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OBJECTIVE: We sought to study long-term (neuro)developmental and behavioral outcome of pregnancies complicated by intrauterine growth restriction at term in relation to induction of labor or an expectant management. STUDY DESIGN: Parents of 2-year-old children included in the Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT) answered the Ages and Stages Questionnaire (ASQ) and Child Behavior Checklist (CBCL). RESULTS: We approached 582 (89.5%) of 650 parents. The response rate was 50%. Of these children, 27% had an abnormal score on the ASQ and 13% on the CBCL. Results of the ASQ and the CBCL for the 2 policies were comparable. Low birthweight, positive Morbidity Assessment Index score, and admission to intermediate care increased the risk of an abnormal outcome of the ASQ. This effect was not seen for the CBCL. CONCLUSION: In women with intrauterine growth restriction at term, neither a policy of induction of labor nor expectant management affect developmental and behavioral outcome when compared to expectant management. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Late-preterm infants (34 weeks 0/7 days-36 weeks 6/7 days' gestation) represent the largest proportion of singleton preterm births. A systematic review was performed to access the short- and/or long-term morbidity of late-preterm infants. STUDY DESIGN: An electronic search was conducted for cohort studies published from January 2000 through July 2010. RESULTS: We identified 22 studies studying 29,375,675 infants. Compared with infants born at term, infants born late preterm were more likely to suffer poorer short-term outcomes such as respiratory distress syndrome (relative risk [RR], 17.3), intraventricular hemorrhage (RR, 4.9), and death <28 days (RR, 5.9). Beyond the neonatal period, late-preterm infants were more likely to die in the first year (RR, 3.7) and to suffer from cerebral palsy (RR, 3.1). CONCLUSION: Although the absolute incidence of neonatal mortality and morbidity in infants born late preterm is low, its incidence is significantly increased as compared with infants born at term. [ABSTRACT FROM AUTHOR]

Background. Thyroid hormones are essential for brain development. We conducted a randomized, controlled trial with thyroxine (T4) supplementation in infants <30 weeks' gestation and with the last neurodevelopmental follow-up moment at the age of 5.5 years. T4 supplementation was associated with improved outcome of infants <28 weeks' gestation and worse outcome of infants of 29 weeks' gestation. We studied gestational age-dependent effects of T4 supplementation at the mean age of 10.5 years in children participating in our randomized, controlled trial. Methods. Questionnaires regarding school outcome, behavior, quality of life, motor problems, and parental stress were sent to the parents and children and their teachers at the same time point for all surviving children (9-12 years of age).Results. Seventy-two percent of the families responded to our questionnaires. Nonrespondents had more sociodemographic risk factors and worse development until 5.5 years. At the mean age of 10.5 years, T4 supplementation was associated with better school outcome in those who were <27 weeks' gestation and better motor outcome in those who were <28 weeks' gestation, whereas the reverse was true for those who were born at 29 weeks' gestation. No other gestational age-dependent outcomes were found.Conclusions. Gestation-dependent effects of T4 supplementation remain stable over time. These effects do not prove beneficial effects of T4 in infants <28 weeks but should be the background for a new randomized, controlled trial with thyroid hormone in this age group. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between invasive mechanical ventilation (IMV) duration and long-term neurodevelopmental outcomes in preterm infants in an era of restricted IMV., Design: Retrospective cohort study., Setting: Single neonatal intensive care unit in Amsterdam., Patients: All ventilated patients with a gestational age between 24 and 30 weeks born between 2010 and 2015., Main Outcome Measures: Neurodevelopmental impairment (NDI) at 24 months corrected age (CA). Data on patient characteristics, respiratory management, neonatal morbidities, mortality and bronchopulmonary dysplasia were collected. The relationship between IMV duration and NDI was determined by multivariate logistic regression analysis., Results: During the study period, 368 admitted infants received IMV for a median duration of 2 days. Moderate and severe bronchopulmonary dysplasia was diagnosed in 33% of the infant. Multivariate regression analysis with adjustment for gestational age, small for gestational age and socioeconomic status showed a significant association between every day of IMV and NDI at 24 months CA (adjusted OR [aOR] 1.08, 95% CI 1.004 to 1.16, p=0.04). This association only reached borderline significance when also adjusting for severe neonatal morbidity (aOR 1.08, 95% CI 1.00 to 1.17, p=0.05)., Conclusion: Even in an era of restricted IMV, every additional day of IMV in preterm infants is strongly associated with an increased risk of NDI at 24 months CA. Limiting IMV should be an important focus in the treatment of preterm infants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although the hope is that many perinatal interventions are performed with an ultimate aim to improve the long-term health and development of the child, long-term outcome is rarely used as a primary end-point in perinatal randomised controlled trials (RCTs)., Objective: To evaluate how often and with which tools long-term follow-up is performed after large obstetric RCTs., Search Strategy: We searched the Cochrane Library for Cochrane reviews published by the Cochrane Pregnancy and Childbirth Group for reviews on interventions that aimed to improve neonatal outcome. Selection criteria  Reviews on perinatal interventions that were not performed to improve the condition of the neonate were excluded. We limited our review to RCTs with more than 350 participating women. For each included study, we checked in Web of Science as to whether the researchers had reported on follow-up in subsequent publications., Data Collection and Analysis: Relevant information was extracted from these RCTs by two reviewers using a predefined data collection sheet. All information was analysed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA)., Main Results: We studied 212 reviews including 1837 RCTs on perinatal interventions, 249 (14%) of which included 350 participants. Only 40 of 249 RCTs (16%) followed the children after discharge from the hospital to evaluate the effect of a specific perinatal intervention. The number of RCTs with long-term follow-up remained stable, with 10 of 67 RCTs (15%) reporting follow-up before 1990, 17 of 115 (15%) between 1990 and 2000, and 13 of 67 (19%) after 2000 (P = 0.68)., Conclusions: Only a small minority of large perinatal RCTs report the long-term follow-up of the child. Future obstetric RCTs should consider performing long-term follow-up at the start of the trial., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Objectives: To develop prediction models for long-term respiratory morbidity. To explore if respiratory distress syndrome (RDS) is a risk-indicator for long-term respiratory morbidity and to identify other perinatal risk-indicators for long-term respiratory morbidity., Study Design: In the Dutch POPS cohort 1338 live born infants delivered in The Netherlands in 1983, either before 32 completed weeks gestation and/or with a birth weight below 1500 g, were followed prospectively. We used multivariable logistic regression analyses to construct three prediction models for respiratory morbidity at 2, 5 and 19 years of age., Results: At 2 years of age, maternal smoking (adjusted OR 1.5, 95% CI 1.0-2.4), prolonged rupture of membranes (adjusted OR 2.3, 95% CI 1.3-4.1), pre-eclampsia (adjusted OR 1.9, 95% CI 1.1-4.1), male gender (adjusted OR 1.5, 95% CI 1.1-2.0) and BPD (adjusted OR 1.9, 95% CI 1.1-3.2) were significantly associated with respiratory morbidity. Prolonged rupture of membranes (adjusted OR 3.7, 95% CI 1.6-8.5), family history of asthma (adjusted OR 5.9, 95% CI 2.7-13.0) and BPD (adjusted OR 1.8, 95% CI 1.1-3.0) were significantly associated with respiratory morbidity at 5 years of age. At 19 years of age only higher social class was associated with decreased respiratory morbidity (adjusted OR 0.64, 95% CI 0.41-0.99). The areas under the curves (AUC) were 0.65, 0.71 and 0.61 respectively. The prediction models for respiratory morbidity at 2 and 5 years of age showed a good calibration, while the calibration plot for respiratory morbidity at 19 year was less optimal., Conclusions: RDS is not a risk-indicator for long-term respiratory morbidity at 2, 5 and 19 years in this cohort (OR 1.2, 95% 0.88-1.7; 1.3, 95% 0.88-2.0; OR 0.91, 95% 0.56-1.5 respectively). Future obstetric studies interested in the effect of a specific perinatal intervention on long-term respiratory morbidity, should consider taking bronchopulmonary dysplasia (BPD) as primary outcome instead of RDS., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Aim: To investigate differences in the quality of mother-child interaction between preterm- and term-born children at age 5, and to study the association of mother-child interaction with sociodemographic characteristics and child disability., Methods: Preterm children (n = 94), born at <30 weeks' gestation and/or birth weight <1000 g, and term children (n = 84) were assessed at corrected age of 5 using a mother-child interaction observation. Disabilities were assessed using an intelligence test, behaviour questionnaires for parents and teachers, and motor and neurological examinations., Results: Mothers of preterm-born children were less supportive of and more interfering with their children's autonomy than mothers of term-born children. This difference was only partly explained by sociodemographic factors. Dyads showed a lower quality of mother-child interaction if children had a severe disability, especially when mothers had a lower level of education., Conclusion: Five years after birth, mother-child interaction of very premature children and their mothers compared unfavourably with term children and their mothers. Mothers with sociodemographic disadvantages, raising a preterm child with severe disabilities, struggle most with giving adequate sensitive support for the autonomy development of their child. Focused specialized support for these at risk groups is warranted., (© 2012 The Author(s)/Acta Paediatrica © 2012 Foundation Acta Paediatrica.)

Aim: This study investigated prediction of separate cognitive abilities at the age of 5 years by cognitive development at the ages of both 2 and 3 years, and the agreement between these measurements, in very preterm children., Methods: Preterm children (n=102; 44 males; 58 females) with a gestational age less than 30 weeks and/or birthweight less than 1000g were assessed at the ages of 2 and 3 years using the second edition of the Bayley Scales of Infant Development, the Child Behaviour Checklist, and a neurological examination, and at the age of 5 years using the third edition of the Wechsler Preschool and Primary Scale of Intelligence., Results: Cognitive development at ages 2 and 3 years explained 44% and 57% respectively of full-scale intelligence at the age of 5 years. Adding psychomotor, neurological, and behavioural outcomes to the regression model could not or only marginally improve the prediction; adding perinatal and sociodemographic characteristics to the regression model increased the explained variance to 57% and 64% respectively. These percentages were comparable for verbal intelligence. Processing speed quotient and especially performance intelligence were predicted less accurately., Interpretation: Not all aspects of intelligence are predicted sufficiently by the Mental Development Index at ages 2 and 3 years. Follow-up of very preterm children until at least the age of 5 years is needed to distinguish between different aspects of cognitive development., (© The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.)

Objective: The objective of the study was to describe neurodevelopmental outcome at the age of 4.5 years in 216 children, born after expectant management of severe early-onset hypertensive complications of pregnancy., Study Design: This was a prospective follow-up study until age 4.5 years from maternal admission onward. Developmental outcome measurements included child intelligence quotient and behavioral, motor, and neurological outcome. Abnormal composite outcome (perinatal mortality or abnormal developmental outcome) was studied in relation to gestational age (GA), birthweight (BW), and perinatal variables., Results: Fetal and neonatal mortality was 9% and 8%, respectively. Of the 178 survivors, 149 (84%) were seen for follow-up. Mean GA was 31.4 weeks and 90% were born growth restricted. Abnormal developmental outcome occurred in 20% and abnormal composite outcome in 37%., Conclusion: Perinatal mortality or abnormal child development occurs in one third of pregnancies with early-onset and severe hypertensive complications and is highest in the lowest GA and BW ranges., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objective: Many obstetric interventions are performed to improve long-term neonatal outcome. However, long-term neonatal outcome is usually not a primary outcome because it is time-consuming and expensive. The aim of this project was to identify different perinatal risk indicators and to develop prediction models for neurologic morbidity at 2 and 5 years of age., Study Design: Data from a Dutch cohort study of preterm and small-for-gestational-age infants was used. Neonates who were born in The Netherlands in 1983 with a gestational age of <34 weeks and without congenital abnormalities were included (n = 753). Infants were divided in 3 groups: no handicap, minor handicap, and major handicap., Results: Common risk indicators for major handicaps at 2 and 5 years of age were male sex (odds ratio, 2.7 and 3.0, respectively), seizures after ≥2 days of life (odds ratio, 5.8 and 5.8, respectively), and intracranial hemorrhage (odds ratio, 3.8 and 2.6, respectively)., Conclusion: In this cohort, male sex, intracranial hemorrhage, and seizures seem to be important risk indicators for long-term neurologic morbidity., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objective: Purpose of this study was to examine maternal parenting stress as a secondary outcome of the Infant Behavioural Assessment and Intervention Program (IBAIP)., Methods: In a randomized controlled trial 86 very preterm infants and their parents were assigned to the intervention group and 90 to the control group. Maternal parenting stress was assessed with the Dutch version of the Parenting Stress Index at 12 and 24 months post term., Results: Mothers in the intervention group mothers assessed their infants as happier and less hyperactive/distractible compared with the control group mothers. However, mothers in the intervention group reported more feelings of social isolation., Conclusions: The IBAIP appears to have made mothers more satisfied about their infants' mood and distractibility, but also may have evoked more feelings of social isolation. Next to long-term evaluation of the development in very preterm born children, follow-up on functioning of their parents is important., (© 2010 Blackwell Publishing Ltd.)

Background: Many perinatal interventions are performed to improve long-term neonatal outcome. To evaluate the long-term effect of a perinatal intervention follow-up of the child after discharge from the hospital is necessary because serious sequelae from perinatal complications frequently manifest themselves only after several years. However, long-term follow-up is time-consuming, is not in the awareness of obstetricians, is expensive and falls outside the funding-period of most obstetric studies. Consequently, short-term outcomes are often reported instead of the primary long-term end-point. With this project, we will assess the current state of affairs concerning follow-up after obstetric RCTs and we will develop multivariable prediction models for different long-term health outcomes. Furthermore, we would like to encourage other researchers participating in follow-up studies after large obstetric trials (> 350 women) to inform us about their studies so that we can include their follow-up study in our systematic review. We would invite these researchers also to join our effort and to collaborate with us on the external validation of our prediction models., Methods/design: A systematic review of neonatal follow-up after obstetric studies will be performed. All reviews of the Cochrane Pregnancy and Childbirth group will be assessed for reviews on interventions that aimed to improve neonatal outcome. Reviews on interventions primary looking at other aspects than neonatal outcome such as labour progress will also be included when these interventions can change the outcome of the neonate on the short or long-term. Our review will be limited to RCTs with more than 350 women. Information that will be extracted from these RCTs will address whether, how and for how long follow-up has been performed. However, in many cases long-term follow-up of the infants will not be feasible. An alternative solution to limited follow-up could be to develop prediction models to estimate long-term health outcomes of the newborn based on specific perinatal outcomes and other covariates. For the development of multivariable prediction models for several health outcomes, we will use data available from a Dutch cohort study of preterm (< 32 weeks) and/or small for gestational age infants (< 1500 g). These infants were born in The Netherlands in 1983 and followed until they reached the age of 19., Discussion: The systematic review will provide insight in the extent and methods used for follow-up assessments after obstetric RCTs in the past. The prediction models can be used by future studies to extrapolate short-term outcomes to a long-term horizon or to indicate for which neonates long-term follow-up is required, as their outcomes (either absence or presence of sequelae) cannot be adequately predicted from short-term outcomes and clinical background characteristics.

Background: Transiently low levels of thyroid hormones occur in approximately 50% of neonates born 24-28 weeks' gestation and are associated with higher rates of cerebral palsy and cognitive impairment. Raising hormone levels shows promise for improving neurodevelopmental outcome., Objective: To identify whether any of 4 thyroid hormone supplementation regimens could raise T(4) and FT(4) without suppressing TSH (biochemical euthyroidism)., Methods: Eligible subjects had gestational ages between 24 07 and 2767 weeks and were randomized <24 hours of birth to one of six study arms (n = 20-27 per arm): placebo (vehicle: 5% dextrose), potassium iodide (30 microg/kg/d) and continuous or bolus daily infusions of either 4 or 8 microg/kg/d of T(4) for 42 days. T(4) was accompanied by 1 microg/kg/d T(3) during the first 14 postnatal days and infused with 1 mg/mL albumin to prevent adherence to plastic tubing., Results: FT(4) was elevated in the first 7 days in all hormone-treated subjects; however, only the continuous 8 microg/kg/d treatment arm showed a significant elevation in all treatment epochs (P < .002 versus all other groups). TT(4) remained elevated in the first 7 days in all hormone-treated subjects (P < .05 versus placebo or iodine arms). After 14 days, both 8 microg/kg/d arms as well as the continuous 4 microg/kg/d arm produced a sustained elevation of the mean and median TT(4), >7 microg/dL (90 nM/L; P < .002 versus placebo). The least suppression of THS was achieved in the 4 microg/kg/d T(4) continuous infusion arm. Although not pre-hypothesized, the duration of mechanical ventilation was significantly lower in the continuous 4 microg/kg/d T(4) arm and in the 8 microg/kg/d T(4) bolus arm (P < .05 versus remaining arms). ROP was significantly lower in the combined 4 thyroid hormone treatment arms than in the combined placebo and iodine arms (P < .04). NEC was higher in the combined 8 microg/kg/d arms (P < .05 versus other arms)., Conclusions: Elevation of TT(4) with only modest suppression of TSH was associated with trends suggesting clinical benefits using a continuous supplement of low-dose thyroid hormone (4 microg/kg/d) for 42 days. Future trials will be needed to assess the long-term neurodevelopmental effects of such supplementation.

Aim: The aim of this work was to study the effect of maternal psychological symptoms on infant development 1 year after early-onset hypertensive disorders of pregnancy., Methods: All mothers were enrolled in the Pre-eclampsia, Eclampsia TRial Amsterdam. Mothers were asked to complete the 90-item Symptom Check List (SCL-90) at the corrected ages of their infants of 0, 3 and 12 months. The total sum score of these three checklists was calculated. Infants were examined at the corrected age of 12 months using the Bayley Scales of Infant Development (Mental Developmental Index [MDI] and Psychomotor Developmental Index [PDI] subscales). The Bayley scores were compared between infants of mothers with SCL-90 sum scores in the highest 25% and lowest 75%., Results: For 141 mother-infant pairs (80%) all three SCL-90 checklists and Bayley scores were available. Mean gestational age was 32 weeks and 90% of the infants were growth restricted. The mean MDI was 87 in the highest 25% and 89 in the lowest 75% group. This was 79 versus 80 for the PDI., Conclusion: In this population of high-risk growth-restricted infants born after a pregnancy complicated by early-onset hypertensive disorders, there is no additional impact of negative maternal psychological symptoms on infant development after 1 year.

A large number of articles exist on thyroid hormone function and its clinical correlates, but only a few exist on trials with thyroid hormones in premature infants. Most of these trials had clinical short-term endpoints, while only one trial had a long-term neurodevelopmental endpoint. None of the trials reported changes in mortality and morbidities. A trend toward a lower occurrence of patent ductus arteriosus is found in thyroid hormone treated infants. A gestational age-dependent effect of thyroxine on neurodevelopmental outcome was found in post-hoc subgroup analyses up until the age of 10 years. Thyroxine treatment was associated with improved mental, motor, and neurological outcomes in infants <28 weeks gestation, but with worse mental and neurological outcome in infants of 29 weeks gestation. Future trials should focus on neurodevelopmental outcomes. Continuous administration of thyroid hormone may be more effective than bolus administration.

Background: Assessment of general movements (GMs) at three months is considered useful for prediction of adverse neurological outcome in high risk infants., Aims: To study the prevalence of abnormal GMs in infants born from women with early-onset hypertensive disorders of pregnancy and the association of GMs with neurodevelopmental outcome at one year., Study Design: Prospective study, part of a randomised controlled trial of pre-birth management strategies., Subjects: Infants born from women with early-onset hypertensive disorders of pregnancy., Outcome Measures: GMs observation and neurological examination at term and three months corrected age; at one year neurological examination and Bayley Scales of Infant Development., Results: From 216 women included, 175 of 178 surviving infants (mean gestational age 31.6 weeks [SD 2.3], mean birth weight 1346 grams [SD 458]), were examined at three months. At term age normal, mildly abnormal and definitely abnormal GMs were observed in 54%, 36% and 10% respectively; and at three months in 47%, 40% and 13%. Mildly or definitely abnormal GMs at three months were not associated with abnormal neurological examination at one year, however, they were associated with delayed psychomotor development at one year (p = 0.01)., Conclusions: In this prospective study, including small for gestational age, preterm infants about half of them did not have normal GMs at term and three months. There was no association of GMs at term nor three months with neurological outcome at one year, but there was a significant association of GMs at three months with one year psychomotor development.

The aim of the present study was to evaluate whether the application of Dutch versus US test procedures and norms of the Bayley Scales of Infant Development - 2nd edition (BSID-II) leads to different developmental outcomes. The BSID-II was administered to 376 preterm infants (191 males, 185 females; mean gestational age 30wks [SD 2.7], mean birth-weight 1242g [SD 385]) at corrected ages of 6, 12, 24, and/or 36 months. Raw scores were calculated twice with US and Dutch test procedures. Raw scores as well as Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) scores, calculated on the basis of Dutch versus US normative data, were compared. Small but statistically significant Dutch-US differences were found between raw scores. Large, clinically relevant Dutch-US differences were found for MDI and PDI scores, especially at 6 and 12 months. These differences were likely to have been caused by a bias in the Dutch normative data, although a slower developmental pace of Dutch children in general could also have a role. This study highlights the problems that can occur when using a test that was developed in another country, even when local standardization is available.

Background: Very preterm neonates are at risk of hypothyroxinemia because of prematurity as well as because of neonatal disease. Hypothyroxinemia is associated with impaired developmental outcome. Preterm infants who cannot be weaned from the ventilator can be treated with dexamethasone. Glucocorticoid administration has been found to alter thyroid hormone parameters. Therefore, dexamethasone treatment in these infants might additionally impair their thyroid function, which could have consequences for developmental outcome., Objective: To assess what changes in thyroid function occur in the first hours after initiating dexamethasone treatment in ventilated preterm infants., Methods: Preterm infants, in whom the decision was taken to start dexamethasone treatment, were included. Thyroxine (T(4)), 3,5,3'-triiodothyronine (T(3)), reverse T(3) (rT(3)), thyroid-stimulating hormone (TSH) and cortisol were determined before and 6-9 h after administration of the first dose of a postnatal dexamethasone course. Details of clinical condition were recorded at both time points., Results: Sixteen very preterm infants were included at a median age of 20 days. While clinical condition was stable between start of dexamethasone and 6-9 h thereafter, TSH and T(3) levels decreased significantly. rT(3) levels significantly increased, resulting in a decrease in the T(3)/rT(3) ratio. There was no statistically significant effect on the levels of T(4)., Conclusion: Postnatal dexamethasone administration negatively affects thyroid functioning the preterm infant with severe chronic lung disease., ((c) 2008 S. Karger AG, Basel.)

Better perinatal care has led to better survival of very preterm children, but may or may not have increased the number of children with cerebral and pulmonary morbidity. We therefore investigated the relationship between changes in perinatal care during one decade, and short-term outcome in very preterm infants. Perinatal risk factors and their effects on 28-day and in-hospital mortality, and on intraventricular haemorrhage and bronchopulmonary dysplasia (BPD) in survivors, were compared in two surveys of very preterm singleton infants in the Netherlands. Between 1983 and 1993, 28-day mortality decreased from 52.1% to 31.8% in infants of 25-27 weeks' gestation and from 15.2% to 11.3% in infants of 28-31 weeks' gestation. The incidence of intraventricular haemorrhage in survivors did not change (44.4% and 43.3% in infants of 25-27 weeks' gestation, and 29.0% and 24.0% in infants of 28-31 weeks' gestation). The incidence of BPD in survivors increased from 40.3% to 60.0% in infants of 25-27 weeks' gestation and remained similar in infants of 28-31 weeks' gestation (8.5% and 9.8% respectively). In multivariable analysis, higher mortality was associated with congenital malformation, low gestational age, low birthweight, no administration of steroids before birth, low Apgar scores and intraventricular haemorrhage, in 1983 as well in 1993, and with male gender in 1993. The effect of maternal age on mortality diminished significantly between 1983 and 1993. Intraventricular haemorrhage in surviving children was associated with low gestational age and artificial ventilation, both in 1983 and in 1993. The effect of artificial ventilation on the incidence of intraventricular haemorrhage diminished significantly between 1983 and 1993. BPD was associated with low gestational age and artificial ventilation, both in 1983 and in 1993, and with low birthweight and caesarean section in 1993. We conclude that the better survival of very preterm infants, especially of those of 25-27 weeks' gestation, has been accompanied by a similar incidence (and thus with an increased absolute number) of children with intraventricular haemorrhage and by an increased incidence of children with BPD.

Objective: To compare the long-term psychosocial and motor effects on children exposed in utero to nifedipine or ritodrine for the management of preterm labour., Design: Randomised controlled trial., Setting: Multicentre study in two university and one primary hospital in the Netherlands., Population: In the original trial, 185 women were randomised to either nifedipine (n = 95) or ritodrine (n = 90). Of the 185 liveborn children, 171 survived (92%), and of these 102 (61%) were followed up at age 9-12 years., Methods: Age-specific questionnaires were administered to the parent and teacher. Additional data were obtained from medical records., Main Outcome Measures: Questionnaires were used to assess the child's behavioural-emotional problems, quality of life (QoL), motor functioning, parenting distress and the child's education., Results: Of the 171 eligible families, 102 (61%) agreed to participate and completed the questionnaires. Response was equal in the ritodrine group (n = 54 of 83 surviving children, 65%) compared with the nifedipine group (n= 48 of 88 surviving children, 55%). After controlling for differing perinatal characteristics at birth, no significant differences between the groups were detected with respect to long-term behaviour-emotional outcome, QoL, education, motor functioning or parenting distress. Psychosocial outcome was slightly better in the nifedipine group., Conclusions: The results do not support any differential postnatal effect of the tocolytic agents ritodrine or nifedipine on the child's long-term psychosocial and motor functioning. The slightly better outcome of children randomised in the nifedipine group is most likely due to more favourable perinatal outcomes in this group. These results merit further investigation in a larger group of survivors.

Extremely low birth-weight newborns (<1000g) experience low levels of thyroid hormone that vary inversely with the severity of neonatal illness and the extent of developmental immaturity with levels reaching a nadir at approximate, equals7 days after birth; this phenomenon can persist for several weeks. In the absence of transplacental passage, 30-50% of these neonates cannot generate sufficient quantities of thyroid hormone to meet postnatal demands, placing them at an increased risk for developmental delay and cerebral palsy. Population surveys and interventional trials suggest that a therapeutic opening exists during a 'window of opportunity' corresponding to this period of diminished capacity. Variables to consider before intervention focus on the consideration that supplementation of both the substrate thyroxine and the active hormone triiodothyronine may be necessary in quantities that do not suppress thyroid-stimulating hormone release, yet overcome the persistence of increased conversion to 3,3'5'-triodo-L-thyronine, terminal deiodination, and activity of the sulfation inactivation pathways, as well as the diminished capacity of the newborn to accommodate postnatal physiologic changes. Single daily replacement doses may suppress levels of converting enzymes in the brain, suggesting that physiologic 'mimicry' provided by a constant infusion may be the preferred dosing option. Properly powered clinical trials targeting long-term developmental outcomes are needed to discern whether these interventions will do more than simply elevate blood levels of thyroid hormones to the target values of either the fetus or developing neonate. Identifying the appropriate indications for supplementation may alleviate individual pain and distress due to disability for several hundred extremely low birth-weight neonates each year in the US alone, and save society a pro-rated lifetime cost of nearly $US1 million per child.

Objective: Follow-up studies in very preterm children usually present outcome for separate developmental domains. Presence of disabilities in more than one developmental domain will show a more serious outcome picture for extreme preterm infants and may be related to a different degree of perinatal problems., Methods: At 5.5 years corrected age, outcome in the neurological, motor, cognitive, and behavioral domain was studied in 157 children born < 30 weeks gestation. The children were divided into a normal, a single, or a multiple disability group. Group differences in background, clinical characteristics, and neurodevelopmental outcome at 2 years were evaluated., Results: Thirty-nine percent had a normal developmental outcome, 17% had a single disability, and 44% had multiple disabilities. Multiple disabilities were associated with lower birth weight, BPD, and difficulties according to neurodevelopmental assessments at 2 years., Conclusion: Assessments of different developmental domains show that most very preterm children had multiple disabilities.

Objective: To assess the results of preimplantation genetic screening (PGS) for numerical chromosomal abnormalities in embryos from women of 35 years of age and older., Design: Prospective, descriptive., Method: Women who were at least 35 years received standard IVF/ICSI treatment including ovarian hyperstimulation, after which matured oocytes were recovered and inseminated. Three days after insemination, one cell was biopsied from each of the available embryos. In these cells, the copy number of 5 (first 21 patients) or 8 chromosomes was determined using fluorescence in situ hybridisation (FISH). Only embryos with a normal or unknown FISH result were implanted in the uterus. Data were collected in an electronic database., Results: PGS was done for 28 IVF- and 22 ICSI-treatments; the average age of the 50 women at the beginning of treatment was 38.5 years. There were 360 embryos generated; of the 288 biopsied embryos 156 (54%) contained an abnormal number of chromosomes. In 45 women, 1 or 2 embryos were transferred. This resulted in 8 ongoing pregnancies (8/50; 16%) and the birth of 9 children, all of whom were found to be healthy on a paediatric examination at 3 to 10 months of age. In 4 cases there was no embryo transfer because all the embryos were chromosomally abnormal., Conclusion: In the first 50 patients in The Netherlands, PGS resulted in an ongoing pregnancy rate of 16% per woman. All children showed normal growth and development.

The concentration of thyroid hormone in preterm infants is lower than that in term infants. This phenomenon is referred to as transient hypothyroxinaemia of prematurity. Low thyroid hormone levels after very preterm birth are associated with worse developmental outcome in childhood, but only one randomized controlled trial has been carried out in the surfactant era to find out whether thyroid hormone supplementation is beneficial for developmental outcome. More studies are required to find out whether thyroid hormone supplementation is beneficial, and if so, for which preterm group.

A randomized, placebo-controlled, masked study was conducted of the responses of thyroid parameters, cortisol, and the cardiovascular system to a single dose of triiodothyronine (T(3)) 24 h after birth, followed by a daily dose of thyroxine (T(4)) during 6 wk to infants <28 wk gestational age. Thirty-one infants were assigned to three groups: 1) group A: T(3) 24 h after birth plus daily T(4) during 6 wk; 2) group B: placebo T(3) and T(4) during 6 wk; and 3) group C: placebo T(3) and placebo T(4). T(4), free T(4), T(3), free T(3), reverse T(3), thyroid-stimulating hormone, and cortisol were measured in cord blood and on days 1, 3, 7, 14, 21, 42, and 56. Data on pulse rate, blood pressure, and cumulative dose of inotropic agents were collected. T(3) (0.5 microg/kg) resulted in a plasma increase until day 3. Thereafter, plasma T(3) levels were comparable between the groups. T(4), free T(4), and reverse T(3) were increased in groups A and B during the period of T(4) administration. Thyroid-stimulating hormone suppression was of shorter duration in group A. T(3) and T(4) administration did not have any effect on cortisol levels. We did not find any effects of T(3) or of T(4) administration on the cardiovascular system. A single injection of T(3) (0.5 microg/kg) given 22-26 h after birth only leads to a 2-d increase of T(3) levels and does not have effects on the cardiovascular system. This study does not support the use of T(3) according to our regimen in preterm infants.

Background: We have conducted a randomized trial with thyroxine (T4) in 200 infants <30 weeks' gestation. T4 treatment was associated with better 5-year outcome in infants <29 weeks' gestation, but with worse outcome in infants of 29 weeks. These effects could be related to low, respectively high free thyroxine (FT4) levels, Methods: For each infant, the average FT4 of 5 scheduled measurements was calculated between day 3 and day 28. Infants of the placebo and the T4 group separately were divided in 2 groups. The placebo group consisted of a group of infants with average FT4 in the lowest quartile and a group in the upper 75%. The T4 group consisted of a group of infants with average FT4 in the upper quartile and a group in the lower 75%. Developmental outcome (mental/cognitive, motor, and neurologic) at 2 and 5.7 years was compared between high and low FT4 groups, and then compared separately for the T4 and placebo group., Results: In the placebo group, low FT4 was associated with worse outcome on all domains at both time points. After correction for confounding variables, mental and neurologic outcome remained significantly different at 2 years, and motor outcome at 5 years. In the T4 group, high FT4 was not associated with worse outcome, neither at 2 nor at 5 years., Conclusions: In untreated infants, low FT4 values during the first 4 weeks after birth in infants born at <30 weeks' gestation are associated with worse neurodevelopmental outcome at 2 and 5 years. In T4-treated infants, high FT4 is not associated with worse outcome. Other factors than high FT4 concentrations must play a role in the worse outcome of the T4-treated group of 29 weeks' gestational age.

Background: Thyroid hormone is crucial for brain development during foetal and neonatal life. In very preterm infants, transient low levels of plasma T4 and T3 are commonly found, a phenomenon referred to as transient hypothyroxinaemia of prematurity. We investigated whether breast milk is a substantial resource of thyroid hormone for very preterm neonates and can alleviate transient hypothyroxinaemia. Both the influence of breast feeding on plasma thyroid hormone levels and the thyroid hormone concentration in preterm human milk were studied., Methods: Two groups were formed from the placebo group of a randomized thyroxine supplementation trial in infants born at < 30 weeks' gestational age on the basis of the mean breast milk intake during the third, fourth and fifth weeks of life. One group received more than 50% breast milk (mean breast milk intake 84%, n = 32) and the other group less than 25% breast milk (mean breast milk intake 3.3%, n = 25). Plasma thyroid hormone concentrations were compared between the two groups. Breast milk was collected from mothers of infants participating in the same trial and the thyroxine concentration in breast milk was measured with RIA after extraction., Results: No significant differences were found between both groups in plasma concentrations of T4, free T4, T3, TSH, rT3 and thyroxine-binding globulin (TBG), which were measured once a week. Thyroxine concentration in breast milk ranged between 0.17 microg/l and 1.83 microg/l (mean 0.83, SD 0.3 microg/l) resulting in a maximum T4 supply of 0.3 microg/kg via ingested breast milk. In formula milk, the T4 concentration was equally low. Protease treatment did not influence the measured T4 concentrations., Conclusions: No differences in plasma thyroid hormone between breast milk-fed and formula-fed infants were found. The amount of T4 present in human milk and formula milk is too low to alter the hypothyroxinaemic state of preterm infants.

Transient hypothyroxinemia occurs frequently in very preterm infants and is caused by a combination of factors as immaturity of the hypothalamo-pituitary-thyroid system, loss of the maternal thyroxine (T4) contribution, immaturity of thyroid hormone metabolism, and neonatal illness. Thyroid hormone is important in maturation of the brain, but also of heart and lungs. Low neonatal T4 concentrations in plasma are related to worse clinical and neurodevelopmental outcome. Despite these relationships, only few randomized clinical trials have been performed to find out whether T4 supplementation can improve clinical and/or neurodevelomental outcome of preterm infants. The currently available evidence does not support use of supplemental T4 in all preterm infants. There are, however, indications that T4 might improve neurodevelopmental outcome in infants born before 27 to 29 weeks of gestation. Therefore, it is necessary that new trials are set up to further study the benefits of thyroid hormones given in the neonatal period of very preterm infants.

Two-hundred infants of <30 weeks gestational age were included in a randomized double-blind controlled trial to study the effect of thyroxine administration on neurodevelopmental outcome in very preterm children. The infants were given either a fixed dose of thyroxine (8 microg/kg birthweight/day) or placebo for the first 6 weeks of life. This paper evaluates the effect of thyroxine administration on behavioural outcome at the age of 2 years. More externalizing, especially destructive, behaviours were found in the group given thyroxine than in the placebo group. This difference was more pronounced in boys and in children born after 27 weeks' gestation. The thyroxine-treated children with behavioural problems had lower plasma-free thyroxine levels than the thyroxine-treated children without behavioural problems. This finding suggests that the presence of more behavioural problems in the group given thyroxine was not an immediate consequence of the treatment.

Thyroid hormones are essential for brain maturation. Very preterm infants, who are at risk of neurodevelopmental disabilities also have low thyroxine (T4) and free thyroxine (FT4) values in the first weeks after birth. This transient hypothyroxinemia may in part be causal to the neurodevelopmental problems. We have carried out a randomized, double-blind, placebo-controlled trial with T4 in 200 infants less than 30 weeks gestation. T4 (or placebo) was given in fixed dose of 8 microg/kg birth weight per day during the first 6 weeks after birth. It resulted in a significant increase of T4, FT4, and reverse triiodothyronine (rT3). Thyrotropin (TSH) secretion was suppressed, and, probably as a result of TSH suppression, triodothyronine (T3) levels were decreased in the T4 group. Mortality was 14% in the T4 group and 21% in the placebo group (NS). No effect was found on morbidity. Heart rate was significantly higher in T4-treated infants less than 28 weeks gestation, but not in T4-treated infants 28 weeks or more, who had the highest FT4 levels. In the study groups as a whole, no clear effect of T4 administration was found on neurodevelopmental outcome. However, there was a strong trend toward improvement of adverse outcome, defined as death or abnormal developmental outcome at 2 years of age. In addition, mental outcome in a subgroup of T4-treated infants less than 27 weeks' gestation was significantly better than in placebo infants of the same age group. In conclusion, this trial does not clearly have conclusive results. New trials of thyroid hormone treatment should be carried out in preterm infants, in order to investigate whether indeed T4 supplementation is required in preterm infants less than 27 or 28 weeks gestation. Addition of T3 to the treatment schedule needs to be considered.

Objective: To study the effect of L-thyroxine supplementation on neurologic maturation in very preterm infants with transient hypothyroxinemia., Design: Randomized, double-blind, placebo-controlled, L-thyroxine supplementation trial., Setting: Level III neonatal intensive care unit., Subjects: A total of 200 infants <30 weeks' gestational age., Intervention: Subjects were randomly assigned to receive L-thyroxine (8 microg/kg birth weight per day) or a placebo during the first 6 weeks of life., Methods: Median nerve somatosensory evoked potentials were recorded, measuring cortical N1 peak latency at 2 weeks of age, at term, and at 6 months (corrected) age., Results: Cortical N1 peak latency was not decreased significantly in the L-thyroxine group compared with the placebo group throughout the study period., Conclusion: L-Thyroxine supplementation during the first 6 weeks of life did not decrease cortical N1 peak latency in infants of <30 weeks' gestational age.

Background: Transient hypothyroxinemia is common in preterm infants and has been associated with neurodevelopmental dysfunction and slow nerve conduction velocity. It is still unknown whether L-thyroxine supplementation is required. During an L-thyroxine supplementation trial, motor nerve conduction velocity was measured to answer the question whether L-thyroxine supplementation improves motor nerve conduction velocity., Methods: Two hundred infants < 30 weeks' gestational age were enrolled in a randomized, double-blind, placebo-controlled L-thyroxine supplementation trial. L-Thyroxine (8 micrograms/kg birthweight per day) or a placebo was administered during the first 6 weeks of life. Motor nerve conduction velocity was measured in the ulnar and posterior tibial nerve shortly after birth, at 2 weeks, at 40 weeks, and at 66 weeks postmenstrual age., Results: At 2 weeks, the ulnar motor nerve conduction velocity had improved in the L-thyroxine group compared with the placebo group, although the difference was not statistically significant (difference between means: 0.8 msec; 95% CI: -0.13 to 1.80; p = 0.06). Later on, no effect of L-thyroxine supplementation on motor nerve conduction velocity was found., Conclusion: This study shows that in infants < 30 weeks' gestational age L-thyroxine supplementation during the first 6 weeks of life does not clearly improve motor nerve conduction velocity.

It is not known how immaturity and disease influence postnatal thyroid function in infants <30 wk of gestational age. We performed serial measurements of plasma thyroxine (T4), free T4 (FT4), triiodothyronine (T3), reverse T3 (rT3), TSH, and T4-binding globulin (TBG) in 100 infants of <30 wk of gestation, during the first 8 postnatal weeks, to investigate the influences of disease and gestational age on the time course of thyroid hormones. One hundred infants were divided twice into two groups: 1) in a group of 25-28 and of 28-30 wk of gestation; and 2) in a sick and a healthy group, with similar gestational ages. The time course of T4, FT4, T3, TSH, and TBG, but not rT3 differed significantly (p < 0.005) between the gestational age groups. T4 and FT4 decreased to levels below the cord blood value with a deeper FT4 nadir on d 7 in the youngest group. Disease decreased T4, FT4, T3, TSH, and TBG concentrations especially during the 1st wk after birth (p < 0.005). However, the FT4 nadir on d 7 was similar in sick and healthy infants. After 3 wk, T4, FT4, T3, and TBG were higher in the sick group compared with the healthy group. rT3 levels were not increased in sick infants. We conclude that the extent of the FT4 decrease after birth in infants of <30 wk gestation is mainly influenced by gestational age and probably reflects a transient depletion of thyroidal hormone reserves. rT3 cannot be used as a marker of nonthyroidal illness in very preterm infants.

Background: Premature infants who have transient hypothyroxinemia in the first weeks of life may have developmental delay and neurologic dysfunction. Whether thyroxine treatment during this period results in improved developmental outcomes is not known., Methods: We carried out a randomized, placebo-controlled, double-blind trial of thyroxine supplementation in 200 infants born at less than 30 weeks' gestation. Thyroxine (8 microg per kilogram of birth weight) or placebo was administered daily, starting 12 to 24 hours after birth, for six weeks. Plasma free thyroxine concentrations were measured weekly for the first eight weeks after birth. Scores on the Bayley Mental and Psychomotor Development Indexes and neurologic function were assessed at 6, 12, and 24 months of age (corrected for prematurity)., Results: Mortality and morbidity up to the time of discharge from the hospital were similar in the study groups. At 24 months of age, 157 infants were evaluated. Overall, neither mental nor psychomotor scores differed significantly between the study groups at any time, nor was the frequency of abnormal neurologic outcome significantly different. In thyroxine-treated infants born at gestational ages of less than 27 weeks, the score on the Bayley Mental Development Index at 24 months of age was 18 points higher than the score for the infants with similar gestational ages at birth in the placebo group (P=0.01); for thyroxine-treated infants born at 27 weeks or later, the mental-development score was 10 points lower than that of their counterparts in the placebo group (P=0.03). There was no relation between the initial plasma free thyroxine concentration and the effect of treatment., Conclusions: In infants born before 30 weeks' gestation, thyroxine supplementation does not improve the developmental outcome at 24 months.

Thyroid hormones are essential for brain maturation. Very preterm infants, who are at risk of neurodevelopmental disabilities also have low T4 and FT4 values in the first weeks after birth. This transient hypothyroxinemia may in part be causal to the neurodevelopmental problems. We have carried out a randomised, double-blind, placebo-controlled trial with T4 in 200 infants < 30 weeks' gestation. In the study groups as a whole (n = 100 in the T4 group, n = 100 in the Placebo group), no clear effect of T4 administration was found. In this study we examined whether gestational age influenced the effect of T4 administration. The T4- and placebo groups were subdivided into 4 groups according to gestational age. FT4-values during the first weeks after birth were lowest in the youngest gestational age group in the T4 as well as in the placebo group. In this group with infants < 27 weeks' gestation mental developmental outcome at 2 years of age was significantly better than in the placebo group of the same gestational age. There was also a trend towards a better psychomotor and neurological outcome. Beyond 27 weeks' gestation, no clear effect of T4 could be found; on the contrary, a possible harmful effect on mental developmental outcome might be the result. In conclusion. T4 treatment possibly improves developmental outcome in infants < 27 weeks' gestation, but seems not necessary beyond this gestational age.

Very preterm infants (less than 30 weeks' gestational age) were treated with thyroxine in three different dosage schemes: 10, 8 and 6 micrograms.kg-1 birthweight.day-1 during the first 6 weeks of life. The aim was to prevent transient hypothyroxinemia of the preterm infant. Plasma levels of thyroxine, free thyroxine, triiodothyronine, reverse triiodothyronine, thyroxine-binding globulin and thyrotropin were measured weekly. Thyroxine administration increased thyroxine and free thyroxine levels most properly in the 8-micrograms supplementation group. It did not result in a change in plasma triiodothyronine levels. Levels of reverse triiodothyronine increased in relation to the thyroxine dosage. Thyrotropin secretion was suppressed in the 6- and 8-micrograms groups during the first 2 weeks, while in the 10-micrograms group suppression lasted 4 weeks. No clinical adverse effects of thyroxine administration were seen. We conclude that 8 micrograms thyroxine.kg-1 birthweight.day-1 for 6 weeks prevents transient hypothyroxinemia. The finding that plasma triiodothyronine concentrations are not influenced by thyroxine administration suggests a specific maturation process in the deiodination of thyroxine.

Lactase-phlorizin hydrolase, a small intestinal disaccharidase, has been considered mainly an enzyme important only for the hydrolysis of lactose. After weaning in most mammals lactase-specific activity falls markedly, and, functionally, adult mammals are considered to be lactase deficient. However, the persistence of low levels of lactase activity in adulthood has never been explained. In addition, it has been suggested that lactase-phlorizin hydrolase is associated with glycosylceramidase activity when the enzyme is prepared by column chromatography, but it is unclear whether this represents copurified activities or two catalytic sites on one peptide. The developmental patterns of lactase-phlorizin hydrolase and other disaccharidases were investigated in homogenates of total rat small intestine; lactase and several glycosylceramidases were measured in immunoprecipitates from these homogenates using a monoclonal antibody. The developmental pattern of total lactase activity showed a steady 2.3-fold increase to adult levels (specific activity decreased eightfold), whereas total phlorizin-hydrolase activity increased 10.7-fold (specific activity decreased threefold). As expected, levels of both total and specific sucrase and maltase activities increased during development. In lactating rats total lactase activity showed a significant increase compared with adult males. The developmental pattern of the enzyme activities for the glycolipid substrates was similar to that found for lactase, and the immunoprecipitated enzyme showed a 40- to 55-fold higher affinity for the glycolipids than for lactose. Galactosyl- and lactosylceramide inhibited lactose hydrolysis by 38%, without a competitive pattern, suggesting two different active sites for lactose and glycolipid hydrolysis, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Three cases of partial anomalous pulmonary venous return, in one case combined with coarctation of the aorta and in another with discrete subaortic stenosis, are described in patients with Turner syndrome. In two of them the right and left superior pulmonary veins drained into the right superior vena cava and left innominate vein respectively. Remarkably, in all three cases the atrial septum was intact. We feel that this unique combination probably is not purely coincidental, but might rather be specific for Turner syndrome.