Obstetric interventions for babies born before 28 weeks of gestation in Europe: results of the MOSAIC study.

OBJECTIVE: To describe obstetric intervention for extremely preterm births in ten European regions and assess its impact on mortality and short term morbidity. DESIGN: Prospective observational cohort study. SETTING: Ten regions from nine countries participating in the 'Models of Organising Access to Intensive Care for Very Preterm Babies in Europe' (MOSAIC) project. POPULATION: All births from 22 to 29 weeks of gestation (n = 4146) in 2003, excluding terminations of pregnancy. METHODS: Comparison of three obstetric interventions (antenatal corticosteroids, antenatal transfer and caesarean section for fetal indication) rates at 22-23, 24-25 and 26-27 weeks to that at 28-29 weeks and the association of the level of intervention with pregnancy outcome. MAIN OUTCOME MEASURES: Use of antenatal corticosteroids, antenatal transfer and caesarean section by two-week gestational age groups as well as a composite score of these three interventions. Outcomes included stillbirth, in-hospital mortality and intraventricular haemorrhage (IVH) grades III and IV and/or periventricular leucomalacia (PVL) and bronchopulmonary dysplasia (BPD). RESULTS: There were large differences between regions in interventions for births at 22-23 and 24-25 weeks. Differences were most pronounced at 24-25 weeks; in some regions these babies received the same care as babies of 28-29 weeks, whereas elsewhere levels of intervention were distinctly lower. Before 26 weeks and especially at 24-25 weeks, there was an association between the composite intervention score and mortality. No association was observed at 26-27 weeks. For survivors at 24-25 weeks, the intervention score was associated with higher rates of BPD, but not with IVH or PVL. CONCLUSIONS: There are large differences between European regions in obstetric practices at the lower limit of viability and these are related to outcome, especially at 24-25 weeks.

Influence of behaviour and risk factors on motor performance in preterm infants at age 2 to 3 years.

The aim of this cross-sectional study was to determine the influence of test-taking behaviour and risk factors for delayed motor performance in 437 preterm infants (244 males, 193 females; < or = 32 weeks of gestation) at the corrected age of 2 to 3 years (mean 29mo [SD 3.3]). Other mean (SD) sample demographics were: postmenstrual age 29(+5) weeks (1(+5)), range 25(+0)-32(+0); birthweight 1213.7g (331.7), range 468-2350; and days in the neonatal intensive care unit 21.1 (21.3), range 1-165. Children (n=23) with a severe disability were excluded. We assessed motor performance and behaviour during testing with the Motor Scale and the Behaviour Rating Scale (BRS) of the Bayley Scales of Infant Development, 2nd edition (BSID-II). Risk factors were tested against delayed motor performance as the dependent variable in binary logistic regression analysis. Median score on the Motor Scale in terms of the BSID-II Psychomotor Developmental Index (PDI) was 86. 'Delayed' motor performance was observed in 46.5% of the children tested, and behaviour was 'not-optimal' in 31.4%. The Motor Scale and BRS scores were significantly correlated (r(s)=0.62, p<0.01). Risk factors for delayed motor performance were: neonatal convulsions (odds ratio [OR] 4.5; 95% confidence interval [CI] 1.6-12.9), low maternal educational level (OR 3.3; 95% CI 1.7-6.5), male sex (OR 2.8; 95% CI 1.8-4.3), and chronic lung disease (OR 2.1; 95% CI 1.1- 4.1). We conclude that preterm infants are at high risk of delayed motor performance and non-optimal test-taking behaviour.

[At the limits of viability: Dutch referral policy for premature birth too reserved]. / Op de grens van levensvatbaarheid: Nederlands verwijsbeleid bij vroeggeboorte te terughoudend.

OBJECTIVE: Evaluation of policy and treatment of deliveries at the limits of viability in the Netherlands and resulting survival figures. DESIGN: Cohort study. METHOD: Within the framework of the European 'Models of organising access to intensive care for very preterm births in Europe' (MOSAIC) study, data was collected on all 512 births in 2003 (terminations excluded) following 22-31 weeks gestation in the catchment areas of the perinatal centres in Nijmegen and Utrecht, the Netherlands. RESULTS: Gynaecologists and neonatologists practised a reserved policy for the active treatment of pregnancies under 25 weeks (5/77; 6%); all infants died. At 25 weeks, an active obstetric policy was used in one quarter of pregnancies, but none of the infants survived. Even at 26 weeks pregnancy, the obstetric policy was reserved and the mortality relatively high (9/31; 29%). From the neonatal deaths, 86 out of 92 (93%) were preceded by a decision either not to start or to discontinue treatment. CONCLUSION: Dutch obstetricians and neonatologists practised a reserved policy at the limits of neonatal viability. There is more need for active antenatal transfer to perinatal centres for those at the lower limit of neonatal viability to enable well-balanced decisions to take place. The parents' wishes should always be taken into account.

[Neurological defects and developmental disorders following neonatal extracorporeal membrane oxygenation: results of a follow-up study after 5 years]. / Neurologische afwijkingen en ontwikkelingsstoornissen na extracorporele membraanoxygenatie van pasgeborenen: resultaten van een follow-uponderzoek na 5 jaar.

OBJECTIVE: Descriptive study of the development of children 5 years after neonatal extracorporeal membrane oxygenation (ECMO). DESIGN: Descriptive. METHOD: 98 treated children were subjected to a paediatric, neurological, psychological, physiotherapeutic and logopaedic examination. The children came from 2 Dutch ECMO-centres (the Erasmus MC-Sophia Children's Hospital in Rotterdam and the University Medical Centre St Radboud in Nijmegen, The Netherlands). RESULTS: Neurological disorders were found in 17 of the 98 investigated children, and in 6 cases these were serious. Among the remaining 92 children, 24 had motor disorders and 11 had delayed cognitive development. The average IQ (100.5) was within the normal range. CONCLUSION: A significant proportion ofthe children that had been treated with ECMO had long-term morbidity in the form of neurological defects and developmental disorders.

Epidemiology of neonatal group B streptococcal disease in the Netherlands before and after introduction of guidelines for prevention.

OBJECTIVES: (1) To describe the epidemiology of neonatal group B streptococcal (GBS) disease over five years (1997-2001) in the Netherlands, stratified for proven and probable sepsis and for very early (<12 h), late early (12 h - <7 days) and late (7-90 days) onset sepsis. (2) To evaluate the effect of the introduction in January 1999 of guidelines for prevention of early onset GBS disease based on risk factors. METHODS: Data on cases were collected in collaboration with the Dutch Paediatric Surveillance Unit and corrected for under-reporting by the capture-recapture technique. RESULTS: Total incidence of proven very early onset, late early onset and late onset GBS sepsis was 0.32, 0.11 and 0.14 per 1000 live births, respectively, and of probable very early onset, late early onset and late onset GBS sepsis was 1.10, 0.18 and 0.02 per 1000 live births, respectively. Maternal risk factors were absent in 46% of the proven early onset cases. Considerably more infants with proven GBS sepsis were boys. 64% of the infants with proven very early onset GBS sepsis were first born compared with 47% in the general population. After the introduction of guidelines the incidence of proven early onset sepsis decreased considerably from 0.54 per 1000 live births in 1997-8 to 0.36 per 1000 live births in 1999-2001. However, there was no decrease in the incidence of meningitis and the case fatality rate in the first week of life. The incidence of late onset sepsis also remained unchanged. CONCLUSION: After the introduction prevention guidelines based on risk factors there has been a limited decrease in the incidence of proven early onset GBS sepsis in the Netherlands. This study therefore recommends changing the Dutch GBS prevention guidelines.

Behavioural and emotional problems in very preterm and very low birthweight infants at age 5 years.

BACKGROUND: Children born very preterm (VP; <32 weeks' gestation) or with very low birth weight (VLBW, <1500 g; hereafter called VP/VLBW) are at risk for behavioural and emotional problems during school age and adolescence. At school entrance these problems may hamper academic functioning, but evidence on their occurrence at this age in VP/VLBW children is lacking. AIM: To provide information on academic functioning of VP/VLBW children and to examine the association of behavioural and emotional problems with other developmental problems assessed by paediatricians. DESIGN, SETTING AND PARTICIPANTS: A cohort of 431 VP/VLBW children aged 5 years (response rate 76.1%) was compared with two large national samples of children of the same age (n = 6007, response rate 86.9%). OUTCOME MEASURES: Behavioural and emotional problems measured by the Child Behavior Checklist (CBCL), and paediatrician assessment of other developmental domains among VP/VLBW children. RESULTS: The prevalence rate of a CBCL total problems score in the clinical range was higher among VP/VLBW children than among children of the same age from the general population (13.2% v 8.7%, odds ratio 1.60 (95% confidence interval 1.18 to 2.17)). Mean differences were largest for social and attention problems. Moreover, they were larger in children with paediatrician-diagnosed developmental problems at 5 years, and somewhat larger in children with severe perinatal problems. CONCLUSION: At school entrance, VP/VLBW children are more likely to have behavioural and emotional problems that are detrimental for academic functioning. Targeted and timely help is needed to support them and their parents in overcoming these problems and in enabling them to be socially successful.

[Vitamin deficiencies in breastfed children due to maternal dietary deficiency]. / Vitaminedeficiënties bij borstgevoede kinderen als gevolg van een tekort bij de moeder.

Dietary deficiencies of vitamin B12 and vitamin D during pregnancy and lactation may result in health problems in exclusively breastfed infants. Vitamin-B12 deficiency in these infants results in irritability, anorexia and failure to thrive during the first 4-8 months of life. Severe and permanent neurodevelopmental disturbances may occur. The most at risk for vitamin-B12 deficiency are breast-fed infants ofveganist and vegetarian mothers. Mothers who cover their skin prevent exposure to the sun and may consequently be at risk for vitamin-D deficiency, as well as putting their offspring at risk. In prenatal and perinatal care, it is important to take the maternal dietary history in order to be able to prevent or treat these disorders. Guidelines for obstetrical and neonatal care should include the topic of vitamin deficiency.

[End-of-life decisions and reluctant treatment of newborns on the borderline of viability in the Netherlands]. / Levenseindebeslissingen en terughoudend behandelen op de grens van levensvatbaarheid bij pasgeborenen in Nederland.

End-of-life decisions are taken in the majority of deaths below one year of age, especially in neonatal intensive-care units. In the Netherlands, the frequency of such decisions has not increased in recent years. Intentional termination of life occurred in 1% of the deaths, which would be about 10 cases each year. However, only 3 such cases are reported to the public prosecutor for review by the responsible physician. Proposals from the government to facilitate reporting of such cases are awaited. Dutch neonatologists are reluctant to administer full neonatal intensive care to extremely preterm infants. Currently, the policy regarding antenatal referral and treatment of extremely preterm infants is being re-evaluated by obstetricians and neonatologists. Behind the stable frequency of end-of-life decisions, difficult ethical issues remain to be solved.

[Twenty-five week limit for viability of the foetus is ethically correct]. / 25 weken als grens voor levensvatbaarheid van de vrucht: ethisch juist.

The outcome in relation to survival and handicaps of premature infants born before 25 weeks gestational age is extremely poor. Treatment for this category of patients means benefiting a tiny minority but also inflicting damage to a much larger group of children. For this reason the policy of treating only infants from 25 weeks gestational age should be supported.

Different pharmacokinetics of tramadol in mothers treated for labour pain and in their neonates.

OBJECTIVE: The aim of the present study was to investigate the pharmacokinetic profile of tramadol hydrochloride in neonates, born from mothers who underwent analgesia with tramadol for the relief of labour pain. METHODS: Intramuscular tramadol (100--250 mg) was administered to 22 mothers giving birth who requested pain relief. At the time of birth (1.5--6.0 h after last tramadol dose), maternal and umbilical blood samples were taken. Another venous blood sample was drawn from each neonate, and at the same time from its mother, at 1, 2, 3, 6 or 12 h post-partum, providing the data for a population pharmacokinetic evaluation of tramadol and its metabolite M1. Routine APGAR scores and a standard neurological and adaptive capacity test were considered for evaluation of the effect of tramadol on the neonates. RESULTS: Serum tramadol concentrations at the time of birth (t(0)) were 243+/-102 ng/ml (mean+/-SD, umbilical vein), 258+/-103 ng/ml (umbilical artery) and 250+/-113 ng/ml (maternal vein). Serum M1 concentrations were 52+/-27 ng/ml (umbilical vein), 47+/-24 ng/ml (umbilical artery) and 56+/-21 ng/ml (maternal vein). The two-compartment type elimination profiles during the first 12 h post-partum for neonates (and mothers, respectively) were characterised by terminal t(1/2) (tramadol)=7.0 (7.2) h and t(1/2) (metabolite M1)=85.0 (5.5) h. CONCLUSION: The intramuscular application of tramadol in birth-giving mothers almost freely reaches the neonate, confirming a high degree of placental permeability. The neonates already possess the complete hepatic capacity for the metabolism of tramadol into its active metabolite. However, the renal elimination of the active tramadol metabolite M1 is delayed, in line with the slow maturation process of renal function in neonates. Despite this difference in pharmacokinetics between neonates and adults, the intramuscular application of tramadol at the recommended dosage range during delivery appears to effective in the relief of labour pain.

Rehospitalization of very preterm infants.

UNLABELLED: Rehospitalization rates of very preterm infants because of reasons that are related to neonatal morbidity states can be decreased with further improvement of neonatal intensive care provided. CONCLUSION: Analysis of rehospitalization data should be included in follow-up programmes as a contribution to the development of strategies to improve neonatal care and the ultimate outcome for very-low-birthweight infants.

Validation of a Dutch language screening instrument for 5-year-old preterm infants.

AIM: The validation of the Dutch Taal Screenings Test (TST), a language-screening test, which is included in a follow-up instrument developed to enable paediatricians to assess 5-y-old preterm infants for their motor, cognitive and speech and language development. METHODS: The speech and language development of 145 5-y-old infants born before 32 wk of gestation and/or with a birth weight of less than 1500 g was assessed by a paediatrician using the TST and by a speech therapist using standardized language tests. RESULTS: All correlations between the instruments were significant. Using the original cut-off point of the TST for abnormal speech and language development (18 points), the paediatrician will only identify 62% of the children who need speech therapy. For this group of children, a cut-off point of 17 is more effective. The positive predictive value of the TST improved from 77% to 82% by using a parent and school questionnaire to evaluate in a more subjective way the speech and language development. CONCLUSION: Using the TST, paediatricians will be able to identify speech or language problems in 5-y-old preterm infants.

Development and evaluation of a follow up assessment of preterm infants at 5 years of age.

BACKGROUND: Long term follow up shows a high frequency of developmental disturbances in preterm survivors of neonatal intensive care formerly considered non-disabled. AIMS: To develop and validate an assessment tool that can help paediatricians to identify before 6 years of age which survivors have developmental disturbances that may interfere with normal education and normal life. METHODS: A total of 431 very premature infants, mean gestational age 30.2 weeks, mean birth weight 1276 g, were studied at age 5 years. Children with severe handicaps were excluded. The percentage of children with a correctly identified developmental disturbance in the domains cognition, speech and language development, neuromotor development, and behaviour were determined. RESULTS: The follow up instrument classified 67% as optimal and 33% as at risk or abnormal. Of the children classified as at risk or abnormal, 60% had not been identified at earlier follow up assessments. The combined set of standardised tests identified a further 30% with mild motor, cognitive, or behavioural disturbances. The paediatrician's assessment had a specificity of 88% (95% CI 83-93%), a sensitivity of 48% (95% CI 42-58%), a positive predictive value of 85% (95% CI 78-91%), and a negative predictive value of 55% (95% CI 49-61%). CONCLUSIONS: Even after standardised and thorough assessment, paediatricians may overlook impairments for cognitive, motor, and behavioural development. Long term follow up studies that do not include detailed standardised tests for multiple domains, especially fine motor domain, may underestimate developmental problems.

[Approaching a child with chronic abdominal pain]. / De benadering van het kind met chronische buikpijn.

A detailed anamnesis and a complete physical examination are essential for establishing the cause of recurrent abdominal pain in a child. Often no medical abnormalities will be found and additional diagnostic procedures may be limited. Most cases are functional in nature or have a psychosomatic origin. The recently established Rome II criteria for the classification of functional abdominal pain in children can be used to diagnose this disorder. The literature provides little evidence for the effectiveness of medication in treating functional recurrent abdominal pain.

[The Dutch College of General Practitioners' practice guidelines, "Examination of the neonate": response from the perspective of pediatrics]. / De standaard 'onderzoek van de pasgeborene' van het Nederlands huisartsen genootschap; reactie vanuit de kindergeneeskunde.

The practice guideline on routine neonatal examination of the Dutch College of General Practitioners describes the examination of the newborn directly after birth, whether at home or in the hospital. It is proposed that examination be limited to inspection, without auscultation and palpation. If conducted strictly according to the guidelines given, this may be sufficient. However, auscultation of the heart is the most reliable way to determine the heart rate. Including auscultation and palpation in the routine examination after birth would contribute to the experience of general practitioners with these techniques in babies. This is of importance, since general practitioners are the first to be consulted in case of any health problems in this patient category. Previously, it was recommended that the general practitioner visit mother and child on the third, fourth or fifth day after delivery and examine the baby. In the new standard, this second examination is considered to be redundant, based on data in the literature. However, it remains the duty of the general practitioner to inform the parents about (non-specific) early signs of disease in newborns. Furthermore, the threshold for consultation of the general practitioner should be low for the early diagnosis and management of serious conditions, such as septicaemia or congenital heart disease.

Neonatal end-of-life decision making: Physicians' attitudes and relationship with self-reported practices in 10 European countries.

CONTEXT: The ethical issues surrounding end-of-life decision making for infants with adverse prognoses are controversial. Little empirical evidence is available on the attitudes and values that underlie such decisions in different countries and cultures. OBJECTIVE: To explore the variability of neonatal physicians' attitudes among 10 European countries and the relationship between such attitudes and self-reported practice of end-of-life decisions. DESIGN AND SETTING: Survey conducted during 1996-1997 in 10 European countries (France, Germany, Italy, the Netherlands, Spain, Sweden, the United Kingdom, Estonia, Hungary, and Lithuania). PARTICIPANTS: A total of 1391 physicians (response rate, 89%) regularly employed in 142 neonatal intensive care units (NICUs). MAIN OUTCOME MEASURES: Scores on an attitude scale, which measured views regarding absolute value of life (score of 0) vs value of quality of life (score of 10); self-report of having ever set limits to intensive neonatal interventions in cases of poor neurological prognosis. RESULTS: Physicians more likely to agree with statements consistent with preserving life at any cost were from Hungary (mean attitude scores, 5.2 [95% confidence interval ¿CI¿, 4.9-5.5]), Estonia (4.9 [95% CI, 4.3-5.5]), Lithuania (5.5 [95% CI, 4.8-6.1]), and Italy (5.7 [95% CI, 5.3-6.0]), while physicians more likely to agree with the idea that quality of life must be taken into account were from the United Kingdom (attitude scores, 7.4 [95% CI, 7.1-7.7]), the Netherlands (7. 3 [95% CI, 7.1-7.5]), and Sweden (6.8 [95% CI, 6.4-7.3]). Other factors associated with having a pro-quality-of-life view were being female, having had no children, being Protestant or having no religious background, considering religion as not important, and working in an NICU with a high number of very low-birth-weight newborns. Physicians with scores reflecting a more quality-of-life view were more likely to report that in their practice, they had set limits to intensive interventions in cases of poor neurological prognosis, with an adjusted odds ratio of 1.5 (95% CI, 1.3-1.7) per unit change in attitude score. CONCLUSIONS: In our study, physicians' likelihood of reporting setting limits to intensive neonatal interventions in cases of poor neurological prognosis is related to their attitudes. After adjusting for potential confounders, country remained the most important predictor of physicians' attitudes and practices. JAMA. 2000;284:2451-2459.

Using potentially life-shortening drugs in neonates and infants.

OBJECTIVE: To describe the frequency, background, and impact of decisions to give analgesic or other drugs that may, intentionally or unintentionally, shorten the life-span of severely ill neonates. SETTING: The Netherlands. DESIGN: Retrospective, cross-sectional study. PATIENTS: Questionnaires were mailed in The Netherlands to physicians reporting 338 consecutive deaths of infants under 1 yr of age from August through November 1995. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Questions were asked about medical end-of-life decisions preceding the death of the infant and about the decision-making process. Potentially life-shortening drugs, mostly opioids, were given in 37% of all deaths. The estimated effect in terms of the shortening of life was <1 wk in 72% of all patients in whom the administration of potentially life-shortening drugs had been the most important end-of-life decision. Most decisions to administer such drugs were discussed with parents and colleagues. The decisions were discussed regarding virtually all patients in whom the physician had intended to hasten death; doses of opioids tended to be larger in this group. CONCLUSIONS: The frequency with which drugs that may shorten life are administered before the death of severely ill infants confirms the important role of modern medicine in dying in neonatology. Most physicians caring for neonates feel that palliative medication may be warranted in dying infants, even if it shortens life. A distinction between intentionally ending life and providing adequate terminal care by alleviating pain or other symptoms, which is important in moral and judicial terms, is probably not easily made for some of these patients.

The human HNF-3 genes: cloning, partial sequence and mutation screening in patients with impaired glucose homeostasis.

Hepatocyte nuclear factors 3 (HNF-3 alpha, -3 beta and -3 gamma) belong to an evolutionarily conserved family of transcription factors that are critical for diverse biological processes such as development, differentiation and metabolism. Gene expression studies have shown that HNF3 proteins are critical regulators of the early-onset type 2 diabetes genes HNF-1 alpha, HNF-4 alpha and IPF-1/PDX-1 (MODY3, 1 and 4, respectively) and of glucagon transcription and pancreatic alpha-cell function. In this study, we investigated whether genetic variation in the genes encoding HNF-3 alpha, HNF-3 beta and HNF-3 gamma predisposes humans to hyperglycemic or hypoglycemic syndromes. In addition, we report the cloning and partial nucleotide sequence of the human HNF-3 alpha, -3 beta and -3 gamma genes. Mutation screening included 96 subjects with type 2 diabetes mellitus, as well as one family with persistent neonatal hypoglycemia. No functional mutations were detected in the coding sequences of the three HNF-3 genes. Our results suggest that mutations in HNF-3 genes are not a common cause of type 2 diabetes mellitus. The data provided will facilitate genetic studies in other populations and will advance our understanding of the role HNF-3 plays in the development of diabetes mellitus and other metabolic disorders of glucose homeostasis.

[Clinical thinking and decision making in practice: a full-term neonate with misunderstood respiratory insufficiency]. / Klinisch denken en beslissen in de praktijk: een voldragen pasgeborene met onbegrepen respiratoire insufficiëntie.

A fullterm newborn boy developed severe respiratory insufficiency, multiple air leaks and severe pulmonary hypertension, leading to his death on the third day of life. Family history revealed that a sister of the patient had died earlier after a similar course with respiratory problems. The most common causes of respiratory insufficiency could be subsequently excluded. After extensive postmortem investigation alveolar proteinosis was found in the lung tissue. DNA investigation was then performed in the parents, and both appeared to be heterozygotic for the 121ins2 mutation. This finding suggests both children in this family to have been homozygotic for the 121ins2 mutation resulting in a lack of synthesis of surfactant protein B (SP-B). Homozygotic SP-B deficiency in the newborn is a fatal disease with no curative perspectives, except for lung transplantation and gene therapy.

End-of-life decisions in neonates.

In a large percentage of the infants who die in the neonatal intensive care setting, an end-of-life decision was made before death, usually a decision to forego life-sustaining treatment. This was confirmed in a recent study in The Netherlands that showed also that a minority of cases include the administration of drugs to hasten death, usually in patients with severe congenital multiple or central nervous system anomalies. Over 80% of Dutch pediatricians support this option under certain conditions. Almost all pediatricians are of the opinion that these cases have to be subject to public review, but they favor review by a committee of independent medical, judicial, and ethical professionals rather than by the public prosecutor. A discussion group on this subject recently made a proposal for such a reviewing procedure to the Dutch governmental authorities and described the requirements concerning end-of-life decisions in neonatal medicine. Proper handling of ethical aspects of medical treatment including review and feedback after end-of-life decisions can contribute to high standards of quality of care.