of LC-PUFA transport across the placenta and the impact on pregnancy outcome and fetal development.

In vivo investigation of the placental transfer of 13 C-labeled fatty acids in humans

Placental fatty acid transfer in humans in vivo was studied using stable isotopes. Four pregnant women undergoing cesarean section received 4 h before delivery an oral dose of [13C]palmitic acid (PA), [13C]oleic acid (OA), [13C]linoleic acid (LA), and [13C]docosahexaenoic acid (DHA). Maternal blood samples were collected at −4 h (basal), −3 h , −2 h, −1 h, 0 h, and +1 h relative to time of cesarean section. At the time of birth, venous cord blood and placental tissue were collected. Fatty acid composition was determined by gas-liquid chromatography and isotopic enrichment by gas chromatography-combustion-isotope ratio mass spectrometry. 13C-enrichment of fatty acids in the nonesterified fatty acids (NEFA) of cord plasma tended to be higher than in NEFA of placenta, with statistically significant differences for the nonesterified OA and DHA ([13C]PA, 0.024 ± 0.011 vs. 0.001 ± 0.001; [13C]OA, 0.042 ± 0.008 vs. 0.005 ± 0.003; [13C]LA, 0.038 ± 0.010 vs. 0.008 ± 0.002; [13C]DHA, 0.059 ± 0.009 vs. 0.010 ± 0.003). The ratio of tracer fatty acid concentrations of placenta to maternal plasma was significantly higher for [13C]DHA than for the other fatty acids ([13C]PA, 7.1 ± 1%; [13C]OA, 3.8 ± 0.4%; [13C]LA, 9.2 ± 1.3%; [13C]DHA, 25.9 ± 3.4%). These results suggest that only a part of the placental NEFA participated in fatty acid transfer, and that the placenta showed a preferential accretion of DHA relative to the other fatty acids.

Omega 3 fatty acids, gestation and pregnancy outcomes.

Pregnancy is associated with a reduction in maternal serum docosahexaenoic acid (DHA, 22:6 n-3) percentage and its possible depletion in the maternal store. Since the synthesis of long chain polyunsaturated fatty acids (LCPUFA) in the fetus and placenta is low, both the maternal LCPUFA status and placental function are critical for their supply to the fetus. Maternal supplementation with DHA up to 1 g/d or 2·7 g n-3 LCPUFA did not have any harmful effect. DHA supplementation in large studies slightly the enhanced length of gestation (by about 2 days), which may increase the birth weight by about 50 g at delivery. However no advice can be given on their general using to avoid preterm deliveries in low or high risk pregnancies. Several studies, but not all, reported improvements of the offspring in some neurodevelopmental tests as a result of DHA supplementation during gestation, or, at least, positive relationships between maternal or cord serum DHA percentages and cognitive skills in young children. The effect seems more evident in children with low DHA proportions, which raises the question of how to identify those mothers who might have a poor DHA status and who could benefit from such supplementation. Most studies on the effects of n-3 LCPUFA supplementation during pregnancy on maternal depression were judged to be of low-to-moderate quality, mainly due to small sample sizes and failure to adhere to Consolidated Standards of Reporting Trials guidelines. In contrast, the effects of n-3 LCPUFA supplementation on reducing allergic diseases in offspring are promising.

Placental transfer of fatty acids and fetal implications

Considerable amounts of long-chain polyunsaturated fatty acids (LC-PUFAs), particularly arachidonic acid and docosahexaenoic acid (DHA, 22:6n-3), are deposited in fetal tissues during pregnancy; and this process is facilitated by placental delivery. Nevertheless, the mechanisms involved in LC-PUFA placental transfer remain unclear. Stable isotope techniques have been used to study human placental fatty acid transfer in vivo. These studies have shown a significantly higher ratio of (13)C-DHA in cord to maternal plasma compared with other fatty acids, which reflects a higher placental DHA transfer. In addition, a selective DHA accumulation in placental tissue, relative to other fatty acids, has been reported. The materno-fetal transfer of fatty acids is a slow process that requires ≥12 h. A high incorporation of dietary (13)C-DHA into maternal plasma phospholipids appears to be important for placental uptake and transfer. DHA in cord blood lipids correlates with placental messenger RNA expression of fatty acid transport protein (FATP)-4, compatible with a role of FATP-4 in DHA transfer. Impaired materno-fetal LC-PUFA transport has been proposed in pregnancies complicated by abnormal placental function (eg, due to gestational diabetes mellitus or intrauterine growth restriction), which should be addressed in future studies. Given that placental DHA transfer is important for child outcomes, elucidation of its potential modulation by transport mechanisms, maternal diet, and disease appears to be important.

Placental transfer of long-chain polyunsaturated fatty acids (LC-PUFA).

Abstract Considerable evidence exists for marked beneficial effects of omega-3 long-chain polyunsaturated fatty acids (LC-PUFA) during pregnancy. The omega-3 LC-PUFA docosahexaenoic acid (DHA) is incorporated in large amounts in fetal brain and other tissues during the second half of pregnancy, and several studies have provided evidence for a link between early DHA status of the mother and visual and cognitive development of her child after birth. Moreover, the supplementation of omega-3 LC-PUFA during pregnancy increases slightly infant size at birth, and significantly reduces early preterm birth before 34 weeks of gestation by 31%. In our studies using stable isotope methodology in vivo, we demonstrated active and preferential materno-fetal transfer of DHA across the human placenta and found the expression of human placental fatty acid binding and transport proteins. From the correlation of DHA values with placental fatty acid transport protein 4 (FATP 4), we conclude that this protein is of key importance in mediating DHA transport across the human placenta. Given the great importance of placental DHA transport for infant outcome, further studies are needed to fully appreciate the effects and optimal strategies of omega-3 fatty acid interventions in pregnancy, dose response relationships, and the potential differences between subgroups of subjects such as women with gestational diabetes or other gestational pathology. Such studies should contribute to optimize substrate intake during pregnancy and lactation that may improve pregnancy outcome as well as fetal growth and development.

Maternal-fetal in vivo transfer of [13C]docosahexaenoic and other fatty acids across the human placenta 12 h after maternal oral intake

BACKGROUND Fetal growth and development require n-3 (omega-3) long-chain polyunsaturated fatty acids, but mechanisms for their placental transfer are not well understood. OBJECTIVE We assessed distribution and human placental transfer of (13)C-labeled fatty acids (FAs) 12 h after oral application. DESIGN Eleven pregnant women received 0.5 mg [(13)C]palmitic acid ((13)C-PA; 16:0), 0.5 mg [(13)C]oleic acid ((13)C-OA; 18:1n-9), 0.5 mg [(13)C]linoleic acid ((13)C-LA; 18:2n-6), and 0.1 mg [(13)C]docosahexaenoic acid ((13)C-DHA; 22:6n-3) per kilogram of body weight orally 12 h before elective cesarean section. Maternal blood samples were collected before tracer intake (-12 h) and at -3, -2, -1, 0, and +1 h relative to the time of cesarean section. At birth, venous cord blood and placental tissue were collected, and FA concentrations in individual lipid fractions and their tracer content (atom percent excess values) were determined. RESULTS Relatively stable tracer enrichment was achieved in maternal lipid fractions 12 h after tracer administration. In maternal plasma, most (13)C-PA and (13)C-OA were found in triglycerides, whereas (13)C-LA and (13)C-DHA were found mainly in plasma phospholipids and triglycerides. In placental tissue, (13)C-FAs were mainly found in phospholipids, which comprise 80% of placental tissue lipids. Placenta-maternal plasma ratios and fetal-maternal plasma ratios for (13)C-DHA were significantly higher than those for any other FA. CONCLUSIONS Twelve hours after oral application of (13)C-labeled FAs, relatively stable tracer enrichment was achieved. We found a significantly higher ratio of (13)C-DHA concentrations in cord plasma than in maternal plasma, which was higher than that for the other studied FAs. (13)C-DHA is predominantly esterified into phospholipids and triglycerides in maternal plasma, which may facilitate its placental uptake and transfer.

Placental regulation of fetal nutrient supply

Purpose of review Placental nutrient uptake and transfer may have a unique role, as changes in trophoblast nutrient-sensing signaling pathways regulate cell metabolism and may affect the fetal growth and health programming in the offspring. Recent findings The functionality of the placenta could affect the neonatal adiposity and the fetal levels of key nutrients such as long-chain polyunsaturated fatty acids. Insulin, oxygen and amino acid concentrations may regulate the mammalian target of rapamycin (mTOR) nutrient sensor in the human placenta affecting trophoblast metabolism and nutrient delivery. Summary The mechanisms involved in both placental uptake and transfer of macronutrients are reviewed. Fatty acid, cholesterol and amino acid transport across the placenta involves a complex system to ensure nutrient delivery to the growing fetus. The placental glucose transfer is important for fetal macrosomia, but lipid disturbances in both maternal and placental compartments may contribute to neonatal fat accretion. Maternal insulin has little effect on the avidity of glucose transport by the placenta, but may interfere in placental metabolism via mTOR nutrient sensor. mTOR is a positive regulator of the amino acid carriers and constitutes a critical link between maternal nutrient availability and fetal growth, thereby influencing the long-term health of the fetus.