Duration of mechanical ventilation and neurodevelopment in preterm infants.

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.

Perinatal risk-indicators for long-term respiratory morbidity among preterm or very low birth weight neonates.

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.

Difference in mother-child interaction between preterm- and term-born preschoolers with and without disabilities.

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.

Effects on (neuro)developmental and behavioral outcome at 2 years of age of induced labor compared with expectant management in intrauterine growth-restricted infants: long-term outcomes of the DIGITAT trial.

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.

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.

A systematic review of severe morbidity in infants born late preterm.

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.

Perinatal risk indicators for long-term neurological morbidity among preterm neonates.

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.

Outcome at 4.5 years of children born after expectant management of early-onset hypertensive disorders of pregnancy.

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.

High incidence of multi-domain disabilities in very preterm children at five years of age.

OBJECTIVES: To describe the prevalence and co-occurrence of disabilities and their association with parental education in preterm children and term control subjects. STUDY DESIGN: In a prospective study, preterm children (n=104), born at <30 weeks' gestation or birth weight <1000 g, and term children (n=95) were assessed at corrected age 5 with an intelligence quotient (IQ) test, behavior questionnaires for parents and teachers, and motor and neurologic tests. A disability was defined as results in the mild abnormal range of each test or below. Associations of outcomes with parental education were studied. RESULTS: Of the preterm children, 75% had at least one disability and 50% more than one, compared with 27% and 8%, respectively, of term control subjects (P<.01). The preterm-term difference in full scale IQ increased from 5 IQ points if parental education was high to 14 IQ points if it was low, favoring the term children in both groups. A similar pattern was found for behavior, but not for motor and neurologic outcome. CONCLUSIONS: Disabilities occur frequently after very preterm birth and tend to aggregate. Neurologic and motor outcomes are mostly influenced by biologic risk, and social risks contribute to cognitive and behavioral outcome.

Long-term health-related and economic consequences of short-term outcomes in evaluation of perinatal interventions.

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.

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.

Phase 1 trial of 4 thyroid hormone regimens for transient hypothyroxinemia in neonates of <28 weeks' gestation.

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.

No association between maternal psychological symptoms and infant outcome after pregnancy complicated by early-onset hypertensive disorders.

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.

Trials with thyroid hormone in preterm infants: clinical and neurodevelopmental effects.

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.

Postnatal administration of dexamethasone for weaning off the ventilator affects thyroid function.

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.

Lower mortality but higher neonatal morbidity over a decade in very preterm infants.

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.

Neonatal thyroxine supplementation for transient hypothyroxinemia of prematurity : beneficial or detrimental?

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.

Transient hypothyroxinemia in severe hypertensive disorders of pregnancy.

OBJECTIVE: Assess whether and to what extent thyroid function is affected in pregnant women with early and severe hypertensive disorders and in their newborns. METHODS: Patients were 80 women with preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome or gestational hypertension combined with fetal growth restriction in the 24th to 34th week of singleton pregnancies. Maternal thyroid hormone levels and thyroid peroxidase antibodies were determined at admission and 3 months postpartum. Neonatal levels were determined from cord blood at delivery. Maternal hypothyroxinemia was defined as free T(4) (fT(4)) value below 9 pM. RESULTS: At admission 26 (33%) women in the study group had fT(4) levels below 9 pM, with spontaneous normalization during pregnancy. There were no statistically significant differences between thyroid hormone values in women in the study group and 10 normotensive pregnant women in their third trimester. Three months postpartum, 97.5% of patients had normal thyroid hormone levels. Thyroid peroxidase antibodies were elevated in 10% of women postpartum. Their infants, born at a median gestational age of 30 6/7 weeks, had lower cord blood fT(4) and thyroid-stimulating hormone values compared with preterm infants of the comparison group, appropriate for gestational age. Cord blood fT(4) had no correlation with gestational age or maternal fT(4), but there was a significant correlation of cord blood fT(4) with umbilical artery pH. CONCLUSION: Women with severe hypertensive disorders of pregnancy may have transiently lower fT(4) levels, without evidence of a thyroid disorder. Their neonates have lower fT(4) levels at birth unrelated to maternal fT(4), but related to prenatal acidosis. LEVEL OF EVIDENCE: II-2.

Ten-year follow-up of children born at <30 weeks' gestational age supplemented with thyroxine in the neonatal period in a randomized, controlled trial.

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.

Very preterm birth is associated with disabilities in multiple developmental domains.

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.