[Questionable basis for 'hopeless and unbearable suffering' as the criterion for the active termination of life in newborns with spina bifida].
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Decision Making↗
Biomedical subjects
P J Sauer
Publications and source records attributed to P J Sauer.
[Deliberate termination of life in newborns in The Netherlands; review of all 22 reported cases between 1997 and 2004].
OBJECTIVE: To gain insight into the reporting and assessment of active termination of life in newborns in The Netherlands. DESIGN; Retrospective. METHOD: Data on all cases of deliberate termination of life in newborns up to the age of 6 months, reported to the public prosecutor as from 1997 onward, were collected and compared. RESULTS: In January 1997-June 2004, 22 cases of deliberate termination of life in newborns were reported. All cases concerned newborns with spina bifida and hydrocephalus. Deliberate termination of life was acceptable to the physicians because of the presence of hopeless suffering, with no means of alleviating the suffering. In all cases, at least 2 doctors were consulted outside the medical team. In 17 of 22 cases, a multidisciplinary spina bifida team was consulted. All parents consented to the termination of life; in 4 cases they explicitly requested it. In 14 cases a combination of analgesics, sedatives and paralyzing drugs were used, in 8 cases only analgesics and sedatives were administered. For the public prosecutor the termination of life was acceptable if 4 requirements were properly fulfilled: the presence of hopeless and unbearable suffering, consent of the parents to termination of life, consultation having taken place and a careful execution ofthe termination. The mean time between reporting of the case and the decision concerning prosecution was 5.3 months. None of the cases led to prosecution. CONCLUSION: Three cases of deliberate termination of life in newborns were reported in The Netherlands annually. The public prosecutor used fixed criteria to assess the case and all cases of active termination of life reported were found to be in accordance with good practice.
Decision Making↗
[Breast feeding during the first few days after birth: sometimes insufficient].
Two newborn infants that were receiving breast-feeding were admitted to hospital for drowsiness and jaundice on the 6th and 4th day of life, respectively; these were a male infant that had been yellow since the very first day and a female infant that did not grasp the breast properly. Both recovered thanks to phototherapy and the administration of extra fluids. Seven days after discharge, the female infant was readmitted for the same symptoms, after which the breast-feeding was found to be insufficient and the infant was put on bottle-feeding. In infants that are being breast-fed, insufficient intake can result in dehydration with all of its consequences. Such insufficient intake may be difficult to recognise. Weight loss greater than 5% implies that more frequent feeding is necessary and a loss of more than 10% may mean that supplementary feeding is necessary, albeit temporarily.
Birth Weight↗
Ethical dilemmas in neonatology: recommendations of the Ethics Working Group of the CESP (Confederation of European Specialists in Paediatrics).
Neonatal intensive care has greatly improved the survival chances of a very sick infant. At the same time, it has also given rise to serious ethical problems. In all circumstances, however, parents and paediatricians and other healthcare team workers should continuously evaluate together what is in the best interest of the infant and react accordingly. It is also clear that the principle "the best interests of the infant" can be interpreted in different ways; therefore no simple guideline is possible.
Critical Care↗
Neurological outcome in school-age children after in utero exposure to coumarins.
The effect of prenatal exposure to coumarins (acenocoumarol, phenprocoumon) on neurological outcome was assessed in a cohort of 306 children aged 7-15 years. Findings were compared with those in a non-exposed cohort of 267 children, matched for sex, age, and demographic region. We used a neurological examination technique which pays special attention to minor neurological dysfunction (MND). None of the children was found to be neurologically abnormal. However, exposure to coumarins during gestation increases the risk for MND in children of school age, odds ratio (OR) 1.9 (CI(95) 1.1-3.4), predominantly after exposure in the second or third trimester, odds ratio 2.1 (CI(95) 1.2-3.8). We found a dose-response relationship with an odds ratio of 1.2 (CI(95) 1.0-1.5) per mg coumarin derivative prescribed per day. The results suggest that coumarins have an influence on the development of the brain which can lead to mild neurological dysfunctions in children of school age.
Acenocoumarol↗
Estimation of gluconeogenesis in newborn infants.
The rate of glucose turnover (R(a)) and gluconeogenesis (GNG) via pyruvate were quantified in seven full-term healthy babies between 24 and 48 h after birth and in twelve low-birth-weight infants on days 3 and 4 by use of [(13)C(6)]glucose and (2)H(2)O. The preterm babies were receiving parenteral alimentation of either glucose or glucose plus amino acid with or without lipids. The contribution of GNG to glucose production was measured by the appearance of (2)H on C-6 of glucose. Glucose R(a) in full-term babies was 30 +/- 1.7 (SD) micromol. kg(-1). min(-1). GNG via pyruvate contributed approximately 31% to glucose R(a). In preterm babies, the contribution of GNG to endogenous glucose R(a) was variable (range 6-60%). The highest contribution was in infants receiving low rates of exogenous glucose infusion. In an additional group of infants of normal and diabetic mothers, lactate turnover and its incorporation into glucose were measured within 4-24 h of birth by use of [(13)C(3)]lactate tracer. The rate of lactate turnover was 38 micromol. kg(-1). min(-1), and lactate C, not corrected for loss of tracer in the tricarboxylic acid cycle, contributed approximately 18% to glucose C. Lactate and glucose kinetics were similar in infants that were small for their gestational age and in normal infants or infants of diabetic mothers. These data show that gluconeogenesis is evident soon after birth in the newborn infant and that, even after a brief fast (5 h), GNG via pyruvate makes a significant contribution to glucose production in healthy full-term infants. These data may have important implications for the nutritional support of the healthy and sick newborn infant.
Amino Acids↗
Leucine kinetics during simultaneously administered insulin and dexamethasone in preterm infants with severe lung disease.
The objective of this study was to determine whether insulin administration would prevent the well-documented catabolic effect of dexamethasone given to preterm infants with chronic lung disease. We studied leucine metabolism in 11 very-low-birth-weight infants before dexamethasone treatment and on d 2, 4, and 7 thereafter. During the first 4 d of dexamethasone, insulin was administered i.v. at a dose of 0.5 (n = 7) or 1.0 (n = 5) IU/kg/d. Leucine turnover was not significantly different between d 0 (337 +/- 41.3 micromol leucine/kg/h), d 2 (288 +/- 27.2 micromol leucine/kg/h), d 4 (302 +/- 22.1 micromol leucine/kg/h), and d 7 (321 +/- 21.2 micromol leucine/kg/h), and neither was leucine breakdown (272 +/- 21.9 micromol leucine/kg/h on d 0, 225 +/- 21.5 micromol leucine/kg/h on d 2, 231 +/- 21 micromol leucine/kg/h on d 4, and 242 +/- 17.6 micromol leucine/kg/h on d 7). Weight gain rates were significantly lower during the first week of dexamethasone treatment compared with the week before treatment or the second and third week. We conclude that during insulin and corticosteroid administration in very-low-birth-weight infants, no changes were observed in leucine kinetics in contrast to previous studies. The decrease in weight gain was not reversed.
Anti-Inflammatory Agents↗
Postprandial chylomicron clearance rate in late teenagers with diabetes mellitus type 1.
A delayed chylomicron (CM) clearance rate, a known risk factor for atherosclerosis, has been described in adults with diabetes type 1 (DM1). We determined the CM clearance rate in late teenagers with DM1, and the relationship between CM clearance rate and elevated plasma lipid concentrations in DM1 teenagers in poor metabolic control (as characterized by HbA(1c) percentage). Plasma lipids and CM clearance were determined in nine patients with DM1 (mean age +/- SD: 17.5 +/- 0.6 y) and four healthy controls (mean age +/- SD: 20.1 +/- 0.8 y), by measuring breath (13)CO(2), plasma triglyceride, retinyl palmitate, and (13)C-labeled oleic acid concentrations, after oral administration of a fat-rich meal together with vitamin A and (13)C-oleic acid. In patients with DM1, fasting triglyceride and cholesterol concentrations were positively correlated with HbA(1c) percentage (p < 0.05). Neither in DM1 patients, nor in controls, was an elevated triglyceride concentration (above 1.7 mmol/L) found. Yet, in 22% of DM1 patients, cholesterol concentration was above 5.2 mmol/L, but not in any of the controls. CM clearance rate in DM1 patients was similar to that in controls and did not significantly correlate with HbA(1c) percentage. Fasting lipid concentrations in DM1 patients were not significantly correlated with CM clearance rate. Present data indicate that elevated lipid concentrations in late teenagers with DM1 are not attributable to a delay in CM clearance rate. A delayed CM clearance rate at late teenager age is not a risk factor contributing to the increased risk for atherosclerosis in DM1.
Adolescent↗
In utero exposure to coumarins and cognition at 8 to 14 years old.
OBJECTIVE: To assess the cognitive abilities in school-aged children who have been exposed to coumarins in utero. BACKGROUND: Coumarin derivatives are an effective option for anticoagulant therapy in pregnant women. However, case reports describe anomalies of the fetal central nervous system after in utero exposure to coumarins. It is unclear whether prenatal exposure has an effect on cognitive functioning later in childhood. METHODS: The exposed cohort consisted of 291 children from mothers who were prospectively registered because of coumarin treatment during pregnancy. The nonexposed cohort included 253 age-matched peers. An IQ was estimated using subtests of the Weschler Intelligence Scale for Children-Revised. Educational achievement was examined with tests for reading, spelling, and arithmetic. In addition, schoolteachers were asked to judge performance on language and arithmetic. The observers were not aware of the exposure status of the child. RESULTS: No differences in mean IQ were found between the exposed and nonexposed cohort (mean difference: -1.1; 95% confidence interval [CI]: -3.2-1.1), but an IQ score below 80 was found in 11 children in the exposed compared with 3 children in the nonexposed cohort (odds ratio [OR] = 3.1; CI: 0.8-11.6). Regarding the tests for educational achievement, exposed children as a group performed as well as nonexposed controls. Exposed boys, in comparison with nonexposed boys, showed a higher frequency of poor performance on reading (OR = 2.9; CI: 1.1-7.4) and spelling (OR = 2.5; CI: 1.0-6.0). CONCLUSION: Cognitive functioning in coumarin-exposed children does not differ from nonexposed controls, but a minority of children seem to be prone to the potential negative effects of coumarins during pregnancy.
Adolescent↗
Coumarins during pregnancy: long-term effects on growth and development of school-age children.
Anticoagulation during pregnancy is complicated because of potential risks for mother and foetus. Unfractionated or low-molecular-weight heparin is used for most anticoagulant indications. Its efficacy, however, in pregnant women with prosthetic heart valves is questioned, therefore coumarins are preferred for this indication. We studied long-term effects of prenatal coumarin-exposure on growth and on neurological, behavioural and cognitive development in 274 school-age children in comparison with 231 age-matched non-exposed controls. No major abnormalities were found. The exposed children had an increased risk for minor neurological dysfunction and for a low intelligence quotient (IQ below 80). The risk for a combination of two or more (minor) abnormalities was higher for the exposed children, RR = 7.6. We conclude that prenatal exposure to coumarins is associated with an increased risk for disturbances in development in school-age children. However, for the vast majority of children there is no clinical significant effect on growth and long-term development.
Abnormalities, Drug-Induced↗
Measurement of parameters of cholic acid kinetics in plasma using a microscale stable isotope dilution technique: application to rodents and humans.
A stable isotope dilution method is described that allows measurement of cholic acid (CA) kinetics, that is, pool size, fractional turnover rate (FTR), and synthesis rate in mice, rats, and humans. Decay of administered [2,2,4,4-2H4]CA enrichment was measured in time in 50-microl plasma samples by gas-liquid chromatography/electron capture negative chemical ionization-mass spectrometry, applying the pentafluorobenzyl-trimethylsilyl derivative. The kinetic data expressed species-dependent differences. The CA pool sizes were 16.8 +/- 2.1, 10.6 +/- 1.2, and 2.4 +/- 0.7 micromol/100 g body weight for mice, rats, and humans, respectively. The FTR values were 0.44 +/- 0.03, 0.88 +/- 0.10, and 0.46 +/- 0.14 per day for mice, rats, and humans. The corresponding synthesis rates were 7.3 +/- 1.6, 9.3 +/- 0.1, and 1.0 +/- 0.2 micromol/100 g body weight per day. The human data agreed well with literature data obtained by conventional isotope dilution techniques. For rats and mice these are the first reported isotope dilution data. The method was validated by confirmation of isotopic equilibrium between biliary CA and plasma CA in the rat. Its applicability was demonstrated by the observation of increased CA FTR and CA synthesis rate in rats fed cholestyramine, which is known to increase fecal bile acid excretion. The presented stable isotope dilution method enables the determination of CA kinetic parameters in small plasma samples. The method can be applied in unanesthetized rodents with an intact enterohepatic circulation and may also be valuable when studying the development of human neonatal bile acid kinetics.
Adult↗
Growth until puberty after in utero exposure to coumarins.
Anticoagulation with coumarins is an effective therapy during pregnancy. Fetal exposure to coumarin derivatives during the first trimester, however, is associated with skeletal anomalies (warfarin or coumarin embryopathy). Information about long-term effects of prenatal coumarin exposure on the skeletal development is not available. We investigated growth and body proportions at school age of children exposed to coumarins in utero. A blind population-based cohort study was conducted on 307 exposed children and 267 non-exposed controls ages 8-15 years. The exposed cohort was based on a prospective registry of coumarin-treated pregnant women. Anthropometric data included height, weight, head circumference, and measurements to evaluate body proportions. The mean height of exposed children did not differ from that of the non-exposed children (mean difference 0.01 SD). In addition, no differences were found for the proportional measures. As a group, children exposed in the first trimester showed no evidence of growth impairment. Two children in this group, however, were born with signs of coumarin embryopathy and one of these displayed a deficit in height at school age. Long-term growth was not affected by a high cumulative dosage or exposure after the first trimester. We conclude that, when exposure during the first trimester is avoided, coumarin therapy during pregnancy has no demonstrable risk for the child's skeletal development.
Abnormalities, Drug-Induced↗
The contribution of newly synthesized cholesterol to bile salt synthesis in rats quantified by mass isotopomer distribution analysis.
A new stable isotope procedure has been developed and validated in rats, applying [1-(13)C]acetate infusion to quantify the production of bile salts from de novo synthesized cholesterol making use of the mass isotopomer distribution analysis (MIDA) principle. Ions (m/z) 458-461, 370-373 and 285-288 were monitored by GC/MS (EI-mode) for the methyl trimethylsilylether derivatives of cholate, chenodeoxycholate and beta-muricholate, respectively. Rats with intact exteriorized enterohepatic circulation and rats with chronic bile diversion were infused with [1-(13)C]acetate for up to 14 h. After 10 h of infusion the enterohepatic circulation of the intact group was interrupted to deplete the existing bile salt pool (acute bile diversion). The fractions of biliary cholesterol and individual bile salts derived from newly synthesized cholesterol were determined by MIDA at t=14 h. In rats with acute bile diversion, these fractions were 20, 25, 27 and 23% for biliary cholesterol, cholate, chenodeoxycholate and beta-muricholate, respectively. After bile diversion for 8 days to induce hepatic cholesterol and bile salt synthesis, these fractions increased significantly to 32, 47, 41 and 47%, respectively. Calculated enrichments of the acetyl-CoA precursor pools were similar for all bile salts and biliary cholesterol within the two rat groups. However, chronic enterohepatic interruption decreased the acetyl-CoA pool size almost two-fold. We conclude that MIDA is a validated new stable isotope technique for studying the synthetic pathway from acetyl-CoA to bile salts. This technique provides an important new tool for studying bile salt metabolism in humans using stable isotopes.
Animals↗
Behavioural outcome of school-age children after prenatal exposure to coumarins.
In utero exposure to coumarin derivatives may affect the development of the central nervous system of the child, irrespective of the period of exposure in pregnancy. Little is known about effects on development in the long term. The aim of the present study was to determine whether prenatal exposure to coumarins affects behavioural outcome in children at school age. Behavioural outcome was assessed in a cohort of 305 exposed children, aged 7-15 years. Findings were compared with those in a cohort of 263 non-exposed controls, matched for sex, age, and demographic region. Behaviour was rated by parents and teachers using standardized questionnaires: the Groningen Behaviour Checklist Family situation (GBF) and the Groningen Behaviour Checklist School situation (GBS), respectively. The findings of the GBF were supported by the results of the GBS, filled in by teachers who were blind for the exposure status of the child. In comparison to the non-exposed children, the coumarin-exposed children scored lower on the cluster 'positive task orientation' (GBF P<0.05, GBS P<0.01), they scored higher on 'emotional instability' (GBF P<0.001, GBS P<0.05), and they had more problems on the social clusters (P<0.01). Based on the results of both questionnaires, we conclude that behavioural development may be negatively influenced in school-age children after in utero exposure to coumarins, leading to less favourable task-oriented and social-emotional behaviour. However, the frequency of clinically relevant 'problem behaviour' (GBF) was not increased in relation to coumarin exposure, the odds ratio was 1.2 (CI(95) 0.7-1.8).
Adolescent↗
Short-term growth and substrate use in very-low-birth-weight infants fed formulas with different energy contents.
BACKGROUND: Currently available preterm formulas with energy contents of 3350 kJ (800 kcal)/L promote weight and length gain at rates at or above intrauterine growth rates but disproportionately increase total body fat. OBJECTIVE: The objective of this study was to determine whether fat accretion in formula-fed, very-low-birth-weight (VLBW) infants could be decreased and net protein gain maintained by reducing energy intakes from 502 kJ (80 kcal)*kg(-)(1)*d(-)(1) [normal-energy (NE) formula] to 419 kJ (100 kcal)*kg(-)(1)*d(-)(1) [low-energy (LE) formula] while providing similar protein intakes (3.3 g*kg(-)(1)*d(-)(1)). DESIGN: The study was a randomized, controlled trial enrolling 20 appropriate-for-gestational-age (AGA) and 16 small-for-gestational-age (SGA) VLBW infants (mean birth weight: 1.1 kg; mean gestational age: 31 wk); energy expenditure and nutrient balance were measured at 4 wk of age and anthropometric measurements were made when infants weighed 2 kg. RESULTS: The percentage of fat in newly formed tissue was significantly lower in AGA infants fed the LE formula (n = 9) than in those fed the NE formula (n = 10) (9% compared with 23%; analysis of variance, P = 0.001). Energy expenditure was higher in AGA infants fed the NE formula than in those fed the LE formula. Skinfold thickness was markedly lower in AGA infants fed the LE formula than in those fed the NE formula, resulting in a lower estimated percentage body fat (8.0 +/- 1.9% and 10.8 +/- 3.5%, respectively; P < 0.05). Three of 6 SGA infants fed the LE formula were excluded during the study because of poor weight gain. CONCLUSIONS: Body composition can easily be altered by changing the energy intakes of formula-fed VLBW infants. Energy intakes in these infants should be >419 kJ (100 kcal)*kg(-)(1)*d(-)(1).
Adipose Tissue↗
Treatment with exogenous surfactant stimulates endogenous surfactant synthesis in premature infants with respiratory distress syndrome.
OBJECTIVE: Treatment of preterm infants with respiratory distress syndrome (RDS) with exogenous surfactant has greatly improved clinical outcome. Some infants require multiple doses, and it has not been studied whether these large amounts of exogenous surfactant disturb endogenous surfactant metabolism in humans. We studied endogenous surfactant metabolism in relation to different amounts of exogenous surfactant, administered as rescue therapy for RDS. DESIGN: Prospective clinical study. SETTING: Neonatal intensive care unit in a university hospital. PATIENTS: A total of 27 preterm infants intubated and mechanically ventilated for respiratory insufficiency. INTERVENTIONS: Infants received a 24-hr infusion with the stable isotope [U-13C]glucose starting 5.3 +/- 0.5 hrs after birth. The 13C-incorporation into palmitic acid in surfactant phosphatidylcholine (PC) isolated from serial tracheal aspirates was measured. Infants received either zero (n = 5), one (n = 4), two (n = 15), or three (n = 3) doses of Survanta (100 mg/kg) when clinically indicated. MEASUREMENTS AND MAIN RESULTS: Using multiple regression analysis, the absolute synthesis rate (ASR) of surfactant PC from plasma glucose increased with 1.3 +/- 0.4 mg/kg/day per dose of Survanta (p = .007) (mean +/- SEM). The ASR of surfactant PC from glucose was increased by prenatal corticosteroid treatment with 1.3 +/- 0.4 mg/kg/day per dose corticosteroid (p = .004), and by the presence of a patent ductus arteriosus with 2.1 +/- 0.7 mg/ kg/day (p = .01). CONCLUSION: These data are reassuring and show for the first time in preterm infants that multiple doses of exogenous surfactant for RDS are tolerated well by the developing lung and stimulate endogenous surfactant synthesis.
Anti-Inflammatory Agents↗
Neonatal blood lymphocyte subpopulations: a different perspective when using absolute counts.
We compared the absolute counts of lymphocyte subpopulations in 15 neonates, and 9 adults using the whole lysed blood technique with 15 different triple immunostainings. To obtain accurate absolute lymphocyte counts in neonatal cord blood samples, the flow cytometric 'lympho-gate' was corrected for the erythroid cell contamination by normoblasts and unlysed erythrocytes. In contrast to earlier studies where relative frequencies were reported, we found that the major difference between neonatal and adult lymphocyte subpopulations concerned the much larger pool of naive 'untriggered' cells in neonates, standby for participation in primary immune responses.
Adult↗
Exogenous surfactant kinetics in infant respiratory distress syndrome: A novel method with stable isotopes.
Little is known about surfactant metabolism in newborn infants, since radioactive isotopes cannot be used in humans. We describe here a new method for studying exogenous surfactant pharmacokinetics in vivo. We measured surfactant half-life, pool size, and turnover time in eight preterm infants (gestational age: 30 +/- 2 wk; birth weight: 1,416 +/- 202 g) who were mechanically ventilated because of infant respiratory distress syndrome. We administered two doses of 100 mg/kg each of a natural porcine surfactant with (13)C-labeled dipalmitoylphosphatidylcholine as a tracer. The (13)C enrichment of surfactant disaturated phosphatidylcholine (DSPC) was measured in serial tracheal aspirates by gas chromatography-mass spectrometry. The DSPC half-life was 34.2 +/- 9.4 h (mean +/- SD; range: 21.8 to 45.9 h). The apparent DSPC pool sizes were 5.8 +/- 6.1 mg/kg (range: 0.1 to 17.0 mg/kg) and 17.3 +/- 13.6 mg/kg (range: 3.3 to 41.0 mg/kg) at the time of the first and second surfactant doses, respectively. We present a novel and safe method that allows the tracing of exogenous surfactant phosphatidylcholine, the major lipid component of pulmonary surfactant, in infants who receive exogenous surfactant. This method could be a valuable tool for studying: (1) therapies that enhance lung/surfactant maturation; (2) the dosing and timing of surfactant therapy in different lung diseases; and (3) the comparison of different surfactant preparations.
1,2-Dipalmitoylphosphatidylcholine↗