Sylvia Veen

Developmental outcome at 18 and 24 months of age in very preterm children: a cohort study from 1996 to 1997

OBJECTIVE To determine the effect of prematurity (gestational age (GA) < 32 weeks) on developmental outcome at the corrected age of 18 and 24 months in a regionally defined, prospective cohort study. STUDY DESIGN The Leiden Follow-Up Project on Prematurity (LFUPP) includes all live-born infants < 32 weeks GA, born in 1996/1997 in three Dutch health regions (n=266). Mental and psychomotor developmental indices (MDI, PDI) were determined with the Bayley Scales of Infant Development I: > or = -1 S.D.: normal, -2 to -1 S.D.: moderate delay and < -2 S.D.: severe delay. RESULTS At 18 months 168 (71%) and at 24 months, 151 children (64%) of 235 survivors were assessed. Moderate to severely delayed mental and/or psychomotor development occurred in 40% of the children at both ages. Children lost to follow-up were of lower socioeconomic status and more frequently of non-Dutch origin. Since non-Dutch origin negatively affected the outcome at both test ages, availability of the data of these children would probably have worsened the outcome. Postnatal treatment with dexamethasone was associated with an increased risk of delayed development. Other independent predictors of delayed development were bronchopulmonary dysplasia at 18 months and ethnicity, maternal age at birth, birthweight and gender at 24 months. After adjustment for these other predictors of delayed development, the mean PDI of dexamethasone-treated infants was 16.1 points lower than of non-treated infants at 18 months (p=0.03) and 12.7 points lower at 24 months (p=0.04). CONCLUSIONS At 18 and 24 months corrected age, 40% of the very prematurely born children had both delayed mental and/or psychomotor development. Treatment with dexamethasone postnatally was a major risk factor for delayed (psychomotor) development.

Perinatal outcome, health, growth, and medical care utilization of 5-to 8-year-old intracytoplasmic sperm injection singletons

OBJECTIVE To evaluate short- and long-term health in intracytoplasmic sperm injection (ICSI) singletons. DESIGN Follow-up study. SETTING University medical center, assessments between March 2004 and May 2005. PATIENT(S) Singletons born between June 1996 and December 1999 after ICSI in the Leiden University Medical Center laboratory were compared with matched singletons born after IVF and natural conception. INTERVENTION(S) Mode of conception. MAIN OUTCOME MEASURE(S) An examiner blinded to the conception mode of the child assessed congenital malformations and growth. Information on pregnancy, perinatal period, birth defects, general health, and medical consumption was obtained through questionnaires. RESULT(S) Outcomes of children conceived by ICSI and IVF (n = 81/81, preterm infants excluded) were comparable or even more positive for ICSI. Perinatal outcomes were poorer after ICSI than natural conception: prematurity: P=.014; low birth weight: odds ratio = 7.4, 95% confidence interval (CI) [0.9; 62.5]; mean birth weight: Delta = 186 g, 95% CI [21; 351]. The ICSI mothers had more pregnancy complications (n = 33 vs. 18) and in-hospital deliveries (prevalence ratio 1.36, 95% CI 1.17; 1.48). No further differences were found between ICSI and natural conception children on congenital malformations, health, growth, and medical consumption (n = 87/85, preterm infants included). CONCLUSION(S) No adverse health outcomes were identified in ICSI singletons up to age 5-8 years compared to IVF and natural conception singletons, besides poorer perinatal outcomes after ICSI versus natural conception.

Neonatal Dexamethasone Treatment for Chronic Lung Disease of Prematurity Alters the Hypothalamus-Pituitary-Adrenal Axis and Immune System Activity at School Age

OBJECTIVE. To compare long-term effects of neonatal treatment with dexamethasone or hydrocortisone for chronic lung disease of prematurity on the hypothalamus-pituitary-adrenal axis and the immune response in children at school age. PATIENTS AND METHODS. A total of 156 prematurely born children were included in this retrospective matched cohort study. Children treated with dexamethasone (n = 52) or hydrocortisone (n = 52) were matched for gestational age, birth weight, grade of infant respiratory distress syndrome, grade of periventricular or intraventricular hemorrhage, gender, and year of birth. A reference group of 52 children not treated with corticosteroids was included for comparison. Plasma adrenocorticotropic hormone and cortisol in response to a social stress task were determined. Cytokine production was analyzed after in vitro stimulation of whole-blood cultures. RESULTS. The Trier Social Stress Test adapted for children induced an adrenocorticotropic hormone and cortisol response in all of the groups. The adrenocorticotropic hormone response was blunted in the dexamethasone group. The overall cortisol level was lower in the dexamethasone than in the hydrocortisone and reference group. Cortisol and adrenocorticotropic hormone in the hydrocortisone and reference groups were similar. The ratio of T-cell mitogen-induced interferon-γ/interleukin-4 secretion was significantly higher in the dexamethasone group than in the hydrocortisone group. Interferon-γ production and the ratios of interferon-γ/interleukin-4 and interferon-γ/ interleukin-10 were significantly higher in the dexamethasone group than the reference group. However, production of these cytokines did not differ between the hydrocortisone and the reference groups. CONCLUSION. Neonatal treatment of prematurely born children with dexamethasone but not with hydrocortisone resulted in long-lasting programming effects on hypothalamus-pituitary-adrenal axis and on the T-helper 1/T-helper 2 cytokine balance. Follow-up of these children is required to investigate long-term clinical consequences. We recommend that authors of previously performed randomized, controlled trials on neonatal glucocorticoid treatment include immune and neuroendocrine analyses in prolonged follow-up of these children.

Do Apparent Diffusion Coefficient Measurements Predict Outcome in Children with Neonatal Hypoxic-Ischemic Encephalopathy?

BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) permits early detection and quantification of hypoxic-ischemic (HI) brain lesions. Our aim was to assess the predictive value of DWI and apparent diffusion coefficient (ADC) measurements for outcome in children with perinatal asphyxia. MATERIALS AND METHODS: Term neonates underwent MR imaging within 10 days after birth because of asphyxia. MR imaging examinations were retrospectively evaluated for HI brain damage. ADC was measured in 30 standardized brain regions and in visibly abnormal areas on DWI. In survivors, developmental outcome until early school age was graded into the following categories: 1) normal, 2) mildly abnormal, and 3) definitely abnormal. For analysis, category 3 and death (category 4) were labeled “adverse,” 1 and 2 were “favorable,” and 2–3 and death were “abnormal” outcome. Differences in outcome between infants with and without DWI abnormalities were analyzed by using χ2 tests. The nonparametric Mann-Whitney U test analyzed whether ADC values in visible DWI abnormalities correlated with age at imaging. Logistic regression analysis tested the predictive value for outcome of the ADC in each standardized brain region. Receiver operating characteristic analysis was used to find optimal ADC cutoff values for each region for the various outcome scores. RESULTS: Twenty-four infants (13 male) were included. Mean age at MR imaging was 4.3 days (range, 1–9 days). Seven infants died. There was no difference in outcome between infants with and without visible DWI abnormalities. Only ADC of the posterior limb of the internal capsule correlated with age. ADC in visibly abnormal DWI regions did not have a predictive value for outcome. Of all measurements performed, only the ADC in the normal-appearing basal ganglia and brain stem correlated significantly with outcome; low ADC values were associated with abnormal/adverse outcome, and higher ADC values, with normal/favorable outcome (basal ganglia: P = .03 for abnormal, P = .01 for adverse outcome; brain stem: P = .006 for abnormal, P = .03 for adverse outcome). CONCLUSIONS: ADC values in normal-appearing basal ganglia and brain stem correlated with outcome, independently of all MR imaging findings including those of DWI. ADC values in visibly abnormal brain tissue on DWI did not show a predictive value for outcome.

Is nephrocalcinosis in preterm neonates harmful for long-term blood pressure and renal function?

OBJECTIVE. The aim of our study was to examine long-term effects of nephrocalcinosis in prematurely born children. PATIENTS AND METHODS. Preterm neonates (gestational age <32 weeks) with (n = 42) and without (n = 32) nephrocalcinosis were prospectively studied at a mean age of 7.5 (±1.0) years. RESULTS. Blood pressure did not differ in ex-preterm infants with and without nephrocalcinosis but was significantly higher than expected for healthy children. In comparison to healthy children, more ex-preterm infants with neonatal nephrocalcinosis had (mild) chronic renal insufficiency (glomerular filtration rate: <85 mL/min per 1.73 m2; 6 of 40); this is in contrast to ex-preterm infants without neonatal nephrocalcinosis (2 of 32). Tubular phosphate reabsorption and plasma bicarbonate were significantly lower in children with nephrocalcinosis compared with children without nephrocalcinosis. In addition, more ex-preterm infants with and without nephrocalcinosis than expected had low values for plasma bicarbonate and early-morning urine osmolality compared with healthy children. Kidney length of ex-preterm infants with and without nephrocalcinosis was significantly smaller than expected in healthy children of the same height. Nephrocalcinosis persisted long-term in 4 of 42 children but was not related to blood pressure, kidney length, or renal function. CONCLUSIONS. Nephrocalcinosis in preterm neonates can have long-term sequelae for glomerular and tubular function. Furthermore, prematurity per se is associated with high blood pressure, relatively small kidneys, and (distal) tubular dysfunction. Long-term follow-up of blood pressure and renal glomerular and tubular function of preterm neonates, especially with neonatal nephrocalcinosis, seems warranted.

Prediction of Short-Term Neurological Outcome in Full-Term Neonates with Hypoxic-Ischaemic Encephalopathy Based on Combined Use of Electroencephalogram and Neuro-Imaging

BACKGROUND In infants with hypoxic-ischaemic encephalopathy (HIE), prediction of the prognosis is based on clinical, neuro-imaging and neurophysiological parameters. METHODS EEG, cranial ultrasound, MRI and follow-up findings of 23 infants (GA 35-42 weeks) with HIE were studied retrospectively to assess 1) the contribution of ultrasound, MRI and EEG in predicting outcome, 2) the accuracy of ultrasound as compared to MRI, and 3) whether patterns of brain damage and EEG findings are associated. RESULTS An abnormal EEG background pattern was highly predictive of adverse outcome [positive predictive value (PPV) 0.88]. If combined with diffuse white and deep and/or cortical grey matter changes on ultrasound or MRI, the PPV increased to 1.00. Abnormal neuro-imaging findings were also highly predictive of adverse outcome. Abnormal signal intensity in the posterior limb of the internal capsule, and diffuse cortical grey matter damage were associated with adverse outcome. MRI showed deep grey matter changes more frequently than ultrasound. Severely abnormal neuro-imaging findings were always associated with abnormal EEG background pattern. CONCLUSIONS Both early EEG and neuro-imaging findings are predictive of outcome in infants with HIE. The predictive value of EEG is strengthened by neuro-imaging.

OUTCOME OF PERIVENTRICULAR-INTRAVENTRICULAR HAEMORRHAG FIVE YEARS OF AGE

The authors studied the relationship between periventricular‐intraventricular haemorrhage in infants of <32 weeks gestation who had undergone routine cranial ultrasound scanning in the neonatal period, and neurodevelopmental outcome at the age of five years. Of 484 infants enrolled into the study, all 304 survivors were available for follow‐up at the age of five years. 85 children had a disability; in 50 of these, the disability caused a handicap. Three children with dilated lateral ventricles and no periventricular‐intraventricular haemorrhage were excluded from further analyses. 26 per cent of the infants with severe (grades III/IV) haemorrhage and 67 per cent of the infants with mild (grades 1/11) haemorrhage survived the neonatal period. Children with mild haemorrhage had a significantly increased risk of disability (including handicap) at the age of five years.

Follow-up Outcomes at 1 and 2 Years of Infants Born Less Than 32 Weeks After Newborn Individualized Developmental Care and Assessment Program

OBJECTIVE. This was a randomized, controlled trial to investigate the effect of Newborn Individualized Developmental Care and Assessment Program on growth, cognitive, psychomotor, and neuromotor development at 1 and 2 years in infants born at <32 weeks’ gestational age. METHODS. Infants were randomly assigned within 48 hours of birth to the newborn individualized developmental care and assessment program group (intervention) or basic developmental care group (control group [ie, incubator covers and nests]). At 1 and 2 years’ corrected age, growth was measured and standardized neurologic examinations were administered. Mental and psychomotor development was assessed by using the Dutch version of the Bayley Scales of Infant Development II. Neurologic outcome, Psychomotor Developmental Index, and Mental Developmental Index scores were combined a total outcome measure. RESULTS. One hundred sixty-eight infants were recruited (intervention: 84; control: 84). Four infants (newborn intervention: 3; control: 1) were excluded because they were admitted less than or died within the first 5 days, leaving a total of 164 infants who met inclusion criteria. In-hospital mortality was 8 of 81 in the intervention group and 3 of 83 in the control group. At 1 year of age 148 children (intervention: 70; control: 78) and at 2 years of age 146 children (intervention: 68; control: 78) were assessed. There was no significant difference in growth at 1 and 2 years of age. There was no significant difference found in neurologic outcomes or mental and psychomotor development at 1 and 2 years of age. When neurologic outcome, Mental Developmental Index and Psychomotor Developmental Index scores were combined, there still remained no significant difference. CONCLUSIONS. Newborn individualized developmental care and assessment program developmental care showed no effect on growth or neurologic, mental, or psychomotor development at 1 and 2 years of age in infants born at <32 weeks. Duration of the intervention was not associated with neurologic and developmental outcome.

Effects of Individualized Developmental Care in a Randomized Trial of Preterm Infants <32 Weeks

OBJECTIVE: The goal was to investigate the effects of the Newborn Individualized Developmental Care and Assessment Program (NIDCAP) on days of respiratory support and intensive care, growth, and neuromotor development at term age for infants born at <32 weeks. METHODS: Infants were assigned randomly, within 48 hours after birth, to a NIDCAP group or basic developmental care (control) group. The NIDCAP intervention consisted of weekly formal behavioral observations of the infants and caregiving recommendations and support for staff members and parents, as well as incubator covers and positioning aids. The control group infants were given basic developmental care, which consisted of only incubator covers and positioning aids. Outcome measures were respiratory support, intensive care, and weight of <1000 g. Growth parameters were measured weekly or biweekly and at term age. Neuromotor development was assessed at term age. RESULTS: A total of 164 infants met the inclusion criteria (NIDCAP: N = 81; control: N = 83). In-hospital mortality rates were 8 (9.9%) of 81 infants in the NIDCAP group and 3 (3.6%) of 83 infants in the control group. No differences in mean days of respiratory support (NIDCAP: 13.9 days; control: 16.3 days) or mean days of intensive care (NIDCAP: 15.2 days; control: 17.0 days) were found. Short-term growth and neuromotor development at term age showed no differences, even with correction for the duration of the intervention. CONCLUSIONS: NIDCAP developmental care had no effect on respiratory support, days of intensive care, growth, or neuromotor development at term age.

Effects of basic developmental care on neonatal morbidity, neuromotor development, and growth at term age of infants who were born at <32 weeks.

OBJECTIVE. The goal of this study was to investigate the effect of basic elements of developmental care (incubator covers and positioning aids) on days of respiratory support and intensive care, growth, and neuromotor development at term age in infants who were born at <32 weeks’ gestation. METHODS. Infants were randomly assigned within 48 hours of birth to the developmental care group or the standard care control group (no covers or nests). The intervention continued until the infant either was transferred to a regional hospital or was discharged from the hospital. Length, weight, and head circumference were measured (bi)weekly and at term age. Neuromotor development was defined as definitely abnormal (presence of a neonatal neurologic syndrome, such as apathy or hyperexcitability, hypotonia or hypertonia, hyporeflexia or hyperreflexia, hypokinesia or hyperkinesia, or a hemisyndrome), mildly abnormal (presence of only part of such a syndrome), or normal. RESULTS. A total of 192 infants were included (developmental care: 98; control: 94). Thirteen infants (developmental care: 7; control: 6) were excluded according to protocol (admitted for less than or died within the first 5 days: n = 12; taken out at parents’ request: n = 1), which left a total of 179 infants who met inclusion criteria. In-hospital mortality was 12 (13.2%) of 91 in the developmental care group and 8 (9.1%) of 88 in the control group. There was no significant difference in the number of days of respiratory support, number of intensive care days, short-term growth, or neuromotor developmental outcome at term age between the developmental care and control groups. Duration of the intervention, whether only during the intensive care period or until hospital discharge, had no significant effect on outcome. CONCLUSIONS. Providing basic developmental care in the NICU had no effect on short-term physical and neurologic outcomes in infants who were born at <32 weeks’ gestation.