Intrapartum and neonatal mortality among low-risk women in midwife-led versus obstetrician-led care in the Amsterdam region of the Netherlands: a propensity score matched study.

OBJECTIVE: To compare intrapartum and neonatal mortality in low-risk term women starting labour in midwife-led versus obstetrician-led care. STUDY DESIGN: We performed a propensity score matched study using data from our national perinatal register, completed with data from medical files. We studied women without major risk factors with singleton pregnancies who gave birth at term between 2005 and 2008 in the Amsterdam region of the Netherlands. Major risk factors comprised non-vertex position of the fetus, previous Caesarean birth, hypertension, (gestational) diabetes mellitus, post-term pregnancy (≥42 weeks), prolonged rupture of membranes (>24 hours), vaginal bleeding in the second half of pregnancy or induced labour. Groups were devided by midwife-led versus obstetrician-led care at the onset of labour. The primary outcome was intrapartum and neonatal (<28 days) mortality. Secondary outcomes included obstetric interventions, 5 min Apgar scores<7 and neonatal intensive care admittance for >24 hours. RESULTS: We studied 57 396 women. Perinatal mortality occurred in 30 of 46 764 (0.64‰) women in midwife-led care and in 2 of 10 632 (0.19‰) women in obstetrician-led care (OR 3.4, 95% CI 0.82 to 14.3). A propensity score matched analysis in a 1:1 ratio with 10 632 women per group revealed an OR for perinatal mortality of 4.0 (95% CI 0.85 to 18.9). CONCLUSION: Among low-risk women, midwife-led care at the onset of labour was associated with a statistically non-significant higher mortality rate.

Accuracy of the Diagnosis of Bronchopulmonary Dysplasia in a Referral-Based Health Care System.

OBJECTIVE: To evaluate the accuracy of the diagnosis of bronchopulmonary dysplasia (BPD) in a national database of a referral-based health care system, where preterm infants are often transferred back to regional hospitals before 36 weeks postmenstrual age (PMA). STUDY DESIGN: We evaluated preterm infants <32 weeks, born between 2004 and 2008 in the Academic Medical Center in Amsterdam with a high-risk profile for BPD. In addition to patient characteristics and outcomes, we collected data on respiratory support at 36 weeks PMA. True incidence of BPD, defined as needing supplemental oxygen and/or positive pressure support at 36 weeks PMA, was compared with the diagnosis registered in the National Perinatal Registry. Two imputation algorithms for patients transferred before 36 weeks PMA were validated. RESULTS: We identified 243 preterm infants with a high-risk BPD profile. Sixty-seven percent of these infants had a correct BPD diagnosis recorded in the National Perinatal Registry, 2% had a false positive, and 31% a false negative diagnosis. Infants with a false negative diagnosis of BPD were twice as often transferred to a regional hospital before 36 weeks PMA compared with a true positive diagnosis. Imputation algorithms did not improve the accuracy of BPD registration. CONCLUSIONS: Registration of the diagnosis BPD in a national database in countries with a referral-based health care system may not be accurate. Optimizing data collection and monitoring data entry is necessary to improve BPD registration before data can be used for national and international benchmarking.

[Decline in foetal and neonatal mortality in the Netherlands: comparison with other Euro-Peristat countries between 2004 and 2010]. / Afname van foetale en neonatale sterfte in Nederland: vergelijking met andere Euro-Peristat-landen in 2004 en 2010.

OBJECTIVE: To compare the change in foetal and neonatal mortality in the Netherlands between 2004 and 2010 with the change in other European countries. DESIGN: Descriptive, population-based study. METHOD: Data from the Euro-Peristat project on foetal and neonatal mortality in European countries were analysed for changes between 2004 and 2010. The Netherlands was compared with 26 other European countries and regions. International differences in registration and policy were taken into account using figures on foetal mortality starting at 28 weeks of pregnancy and neonatal mortality starting at 24 weeks of pregnancy. RESULTS: Foetal mortality in the Netherlands declined by 33%, from 4.3 per 1000 births in 2004 to 2.9 per 1000 births in 2010 while neonatal mortality declined by 21%, from 2.8 per 1000 live births in 2004 to 2.2 per 1000 live births in 2010. Perinatal mortality (the sum of foetal mortality and neonatal mortality) declined by 27%, from 7.0 to 5.1 per 1000. In the European ranking, the Netherlands shifted from 23rd to 13th place for foetal mortality; it remained the same for neonatal mortality (15th of 22 countries) and virtually the same for perinatal mortality (from 15th to 13th of 22 countries). CONCLUSIONS: Both foetal mortality at 28+ weeks and neonatal mortality at 24+ weeks declined in the Netherlands between 2004 and 2010. However, the relatively unfavourable position of the Netherlands in the European ranking for foetal and neonatal mortality improved only for foetal mortality. In that respect, the Netherlands holds an average position.

The validity of the variable "NICU admission" as an outcome measure for neonatal morbidity: a retrospective study.

OBJECTIVE: To determine whether "neonatal intensive care unit (NICU) admission" is a valid surrogate outcome measure to assess neonatal condition in clinical studies. DESIGN: Retrospective study. SETTING: Tertiary hospital in the Netherlands. POPULATION: Neonates admitted to NICU during a 10-year period. Inclusion was restricted to singletons born beyond 37 weeks of gestation, and admitted to NICU in the first 24 h for delivery-related morbidity. METHODS: Patient characteristics and admission data were compared for four groups based on the line of care during delivery, i.e. home birth (Ia), midwife-led hospital delivery (Ib), secondary care (II), tertiary care (III). MAIN OUTCOME MEASURES: Percentage of neonates/infants that died during NICU admission, diagnosis on admission, treatment received and a Neonatal Therapeutic Intervention Score System (NTISS). RESULTS: We studied 776 newborns (Ia 52, Ib 25, II 160, III 512, 27 unknown). The mortality rate differed significantly (Ia 15%, Ib 12%, II 22%, III 1%, p < 0.01), as did the NTISS morbidity scores at admission [Ia 12.0 (6.0-23.0), Ib 8.5 (6.3-10.0), II 21.0 (15.0-30.0), III 6.0 (4.0-9.0); p < 0.01], diagnosis at admission, received treatment and the duration of admission. CONCLUSIONS: The severity of neonatal illness after 37 weeks of gestation differed depending on the line of care in which they were born, with neonates born in secondary care consistently having the highest morbidity, and those born in tertiary care having the lowest. NICU admission should not be used as an outcome measure for neonatal morbidity, specifically not when comparing different birth settings.

Antenatal prediction of neonatal mortality in very premature infants.

OBJECTIVE: To develop a prognostic model for antenatal prediction of neonatal mortality in infants threatening to be born very preterm (<32 weeks). STUDY DESIGN: Nationwide cohort study in The Netherlands between 1999 and 2007. We studied 8500 singletons born between 25(+0) and 31(+6) weeks of gestation where fetus was alive at birth without congenital anomalies. We developed a multiple logistic regression model to estimate the risk of neonatal mortality within 28 days after birth, based on characteristics that are known before birth. We used bootstrapping techniques for internal validation. Discrimination (AUC), accuracy (Brier score) and calibration (graph, c-statistics) were used to assess the model's predictive performance. RESULTS: Neonatal mortality occurred in 766 (90 per 1000) live births. The final model consisted of seven variables. Predictors were low gestational age, no antental corticosteroids, male gender, maternal age ≥35 years, Caucasian ethnicity, non-cephalic presentation and non-3rd level of hospital. The predicted probabilities ranged from 0.003 to 0.697 (IQR 0.02-0.11). The model had an AUC of 0.83, the Brier score was 0.065. The calibration graph showed good calibration, and the test for the Hosmer Lemeshow c-statistic showed no lack of fit (p=0.43). CONCLUSIONS: Neonatal mortality can be predicted for very preterm births based on the antenatal factors gestational age, antental corticosteroids, fetal gender, maternal age, ethnicity, presentation and level of hospital. This model can be helpful in antenatal counseling.

A comparison of perinatal outcomes in singletons and multiples born after in vitro fertilization or intracytoplasmic sperm injection stratified for neonatal risk criteria.

OBJECTIVE: To compare perinatal singleton and multiple outcomes in a large Dutch in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) population and within risk subgroups. Newborns were assigned to a risk category based on gestational age, birthweight, Apgar score and congenital malformation. DESIGN: Register-based retrospective cohort study. SETTING: Netherlands Perinatal Registry data. SAMPLE: A total of 3041 singletons and 1788 multiple children born from IVF/ICSI in 2003-2005. METHODS: Student's t-test or Mann-Whitney U-test was used to analyze continuous data, chi-squared analyses were used for categorical data. Multivariate logistic and linear regression analysis was performed to analyze whether the risk stratification criteria were associated with neonatal hospital admission and length of stay. MAIN OUTCOME MEASURES: Start of labor, mode of delivery, gestational age, birthweight, 5-min Apgar score, congenital malformation, neonatal hospital admission, neonatal intensive care unit admission and mortality. RESULTS: IVF/ICSI-conceived multiples had considerably poorer outcomes than singletons in terms of cesarean section rate, preterm birth, birthweight, being small-for-gestational-age, Apgar score, neonatal hospital admission, neonatal intensive care unit admission and neonatal mortality. As opposed to the results found in the total study population and the low-risk and moderate-risk populations, high-risk multiples showed better outcomes than high-risk singletons regarding cesarean section rate, birthweight and Apgar score. All risk stratification variables were associated with being hospitalized after birth. Length of stay was associated with all risk stratification criteria except Apgar score. CONCLUSIONS: Perinatal outcomes in IVF/ICSI-conceived multiples are considerably poorer than in singletons. This finding mainly pertains to low-risk children. High-risk multiples had significantly better perinatal outcomes than high-risk singletons.

Prediction of cognitive abilities at the age of 5 years using developmental follow-up assessments at the age of 2 and 3 years in very preterm children.

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.

Prediction of mortality in very premature infants: a systematic review of prediction models.

CONTEXT: Being born very preterm is associated with elevated risk for neonatal mortality. The aim of this review is to give an overview of prediction models for mortality in very premature infants, assess their quality, identify important predictor variables, and provide recommendations for development of future models. METHODS: Studies were included which reported the predictive performance of a model for mortality in a very preterm or very low birth weight population, and classified as development, validation, or impact studies. For each development study, we recorded the population, variables, aim, predictive performance of the model, and the number of times each model had been validated. Reporting quality criteria and minimum methodological criteria were established and assessed for development studies. RESULTS: We identified 41 development studies and 18 validation studies. In addition to gestational age and birth weight, eight variables frequently predicted survival: being of average size for gestational age, female gender, non-white ethnicity, absence of serious congenital malformations, use of antenatal steroids, higher 5-minute Apgar score, normal temperature on admission, and better respiratory status. Twelve studies met our methodological criteria, three of which have been externally validated. Low reporting scores were seen in reporting of performance measures, internal and external validation, and handling of missing data. CONCLUSIONS: Multivariate models can predict mortality better than birth weight or gestational age alone in very preterm infants. There are validated prediction models for classification and case-mix adjustment. Additional research is needed in validation and impact studies of existing models, and in prediction of mortality in the clinically important subgroup of infants where age and weight alone give only an equivocal prognosis.

Long term costs and effects of reducing the number of twin pregnancies in IVF by single embryo transfer: the TwinSing study.

BACKGROUND: Pregnancies induced by in vitro fertilisation (IVF) often result in twin gestations, which are associated with both maternal and perinatal complications. An effective way to reduce the number of IVF twin pregnancies is to decrease the number of embryos transferred from two to one. The interpretation of current studies is limited because they used live birth as outcome measure and because they applied limited time horizons. So far, research on long-term outcomes of IVF twins and singletons is scarce and inconclusive. The objective of this study is to investigate the short (1-year) and long-term (5 and 18-year) costs and health outcomes of IVF singleton and twin children and to consider these in estimating the cost-effectiveness of single embryo transfer compared with double embryo transfer, from a societal and a healthcare perspective. METHODS/DESIGN: A multi-centre cohort study will be performed, in which IVF singletons and IVF twin children born between 2003 and 2005 of whom parents received IVF treatment in one of the five participating Dutch IVF centres, will be compared. Data collection will focus on children at risk of health problems and children in whom health problems actually occurred. First year of life data will be collected in approximately 1,278 children (619 singletons and 659 twin children). Data up to the fifth year of life will be collected in approximately 488 children (200 singletons and 288 twin children). Outcome measures are health status, health-related quality of life and costs. Data will be obtained from hospital information systems, a parent questionnaire and existing registries. Furthermore, a prognostic model will be developed that reflects the short and long-term costs and health outcomes of IVF singleton and twin children. This model will be linked to a Markov model of the short-term cost-effectiveness of single embryo transfer strategies versus double embryo transfer strategies to enable the calculation of the long-term cost-effectiveness. DISCUSSION: This is, to our knowledge, the first study that investigates the long-term costs and health outcomes of IVF singleton and twin children and the long-term cost-effectiveness of single embryo transfer strategies versus double embryo transfer strategies.

Short- and long-term outcome of infants born after maternal (pre)-eclampsia, HELLP syndrome and thrombophilia: a retrospective, cohort study.

OBJECTIVES: To investigate the short- and long-term outcome of children born from mothers with pre-eclampsia, eclampsia and/or HELLP syndrome, and to determine the differences between children born from mothers with and without underlying thrombophilic disorder. STUDY DESIGN: Four hundred and nine infants (from 370 women) born between February 1991 and January 2006 were eligible for evaluation and were classified into group A (n = 162) and group B (n = 247). Thirty-four infants were not admitted to the hospital. Between-group differences were tested with regard to neonatal mortality, morbidity and follow-up measurements for neuromotor and mental development at 9 months and 2 years of age, using two-tailed Student's t-tests, Fisher's exact tests and logistic regression models. RESULTS: Of the 409 infants, 44 infants (10.8%; n = 20 group A/n = 24 group B) died. The mean gestational age in both groups was 31.9 (SD: 3.5) weeks. Of the 375 admitted infants 152 (40.5%) were related to a thrombophilic mother and 223 (59.5%) were not. Six children were lost to follow-up. At 9 months and 2 years of age development was assessed in 326 surviving children. At 9 months of age, 193 (59.2%; n = 66 group A/n = 127 group B) children showed a normal (52% group A versus 63.8% group B, P=0.046), 24 (7.4%; n = 9 group A/n = 15 group B) a suspect and 14 (4.3%; n = 6 group A, n=8 group B) an abnormal development during follow-up assessment. Ninety-five children (29.1%; n = 46 group A/n = 49 group B) did not have a follow-up assessment. At 2 years of age, 112 children (34.4%; n = 43 group A/n = 69 group B) had a normal, 21 (6.4%; n = 11 group A/n = 10 group B) a suspect and 17 (5.2%; n = 5 group A/n = 12 group B) an abnormal development. 176 children (54%; n = 70 group A/n = 106 group B) did not have a follow-up assessment. CONCLUSION: Short-term outcome was not different between infants from mothers with or without thrombophilic disorders. At 9 months of age, the probability of having a normal development was significantly lower in children born from a mother with an underlying thrombophilic disorder than in those without. At 2 years of age, no differences in development were observed.

Improvement of developmental outcome between 24 and 36 months corrected age in very preterm infants.

AIM: To study early developmental course in preschool-aged very preterm infants and its association with perinatal risk factors and test-taking behaviour. METHODS: Children born <30 weeks gestation and/or <1000g in the Academic Medical Center of Amsterdam were assessed at 24 and 36 months corrected age with the Dutch Bayley Scales of Infant Development-II (BSID-II-NL) and neurological examination. Linear regression analyses for developmental change were performed with perinatal risk factors. RESULTS: One hundred and forty-six children, mean GA 28 weeks and mean birth weight 1043 g, participated. Mental and psychomotor scores improved significantly with 6 and 7 points, respectively, from 24 to 36 months (p < 0.01). Mild to severe problems on at least one domain occurred less often at 36 (32%) compared to 24 months (63%) (p < 0.01), using corrected scores. Mental improvement was associated with being born very small for gestational age or <28 weeks; psychomotor improvement was associated with not being treated with indomethacin. Difficult test behaviour occurred mostly at 24 months and was associated with non-optimal development at 36 months. CONCLUSION: Improved developmental outcome and test behaviour were found at 36 compared to 24 months in a cohort of very preterm children. Long-term outcome studies and retesting of behaviourally difficult children are recommended.

Free thyroxine levels during the first weeks of life and neurodevelopmental outcome until the age of 5 years in very 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.

The quantity of thyroid hormone in human milk is too low to influence plasma thyroid hormone levels in the very preterm infant.

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.