John Van Aerde

Intravenous Fish Oil Emulsion Attenuates Total Parenteral Nutrition-Induced Cholestasis in Newborn Piglets

Total parenteral nutrition (TPN) causes intrahepatic cholestasis and membrane phospholipid changes. Fatty acid (FA) composition of bile and hepatocyte phospholipid is influenced by dietary FA composition. We hypothesized that altering FA composition of i.v. lipid emulsions modifies 1) severity of TPN-induced cholestasis; 2) hepatocyte membrane composition and function; 3) bile flow and composition. Newborn piglets received either sows milk, TPN with i.v. soybean oil or TPN with i.v. fish oil (FO). After 3 wk, basal and stimulated bile flow were measured after bolus injections of 20, 50, and 100 µmol/kg of taurocholate (TCA). Bile was analyzed for bile acids, cholesterol, phospholipids, and phospholipid-FA. Sinusoidal and canalicular membrane PL-FA, fluidity, and Na+/K+-ATPase were measured. Although the soybean oil-fed animals developed cholestasis, the FO and milk group had similar liver and serum bilirubin. Basal and stimulated bile flow rates were impaired in the soybean oil but not in the FO group. Hepatocyte membrane FA composition reflected dietary FA. Changes in sinusoidal and canalicular membrane fluidity and sinusoidal Na+/K+-ATPase activity did not explain the effect of FO on TPN-induced cholestasis. Intravenous FO reduces TPN-induced cholestasis by unknown mechanisms.

Teratogenicity Associated With Pre-Existing and Gestational Diabete

OBJECTIVE To review the teratogenesis associated with pre-existing and gestational diabetes, to provide guidelines to optimize prevention and diagnosis of fetal abnormalities in women with diabetes, and to identify areas specific to fetal abnormalities and diabetes requiring further research. OPTIONS Pre-conception counselling, pre-conception and first trimester folic acid supplementation, and glycemic control. OUTCOMES Increased awareness of fetal abnormalities associated with pre-existing and gestational diabetes. EVIDENCE The Cochrane Library and Medline were searched for English-language articles, published from 1990 to February 2005, relating to pre-existing and gestational diabetes and fetal abnormalities. Search terms included pregnancy, diabetes mellitus, pre-existing diabetes, type 1 diabetes, type 2 diabetes, insulin dependent diabetes, gestational diabetes, impaired glucose tolerance, congenital anomalies, malformations, and stillbirth. Additional publications were identified from the bibliographies of these articles as well as the Science Citation Index. All study types were reviewed. Randomized controlled trials were considered evidence of the highest quality, followed by cohort studies. Key studies and supporting data for each recommendation are summarized with evaluative comments and referenced. VALUES The evidence collected was reviewed by the Genetics and Maternal Fetal Medicine Committees of the Society of Obstetricians and Gynaecologists of Canada (SOGC) and quantified using the criteria and classifications of the Canadian Task Force on Preventive Health Care. RECOMMENDATIONS 1. Experimental studies suggest that hyperglycemia is the major teratogen in diabetic pregnancies, but other diabetes-related factors may also affect fetal outcomes. Further research using animal models is required to clarify the teratogenic factors associated with pre-existing and gestational diabetes. (II-3C) 2. Prospective and retrospective cohort studies have demonstrated an increased risk of congenital abnormalities with pre-existing diabetes. Further studies that include outcomes from first and second trimester pregnancy terminations, account for potential confounding variables, and use appropriate control groups are required. (II-2A) 3. Prospective and retrospective cohort studies have demonstrated an increased risk of congenital abnormalities with gestational diabetes. This observation is probably related to the inclusion of women with unrecognized type 2 diabetes. Clarification of the relationship between gestational diabetes and congenital abnormalities by studies that include outcomes from first and second trimester pregnancy terminations, account for potential confounding variables, and use appropriate control groups are required. (II-2A) 4. In some women, type 2 diabetes may be identified for the first time in pregnancy. Pre-conception recognition of women at high risk for type 2 diabetes and optimal glycemic control may reduce the risk of congenital anomalies. (II-2A) 5. Second generation sulfonylureas have not been associated with congenital abnormalities in human studies. The use of biguanides may be associated with other adverse perinatal outcomes. The use of other oral antihyperglycemic agents is not recommended in pregnancy. (II-2A) 6. The risk of congenital anomalies is increased in the offspring of obese women with diabetes. A healthy diet and regular exercise may help optimize pre-pregnancy weight and reduce the risk of congenital anomalies. (II-2A) 7. Accurate determination of gestational age is required in women with diabetes. Given the increased risk of congenital abnormalities, they should be offered appropriate biochemical and ultrasonographic screening and a detailed evaluation of fetal cardiac structures. (II-2A) 8. Women with diabetes should be offered pre-conception counselling with a multidisciplinary team to optimize general health and glycemic control and to review the risks of congenital anomalies. (II-2A) 9. A careful history should be obtained to identify other factors, such as a positive family history or advanced maternal age, that may further increase the risk of congenital structural or chromosomal abnormalities. (II-2A) 10. Pregnancy in women with diabetes should be planned. Good contraceptive advice and pre-pregnancy counselling are essential. Euglycemia should be maintained before and during pregnancy. (II-2A) 11. All women with diabetes should be counselled regarding intake of foods high in folic acid, folate-fortified foods, and appropriate folic acid supplementation of 4 to 5 mg per day pre-conceptionally and in the first 12 weeks of gestation. (II-2A) 12. A substantial number of women with diabetes do not access pre-conception care programs. Strategies are needed to improve access to such programs and to maximize interventions associated with improved pregnancy outcomes, such as folic acid use. (II-2A) VALIDATION: These guidelines have been reviewed by the Genetics Committee and the Maternal Fetal Medicine Committee of the SOGC. Final approval has been given by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada.

Polyunsaturated fatty acids and T-cell function: implications for the neonate.

Infant survival depends on the ability to respond effectively and appropriately to environmental challenges. Infants are born with a degree of immunological immaturity that renders them susceptible to infection and abnormal dietary responses (allergies). T-lymphocyte function is poorly developed at birth. The reduced ability of infants to respond to mitogens may be the result, of the low number of CD45RO+ (memory/antigen-primed). T cells in the infant or the limited ability to produce cytokines [particularly interferon-γ, interleukin (IL)-4, and IL-10]. There have been many important changes in optimizing breast milk substitutes for infants; however, few have been directed at replacing factors in breast milk that convey immune benefits. Recent research has been directed at the neurological, retinal, and membrane benefits of adding 20∶4n−6 (arachidonic acid; AA) and 22∶6n−3 (docosahexaenoic acid; DHA) to infant formula. In addults and animals, feeding DHA affects T-cell function. However, the effect of these lipids on the development and function of the infants immune system is not known. We recently reported the effect of adding DHA+AA to a standard infant formula on several functional indices of immune development. Compared with standard formula, feeding a formula containing DHA+AA increased the proporition of antigen mature (CD45RO+) CD4+ cells, improved IL-10 production, and reduced IL-2 production to levels not different from those of human milk-fed infants. This review will briefly describe T-cell development and the potential immune effect of feeding long-chain polyunsaturated fatty acids to the neonate.

Evaluation of a long-chain polyunsaturated fatty acid supplemented formula on growth, tolerance, and plasma lipids in preterm infants up to 48 weeks postconceptional age

BACKGROUND The last trimester of pregnancy is a period of rapid accretion of long-chain polyunsaturated fatty acids, both in the central nervous system and the body as a whole. Human milk contains these fatty acids, whereas some preterm infant formulas do not. Infants fed formulas without these fatty acids have lower plasma and erythrocyte concentrations than infants fed human milk. Preclinical and clinical studies have demonstrated that single-cell sources (algal and fungal) of long-chain polyunsaturated fatty acids are bioavailable. A balanced addition of fatty acids from these oils to preterm formula results in blood fatty acid concentrations in low birth weight infants comparable to those of infants fed human milk. METHODS In the present study the growth, acceptance (overall incidence of discontinuation, reasons for discontinuation, overall incidence and type of individual adverse events), and plasma fatty acid concentrations were compared in three groups of infants fed a long-chain polyunsaturated fatty acid-supplemented preterm infant formula, an unsupplemented control formula, or human milk. The study was prospective, double-blind (formula groups only), and randomized (formula groups only). Two hundred eighty-eight infants were enrolled (supplemented formula group, n = 77; control formula group, n = 78; human milk group, n = 133). RESULTS Anthropometric measurements at enrollment, at first day of full oral feeding, and at both 40 and 48 weeks postconceptional age did not differ between the formula groups, whereas the human milk-fed group initially grew at a lower rate. The incidence of severe adverse events was rare and not significantly different between formula groups. The groups fed either human milk or supplemented formula had long-chain polyunsaturated fatty acid concentrations higher than those in the control formula group. CONCLUSIONS The results of this study demonstrate the safety and efficacy of a preterm formula supplemented with long-chain polyunsaturated fatty acids from single-cell oils.

Guidelines for the Number of Embryos toTransfer Following In Vitro Fertilization

OBJECTIVE To review the effect of the number of embryos transferred on the outcome of in vitro fertilization (IVF), to provide guidelines on the number of embryos to transfer in IVF-embryo transfer (ET) in order to optimize healthy live births and minimize multiple pregnancies. OPTIONS Rates of live birth, clinical pregnancy, and multiple pregnancy or birth by number of embryos transferred are compared. OUTCOMES Clinical pregnancy, multiple pregnancy, and live birth rates. EVIDENCE The Cochrane Library and MEDLINE were searched for English language articles from 1990 to April 2006. Search terms included embryo transfer (ET), assisted reproduction, in vitro fertilization (IVF), ntracytoplasmic sperm injection (ICSI), multiple pregnancy, and multiple gestation. Additional references were identified through hand searches of bibliographies of identified articles. VALUES Available evidence was reviewed by the Reproductive Endocrinology and Infertility Committee and the Maternal-Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada and the Board of the Canadian Fertility and Andrology Society, and was qualified using the Evaluation of Evidence Guidelines developed by the Canadian Task Force on the Periodic Health Exam. BENEFITS, HARMS, AND COSTS This guideline is intended to minimize the occurrence of multifetal gestation, particularly high-order multiples (HOM), while maintaining acceptable overall pregnancy and live birth rates following IVF-ET.

Effect of providing a formula supplemented with long-chain polyunsaturated fatty acids on immunity in full-term neonates

To determine the effect of feeding formula containing long-chain PUFA (LCP) on immune function, healthy term infants were randomised at age 2 weeks to either a standard term formula (Formula; n 14) or the same formula supplemented with the LCP 20 : 4n-6 and 22 : 6n-3 (Formula+LCP; n 16). Peripheral blood was collected at 2 and 6 weeks to measure immune cell response (the rate of [3H]thymidine uptake and cytokine production after stimulation with phytohaemagglutinin (PHA)). Compared with cells from infants receiving only human milk (HM), the rate of [3H]thymidine uptake in response to PHA, but not IL-2 production, was lower for Formula+LCP infants (P < 0.05). Compared with HM-fed infants, Formula-fed infants (but not Formula+LCP infants) produced more TNF-alpha (unstimulated) and had a fewer CD3+CD44+ cells before stimulation and fewer CD11c+ cells post-stimulation (P < 0.05). However, compared with Formula-fed infants, the Formula+LCP infants had an immune cell distribution (higher percentage CD3+CD44+ and CD4+CD28+ cells) and cytokine profile (lower production of TNF-alpha post-stimulation) that did not differ from HM infants. Additionally, it was found that feeding infants formula during the first 10 d of life influenced immune function. These infants had a higher percentage of CD3+, CD4+CD28+, and lower percentage of CD14+ cells and produced more TNF-alpha and interferon-gamma after PHA stimulation than HM-fed infants (P < 0.05). These results demonstrate that early diet influences both the presence of specific cell types and function of infant blood immune cells. Since many diseases have a strong immunological component, these immune changes may be of physiological importance to the developing infant.

Growth, Efficacy, and Safety of Feeding an Iron-Fortified Human Milk Fortifier

Objective. Survival rates for preterm infants who weigh between 501 and 1500 g at birth have continued to improve over time. In response to this continuing decrease in birth weight of surviving preterm infants, Enfamil Human Milk Fortifier has recently been reformulated to meet the nutritional requirements of these smaller, more rapidly growing infants. It now provides an increased protein level of 1.1 g/58 kJ, a decreased carbohydrate level of 0.2 g/58 kJ, and a combined linoleic and α-linolenic fatty acid content of 157 mg/58 kJ. As these very small preterm infants have an increased requirement for dietary iron, the fortifier has been supplemented with 1.44 mg/58 kJ of iron, an amount of iron similar to that provided in a typical iron-fortified term infant formula. An iron-fortified product obviates the need for administration of an iron supplement, a hyperosmolar-inducing intervention. The purpose of this prospective, double-blind, randomized, controlled study was to evaluate growth, safety, and efficacy in a population of very low birth weight (VLBW) preterm infants who received human milk fortified with either the reformulated iron-fortified powdered human milk fortifier test product (HMF-T) or a powdered commercially available human milk fortifier control product (HMF-C). Methods. Infants who weighed ≤1500 g, had a gestational age ≤33 weeks postmenstrual age, and had an enteral intake of at least 100 mL/kg per day of unfortified human milk were stratified by gender and birth weight and randomized to receive HMF-T or HMF-C product from study day 1 to study day 28, hospital discharge, or the termination of human milk feedings, whichever came first. Unless medically indicated, investigators were not to administer iron supplements from study days 1 to 14. Infants were assessed serially for growth; enteral and parenteral intake; serum chemistry and hematologic values; clinical histories, including the administration of blood transfusions; feeding tolerance; respiratory outcomes; and morbidities, including adverse events. Results. Of the 181 participating infants in this study, 96 received HMF-T and 85 received HMF-C. At randomization, there were no significant differences in infant characteristics between the fortifier groups. The percentage of participants who remained in the study for 28 days was similar between fortifier groups (57% HMF-T, 46% HMF-C). For both fortifier groups, the most frequent reasons for discontinuing the study before study day 28 were unavailability of human milk and hospital discharge. Rate of weight gain was similar between the fortifier groups (17.5 ± 0.53 g/kg per day for HMF-T and 17.3 ± 0.59 g/kg per day for HMF-C). Mean achieved weight, length, and head circumference were comparable between groups across the 28-day study period. Total protein intake from enteral and parenteral nutrition was significantly greater for the HMF-T fortifier group; however, this difference did not result in any difference in growth between the 2 fortifier groups. An analysis of the growth and energy intake data of a subset of the intent-to-treat population who adhered more strictly to the study feeding protocol yielded results similar to those seen for the intent-to-treat population. There were no clinically significant differences in the results of laboratory studies between the groups at study days 0, 14, and 28. Anemia of prematurity was prevalent in both study groups; by study day 28, median hematocrit levels were 27.0% (interquartile range [IQR]: 24.0%–29.6%) for the HMF-T group and 26.0% (IQR: 24.0%–31.0%) for the HMF-C group. Median ferritin levels were 77.0 ng/mL (IQR: 37-155 ng/ml) for HMF-T and 92.0 ng/mL (IQR: 33-110 ng/mL) for HMF-C. There were no significant differences between the study fortifier groups in regard to the receipt of medically indicated iron supplements on or before study day 14 or in the administration of blood transfusions before study day 0 or from study days 0 through 14. However, from study day 15 to study day 28, fewer HMF-T infants (n = 12) required a blood transfusion than did HMF-C infants (n = 20). Although the higher levels of iron in the HMF-T fortifier (1.44 mg vs 0.35 mg for HMF-C per 4 packets of powdered fortifier) did not prevent anemia per se, it did reduce the frequency of one of the most serious outcomes of anemia: the need for a blood transfusion. There was no statistically significant difference between fortifier groups in regard to feeding tolerance. Rates of suspected sepsis (26% HMF-T vs 31% HMF-C) and confirmed sepsis (5% HMF-T, 7% HMF-C) were low as were the rates of suspected necrotizing enterocolitis (NEC; 6% HMF-T and 5% HMF-C) and confirmed Bells stage 2 or more NEC (1% HMF-T and 1% HMF-C). There were no statistically significant differences between the study fortifier groups in regard to the incidence of confirmed and suspected sepsis and NEC. Conclusion. Both human milk fortifiers studied are safe, are well tolerated, and facilitate comparable good growth; however, using the iron-fortified product may reduce the need for blood transfusions in VLBW infants. The similar low rates of suspected and confirmed NEC and sepsis seen in both fortifier groups in this study refutes the premise that the inclusion of iron in fortifiers will increase the incidence of sepsis and NEC. Indeed, the incidence for NEC and sepsis for both groups in this study was lower than is reported for VLBW infants and similar to that seen for infants who are fed human milk.

Total parenteral nutrition impairs bile flow and alters bile composition in newborn piglet

Cholestatic liver disease complicates total parenteral nutrition (TPN) in premature neonates. We investigated TPN-induced liver disease in the newborn piglet, hypothesizing that: (1) TPN impairs bile flow by reducing the bile acid-dependent (BADF) and the bile acid-independent component of bile flow (BAIF); and (2) TPN changes bile composition. For three weeks, eight piglets received TPN and nine piglets were fed milk. Basal bile flow was measured and bile composition analyzed for bile acids, cholesterol (C), phospholipids (PL), and PL fatty acids. Bile flow was also measured after stimulation with 20, 50, and 100 µmol/kg taurocholic acid (TCA). Liver histology and bilirubin content were examined. Basal bile flow was reduced from 11.6±1.2 µl/g liver/10 min in orally fed animals to 1.6±0.4 µl/g liver/10 min in the TPN group. The stimulated bile flow in the TPN group did not respond to TCA and was lower than in the orally fed animals at each TCA dose. Both BADF and BAIF were significantly lower in the TPN group. Bile acid secretion was less than 50% of control values and total C and PL secretions were less than 5% of control. Liver and serum bilirubin were elevated in the TPN group. The newborn piglet is a valid model to study TPN-induced cholestasis, characterized by decreased bile acid secretion, impaired BADF and BAIF, and reduced bile flow stimulation after intravenous TCA.

Pre-treatment with an intravenous lipid emulsion containing fish oil (eicosapentaenoic and docosahexaenoic acid) decreases inflammatory markers after open-heart surgery in infants: a randomized, controlled trial.

BACKGROUND & AIMS This study assessed the effects of administering a lipid emulsion containing eicosapentaenoic and docosahexaenoic acid before and after open-heart surgery on cytokine production and length of hospital stay in infants. METHODS Thirty-two infants (40 ± 2.3 weeks gestational age; 10.6 days at time of surgery) undergoing open-heart surgery with cardiopulmonary bypass were randomized to receive an intravenous lipid emulsion with (treatment) or without (control) eicosapentaenoic and docosahexaenoic acid in this prospective, randomized, double-blind, controlled trial. RESULTS Mean plasma TNF-α concentration was significantly (p = 0.003) lower in the treatment (5.9 pg/mL) compared to the control group (14.8 pg/mL). In infants without sepsis, plasma TNF-α did not differ according to treatment, however when sepsis developed, mean plasma TNF-α was 21.1 pg/mL and 1.5 pg/mL (p = 0.0007) in control and treatment groups, respectively. Plasma TNF-α was positively correlated with length of hospital stay in the control group (p = 0.01), and negatively correlated with length of stay in the treatment group (p = 0.004), with a significant time by treatment interaction (p = 0.02). CONCLUSIONS Providing a lipid emulsion containing eicosapentaenoic and docosahexaenoic acid reduces TNF-α concentrations in infants undergoing open-heart surgery. Lipid emulsions containing eicosapentaenoic and docosahexaenoic acid may ameliorate the inflammatory response among critically ill infants.

Low Energy Intakes Are Associated With Adverse Outcomes in Infants After Open Heart Surgery

BACKGROUND Infants with congenital heart lesions who undergo open heart surgery may experience physiologic and metabolic stress in the postoperative period, leading to altered metabolism and hypercatabolism. The purpose of this study was to determine the relationship between energy intake and hospital outcomes during the first 10 days following neonatal open heart surgery. MATERIALS AND METHODS A post hoc analysis of all patients in a prospective randomized controlled trial was performed. Nutrition intake and hospital outcomes were assessed in 32 infants (40 ± 2.2 weeks, 3.4 ± 0.5 kg) in the neonatal and pediatric intensive care units. Infants received parenteral nutrition (PN) for 1-4 days before and 10 days after open heart surgery. Infants were separated into those who received a cumulative energy intake of <689 kcal (average 63 kcal/kg/d) and those who received an intake ≥689 kcal during postoperative days 0-10. RESULTS Lower energy intake was associated with a significantly increased duration of artificial ventilation (5 ± 1.2 days), time to chest closure (1.4 ± 0.5 days), time in intensive care (5 ± 1.8 days), and stay in the hospital (25 ± 6.4 days). Lower energy intake was also associated with a significant increase in the length of time infants required PN (8 ± 2.9 days) and longer time to achieve full enteral intake of 100 mL/kg/d (7 ± 2.2 days) and before enteral feeds could be initiated (5 ± 1.5 days). CONCLUSIONS Providing <63 kcal/kg/d to infants after open heart surgery was associated with adverse pediatric intensive care outcomes.