Pieter J. J. Sauer

Prenatal Exposure to Organohalogens, Including Brominated Flame Retardants, Influences Motor, Cognitive, and Behavioral Performance at School Age

Background Organohalogen compounds (OHCs) are known to have neurotoxic effects on the developing brain. Objective We investigated the influence of prenatal exposure to OHCs, including brominated flame retardants, on motor, cognitive, and behavioral outcome in healthy children of school age. Methods This study was part of the prospective Groningen infant COMPARE (Comparison of Exposure-Effect Pathways to Improve the Assessment of Human Health Risks of Complex Environmental Mixtures of Organohalogens) study. It included 62 children in whose mothers the following compounds had been determined in the 35th week of pregnancy: 2,2′-bis-(4 chlorophenyl)-1,1′-dichloroethene, pentachlorophenol (PCP), polychlorinated biphenyl congener 153 (PCB-153), 4-hydroxy-2,3,3′,4′,5-pentachlorobiphenyl (4OH-CB-107), 4OH-CB-146, 4OH-CB-187, 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), BDE-99, BDE-100, BDE-153, BDE-154, and hexabromocyclododecane. Thyroid hormones were determined in umbilical cord blood. When the children were 5–6 years of age, we assessed their neuropsychological functioning: motor performance (coordination, fine motor skills), cognition (intelligence, visual perception, visuomotor integration, inhibitory control, verbal memory, and attention), and behavior. Results Brominated flame retardants correlated with worse fine manipulative abilities, worse attention, better coordination, better visual perception, and better behavior. Chlorinated OHCs correlated with less choreiform dyskinesia. Hydroxylated polychlorinated biphenyls correlated with worse fine manipulative abilities, better attention, and better visual perception. The wood protective agent (PCP) correlated with worse coordination, less sensory integrity, worse attention, and worse visuomotor integration. Conclusions Our results demonstrate for the first time that transplacental transfer of polybrominated flame retardants is associated with the development of children at school age. Because of the widespread use of these compounds, especially in the United States, where concentrations in the environment are four times higher than in Europe, these results cause serious concern.

The very low birth weight premature infant is capable of synthesizing arachidonic and docosahexaenoic acids from linoleic and linolenic acids.

Infants fed formulas devoid of long-chain polyunsaturated fatty acids (LCP) exhibit low plasma LCP concentrations and have poorer retinal and neurologic development in comparison with their human milk-fed counterparts. It is not known whether the low plasma LCP concentrations result from an impaired biosynthetic capacity, a high need, or a low dietary intake. With stable isotope technology and high sensitivity tracer detection using gas chromatography-isotope ratio mass spectrometry we measured the conversion of[13C]linoleic acid (C18:2n-6) and [13C]linolenic acid (C18:3n-3) into their longer chain derivatives in five 1-mo-old formula-fed preterm infants (birth weight 1.17 ± 0.12 kg and gestational age 28.4 ± 1.3 wk). Carbon-13-labeled linoleic acid and inolenic were mixed with the formula and administered continuously for 48 h. Both tracers were rapidly incorporated in plasma phospholipids, and their metabolic products including arachidonic acid (C20:4n-6) and docosahexaenoic acid (C22:6n-3) became highly enriched. We demonstrate that the preterm infant is capable of synthesizing LCP from their 18-carbon precursors, and our data do not support the hypothesis that a reduced δ6 desaturation is a main factor leading to low arachidonic acid and docosahexaenoic acid levels.

Immunologic Effects of Background Prenatal and Postnatal Exposure to Dioxins and Polychlorinated Biphenyls in Dutch Infants

ABSTRACT: Immunologic effects of pre- and postnatal polychlorinated biphenyl (PCB)/dioxin exposure in Dutch infants from birth to 18 mo of age are explored. The total study group consisted of 207 healthy mother-infant pairs, of which 105 infants were breast-fed and 102 children were bottle-fed. Prenatal PCB exposure was estimated by the PCB sum (PCB congeners 118, 138, 153, and 180) in maternal blood and the total toxic equivalent (TEQ) level in human milk (17 dioxin and 8 dioxin-like PCB congeners). Postnatal PCB/dioxin exposure was calculated as a product of the total TEQ level in human milk multiplied by the weeks of breast-feeding. The number of periods with rhinitis, bronchitis, tonsillitis, and otitis during the first 18 mo of life was used as an estimate of the health status of the infants. Humoral immunity was measured at 18 mo of age by detecting antibody levels to mumps, measles, and rubella. White blood cell counts (monocytes, granulocytes, and lymphocytes) and immunologic marker analyses CD4+ T-lymphocytes, CD8+ T-lymphocytes, activated T-lymphocytes (HLA-DR+CD3+), as well as T cell receptor (TcR) αβ+, TcRγδ+, CD4+CD45RA+ and CD4+CD45RO+ T-lymphocytes, B-lymphocytes (CD19+ and/or CD20+) and NK cells (CD16+ and/or CD56+/CD3−) in cord blood and venous blood at 3 and 18 mo of age were assessed in a subgroup of 55 infants. There was no relationship between pre-and postnatal PCB/dioxin exposure and upper or lower respiratory tract symptoms or humoral antibody production. A higher prenatal PCB/ dioxin exposure was associated with an increase in the number of TcRγδ+ T cells at birth and with an increase in the total number of T cells and the number of CD8+ (cytotoxic), TcRαβ+, and TcRγδ+ T cells at 18 mo of age. A higher prenatal as well as postnatal PCB/dioxin exposure was associated with lower monocyte and granulocyte counts at 3 mo of age. In conclusion, our study suggests that background levels of PCB/dioxin exposure influences the human fetal and neonatal immune system.

Structural position and amount of palmitic acid in infant formulas: Effects on fat, fatty acid, and mineral balance

The structure of the triglycerides (TG) in human milk (HM) differs from those of vegetable oils used in infant formulas. In HM, palmitic acid is predominantly esterified to the center or beta-position of the TG, in vegetable oil, it is mainly at the external or alpha-positions. These differences in configuration affect intestinal fat absorption. Fat and mineral balances were investigated in three groups of 9 healthy term infants aged 5 weeks. Infants were randomly assigned to receive one of the three study formulas from birth: (a) formula beta, resembling the structure of HM fat most closely (24% palmitic acid, 66% esterified to beta-position), (b) formula intermediate (24% palmitic acid, 39% esterified to the beta-position), and (c) regular formula (20% palmitic acid; 13% esterified to the beta-position). Fat absorption was highest in infants fed the beta formula (97.6 +/- 0.9%), intermediate in those fed with the intermediate formula (93.0 +/- 1.8%), and lowest in infants receiving the regular formula (90.4 +/- 4.6%). Fecal calcium excretion was significantly lower in the beta group than in the other two groups (43.3 +/- 18.1 vs. 59.9 +/- 15.1 vs. 68.4 +/- 22.3 mg.kg-1.day-1 for beta, intermediate, and regular respectively). Dietary TG containing palmitic acid predominantly at the beta-position, as in HM, have significant beneficial effects on the intestinal absorption of fat and calcium in healthy term infants.

A 12-Week Aerobic Exercise Program Reduces Hepatic Fat Accumulation and Insulin Resistance in Obese, Hispanic Adolescents

The rise in obesity‐related morbidity in children and adolescents requires urgent prevention and treatment strategies. Currently, only limited data are available on the effects of exercise programs on insulin resistance, and visceral, hepatic, and intramyocellular fat accumulation. We hypothesized that a 12‐week controlled aerobic exercise program without weight loss reduces visceral, hepatic, and intramyocellular fat content and decreases insulin resistance in sedentary Hispanic adolescents. Twenty‐nine postpubertal (Tanner stage IV and V), Hispanic adolescents, 15 obese (7 boys, 8 girls; 15.6 ± 0.4 years; 33.7 ± 1.1 kg/m2; 38.3 ± 1.5% body fat) and 14 lean (10 boys, 4 girls; 15.1 ± 0.3 years; 20.6 ± 0.8 kg/m2; 18.9 ± 1.5% body fat), completed a 12‐week aerobic exercise program (4 × 30 min/week at ≥70% of peak oxygen consumption (VO2peak)). Measurements of cardiovascular fitness, visceral, hepatic, and intramyocellular fat content (magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS)), and insulin resistance were obtained at baseline and postexercise. In both groups, fitness increased (obese: 13 ± 2%, lean: 16 ± 4%; both P < 0.01). In obese participants, intramyocellular fat remained unchanged, whereas hepatic fat content decreased from 8.9 ± 3.2 to 5.6 ± 1.8%; P < 0.05 and visceral fat content from 54.7 ± 6.0 to 49.6 ± 5.5 cm2; P < 0.05. Insulin resistance decreased indicated by decreased fasting insulin (21.8 ± 2.7 to 18.2 ± 2.4 µU/ml; P < 0.01) and homeostasis model assessment of insulin resistance (HOMAIR) (4.9 ± 0.7 to 4.1 ± 0.6; P < 0.01). The decrease in visceral fat correlated with the decrease in fasting insulin (R2 = 0.40; P < 0.05). No significant changes were observed in any parameter in lean participants except a small increase in lean body mass (LBM). Thus, a controlled aerobic exercise program, without weight loss, reduced hepatic and visceral fat accumulation, and decreased insulin resistance in obese adolescents.

Strength exercise improves muscle mass and hepatic insulin sensitivity in obese youth.

INTRODUCTION Data on the metabolic effects of resistance exercise (strength training) in adolescents are limited. PURPOSE The objective of this study was to determine whether a controlled resistance exercise program without dietary intervention or weight loss reduces body fat accumulation, increases lean body mass, and improves insulin sensitivity and glucose metabolism in sedentary obese Hispanic adolescents. METHODS Twelve obese adolescents (age = 15.5 ± 0.5 yr, body mass index = 35.3 ± 0.8 kg·m; 40.8% ± 1.5% body fat) completed a 12-wk resistance exercise program (two times 1 h·wk, exercising all major muscle groups). At baseline and on completion of the program, body composition was measured by dual-energy x-ray absorptiometry, abdominal fat distribution was measured by magnetic resonance imaging, hepatic and intramyocellular fat was measured by magnetic resonance spectroscopy, peripheral insulin sensitivity was measured by the stable-label intravenous glucose tolerance test, and hepatic insulin sensitivity was measured by the hepatic insulin sensitivity index = 1000/(GPR × fasting insulin). Glucose production rate (GPR), gluconeogenesis, and glycogenolysis were quantified using stable isotope gas chromatography/mass spectrometry techniques. RESULTS All participants were normoglycemic. The exercise program resulted in significant strength gain in both upper and lower body muscle groups. Body weight increased from 97.0 ± 3.8 to 99.6 ± 4.2 kg (P < 0.01). The major part (∼80%) was accounted for by increased lean body mass (55.7 ± 2.8 to 57.9 ± 3.0 kg, P ≤ 0.01). Total, visceral, hepatic, and intramyocellular fat contents remained unchanged. Hepatic insulin sensitivity increased by 24% ± 9% (P < 0.05), whereas peripheral insulin sensitivity did not change significantly. GPR decreased by 8% ± 1% (P < 0.01) because of a 12% ± 5% decrease in glycogenolysis (P < 0.05). CONCLUSIONS We conclude that a controlled resistance exercise program without weight loss increases strength and lean body mass, improves hepatic insulin sensitivity, and decreases GPR without affecting total fat mass or visceral, hepatic, and intramyocellular fat contents.

Effects of prenatal exposure to betamethasone and indomethacin on the glomerular filtration rate in the preterm infant.

ABSTRACT: The effects of gestational age (GA), body weight, and prenatal exposure to betamethasone and indomethacin on the glomerular filtration rate (GFR) on d 3 of life in preterm infants were studied. GFR measurements were performed in 147 preterm infants with a GA between 23.4 and 37.0 wk by means of the continuous inulin infusion technique. Mean GFR values increased significantly with GA (r = 0.60, p < 0.001) and with body weight (r = 0.44, p < 0.001). Multivariate analysis indicated that GA was the most important determinant for this increase. Prenatal exposure to indomethacin resulted in significantly lower GFR values (-0.15 ± 0.03 mL/min, p < 0.001) at d 3 after birth. Prenatal administration of betamethasone and indomethacin significantly (p < 0.001) increased the GFR in comparison with exposure to indomethacin alone to levels not different than those seen in patients who were not prenatally exposed to betamethasone or indomethacin. GFR measurements were repeated in 40 preterm infants on d 10 after birth. During this 7-d period, a significant increase in GFR values (0.17 ± 0.03 mL/min, p < 0.001) was detected. This postnatal increase in GFR values was independent of GA and was not influenced by prenatal exposure to betamethasone or indomethacin. We conclude that prenatal exposure to betamethasone or indomethacin exerts significant effects on the renal function of preterm infants in the first days of life.

Association between depressive symptoms in childhood and adolescence and overweight in later life : review of the recent literature

OBJECTIVE To present an overview of the association between depressive symptoms in childhood and adolescence and subsequent overweight in later life. DATA SOURCES MEDLINE, EMBASE, and Web of Science for all indexed journals from January 1, 1997, to May 30, 2007. STUDY SELECTION Abstracts of 513 articles were reviewed manually. Studies were excluded if unrelated to depressive symptoms and overweight (n = 460), if they were conducted in an adult population (n = 10) or in a population of all age groups (n = 2), or if they were performed in clinic-based populations of overweight participants. In total, 32 articles were reviewed including 21 cross-sectional and 11 longitudinal reports. Main Exposure Depressive symptoms in childhood and adolescence. Main Outcome Measure Overweight. RESULTS Four cross-sectional studies that satisfied our quality criteria revealed an association between depressive symptoms and overweight in girls aged 8 to 15 years, reporting different effect sizes including a correlation coefficient of 0.14 and a regression coefficient of 0.27. Four longitudinal studies in accord with our quality criteria suggest that depressive symptoms in childhood or adolescence are associated with a 1.90- to 3.50-fold increased risk of subsequent overweight (95% confidence intervals varying from 1.02 to 5.80, respectively). CONCLUSION These results support a positive association between depressive symptoms at age 6 to 19 years and overweight in later life, assessed after a period of 1 to 15 years.

Plasma and Red Blood Cell Fatty Acid of Very Low Birth Weight Infants Fed Exclusively with Expressed Preterm Human Milk

The fatty acid composition of plasma phospholipids, triglycerides, sterol esters, and red blood cell phospholipids were determined at birth and again on d 7, 14, and 28 of life in 22 very low birth weight infants (birth weight 1180± 290 g, gestational age 29.8 ± 2.4 wk) fed exclusively with preterm human milk starting from the first hours postpartum. Milk intake was recorded daily, and intakes of fat and individual fatty acids were measured weekly. The intakes of linoleic acid and linolenic acid rose significantly during the study period, so did their incorporation into plasma and red blood cell lipids. The intakes of arachidonic acid (29.2 ± 2.4versus 30.4 ± 2.1 mg·kg-1·day-1) and docosahexaenoic acid (18.8 ± 1.7 versus 17.0 ± 1.2 mg·kg-1·day-1) on d 14 and 28, respectively, were not different; however, their plasma levels declined significantly. The percentages of arachidonic acid declined in all plasma and red blood cell lipids, whereas the fall of docosahexaenoic acid was more notable in triglycerides and sterol esters, intermediate in plasma phospholipids, and less pronounced in red blood cell phospholipids. We conclude that very low birth weight infants fed exclusively with preterm milk, which unlike most preterm formulas contains long chain polyunsaturated fatty acids, exhibit declining levels of arachidonic acid and docosahexaenoic acid from birth up to 28 d of life.

Physician Medical Decision-making at the End of Life in Newborns: Insight Into Implementation at 2 Dutch Centers

OBJECTIVE. Decisions regarding end-of-life care in critically ill newborns in the Netherlands have received considerable criticism from the media and from the public. This might be because of a lack of proper information and knowledge. Our purpose was to provide detailed information about how and when the implementation of end-of-life decisions, which are based on quality-of-life considerations, takes place. METHODS. We reviewed the charts of all infants who died within the first 2 months of life at 2 university hospitals in the Netherlands from January to July 2005 and extracted all relevant information about the end-of-life decisions. We interviewed the responsible neonatologists about the end-of-life decisions and the underlying quality-of-life considerations and about the process of implementation. RESULTS. Of a total of 30 deaths, 28 were attributable to withholding or withdrawing life-sustaining treatment. In 18 of 28 cases, the infant had no chance to survive; in 10 cases, the final decision was based on the poor prognosis of the infant. In 6 patients, 2 successive different end-of-life decisions were made. The arguments that most frequently were used to conclude that quality of life was deemed poor were predicted suffering and predicted inability of verbal and nonverbal communication. Implementation consisted of discontinuation of ventilatory support and alleviation of pain and symptoms. Neuromuscular blockers were added shortly before death in 5 cases to prevent gasping, mostly on parental request. CONCLUSIONS. The majority of deaths were attributable to withholding or withdrawing treatment. In most cases, the newborn had no chance to survive and prolonging of treatment could not be justified. In the remaining cases, withholding or withdrawing treatment was based on quality-of-life considerations, mostly the predicted suffering and predicted inability of verbal and nonverbal communication. Potentially life-shortening medication played a minor role as a cause of death.