Neonatal glucocorticoid treatment: long-term effects on the hypothalamus-pituitary-adrenal axis, immune system, and problem behavior in 14-17 year old adolescents.

Neonatal glucocorticoid (GC) treatment is used to prevent bronchopulmonary dysplasia (BPD) in prematurely born babies. In the 1990s, treatment regimens with relatively high doses of dexamethasone (DEX) were common. As an alternative, hydrocortisone (HC) was used. Earlier, we compared long-term effects of both GCs in children aged 7-10 and detected adverse effects of neonatal DEX treatment, but not of HC, on a range of outcomes. The aim of the current cohort study was to investigate whether long-term effects of neonatal DEX were maintained and whether effects of HC remained absent at adolescent age (14-17years). We compared 71 DEX-treated and 67 HC-treated adolescents. In addition, 71 adolescents who were not neonatally treated with GCs participated. All were born <32weeks of gestation. DEX-treated girls showed increased adrenocorticotropic hormone (ACTH) and cortisol responses in the Trier Social Stress Test. The cortisol awakening response was lower in HC-treated participants compared to untreated participants. Negative feedback function of the HPA-axis in the dexamethasone suppression test did not differ between groups. In contrast to our observations at the age of 7-10years, we did not observe group differences in mitogen-induced cytokine production at the age of 14-17years. DEX-treated girls showed more social problems and anxious/depressed behavior than HC-treated girls. Untreated girls showed more problem behavior as well. In conclusion, our results suggest that, especially in girls, neonatal DEX has a programming effect on the HPA-axis and on the ability to adjust to the environment. The loss of group differences on immune system measures indicate that potentially negative effects detected at a younger age subsided.

Early life intervention with glucocorticoids has negative effects on motor development and neuropsychological function in 14-17 year-old adolescents.

OBJECTIVE: To reduce the risk of bronchopulmonary dysplasia, preterm infants receive neonatal treatment with glucocorticoids, mostly dexamethasone (DEX). Compared to current protocols, treatment regimens of the late 1980s - early 1990s prescribed high doses of DEX for an extensive period up to 6 weeks. Worldwide at least one million children have been treated with this dose regimen. Previous studies have shown adverse effects of neonatal treatment with the glucocorticoid dexamethasone (DEX) on outcome in children aged 7-10 years. On the other hand, treatment with another glucocorticoid, hydrocortisone (HC), was not related to adverse effects in childhood. In the current study we determined the consequences of early life intervention with DEX or HC in adolescents (age 14-17 years). Besides motor function and intellectual capacities, we also examined fundamental neuropsychological functions which have so far received little attention. METHODS: In an observational cohort study we compared 14-17 year-old adolescents who received DEX (.5 mg/kg/day tapering off to .1 mg/kg/day over 21 days, n=63), or HC (5 mg/kg/day tapering off to 1 mg/kg/day over 22 days, n=67), or did not receive neonatal glucocorticoids (untreated, n=71) after premature birth (gestational age<32 weeks). Because gestational age was shorter and duration of ventilation was longer in the DEX-treated group, all analyses were corrected for these potential confounders. Motor function, IQ, and neuropsychological functions were assessed. RESULTS: DEX-treated group participants scored lower on gross motor skill tasks than their HC-treated and untreated counterparts. A higher proportion of DEX-treated girls needed special education compared to the other groups. DEX-treated adolescents performed poorer on neuropsychological tasks measuring alertness, visuomotor coordination, and emotion recognition. The HC-treated group did not differ from the untreated group. CONCLUSIONS: Even after 14-17 years, neonatal treatment with .5 mg/kg/day DEX was associated with adverse effects on motor function, school level, and neuropsychological functions, whereas treatment with the clinically equally effective dose of 5 mg/kg/day HC was not. Potential physiological mechanisms underlying the differences in dexamethasone and hydrocortisone effects are discussed. Based on the current findings, we recommend early identification of neuropsychological deficits after DEX treatment in order to specify extra educational needs.

Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials.

OBJECTIVE: Free-radical-induced reperfusion injury has been recognised as an important cause of brain tissue damage after birth asphyxia. Allopurinol reduces the formation of free radicals, thereby potentially limiting the amount of hypoxia-reperfusion damage. In this study the long-term outcome of neonatal allopurinol treatment after birth asphyxia was examined. DESIGN: Follow-up of 4 to 8 years of two earlier performed randomised controlled trials. SETTING: Leiden University Medical Center, University Medical Center Groningen and University Medical Center Utrecht, The Netherlands. PATIENTS: Fifty-four term infants were included when suffering from moderate-to-severe birth asphyxia in two previously performed trials. INTERVENTION: Infants either received 40 mg/kg allopurinol (with an interval of 12 h) starting within 4 h after birth or served as controls. MAIN OUTCOME MEASURES: Children, who survived, were assessed with the Wechsler Preschool and Primary Scales of Intelligence test or Wechsler Intelligence Scale for Children and underwent a neurological examination. The effect of allopurinol on severe adverse outcome (defined as mortality or severe disability at the age of 4-8 years) was examined in the total group of asphyxiated infants and in a predefined subgroup of moderately asphyxiated infants (based on the amplitude integrated electroencephalogram). RESULTS: The mean age during follow-up (n=23) was 5 years and 5 months (SD 1 year and 2 months). There were no differences in long-term outcome between the allopurinol-treated infants and controls. However, subgroup analysis of the moderately asphyxiated group showed significantly less severe adverse outcome in the allopurinol-treated infants compared with controls (25% vs 65%; RR 0.40, 95%CI 0.17 to 0.94). CONCLUSIONS: The reported data may suggest a (neuro)protective effect of neonatal allopurinol treatment in moderately asphyxiated infants.

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.

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 neonatal dexamethasone treatment on the cardiovascular stress response of children at school age.

OBJECTIVE: The goal was to investigate cardiovascular responses to a psychosocial stressor in school-aged, formerly premature boys and girls who had been treated neonatally with dexamethasone or hydrocortisone because of chronic lung disease. METHODS: We compared corticosteroid-treated, formerly preterm infants with formerly preterm infants who had not been treated neonatally with corticosteroids (reference group). Children performed the Trier Social Stress Test for Children, which includes a public speaking task and a mental arithmetic task. Blood pressure was recorded continuously before, during, and after the stress test. Plasma norepinephrine levels were determined before the test, directly after the stress task, and after recovery. RESULTS: Overall, in response to stress, girls had significantly larger changes in systolic blood pressure and mean arterial pressure and in stroke volume and cardiac output, compared with boys. Boys exhibited larger total peripheral resistance responses, compared with girls. The hydrocortisone group did not differ significantly from the reference group in any of the outcome measures. However, dexamethasone-treated children had smaller stress-induced increases in systolic and mean arterial blood pressure than did hydrocortisone-treated children. In addition, the dexamethasone group showed smaller increases in stroke volume and blunted norepinephrine responses to stress, compared with children in the reference group. Correction for gender did not affect these results. CONCLUSIONS: The differences in cardiovascular stress responses between girls and boys are consistent with known gender differences in adult cardiovascular stress responses. Our data demonstrate that neonatal treatment with dexamethasone has long-term consequences for the cardiovascular and noradrenergic stress responses; at school age, the cardiovascular stress response was blunted in dexamethasone-treated children. Hydrocortisone-treated children did not differ from the reference group, which suggests that hydrocortisone might be a safe alternative to dexamethasone for treating chronic lung disease of prematurity.

Cardiovascular follow-up at school age after perinatal glucocorticoid exposure in prematurely born children: perinatal glucocorticoid therapy and cardiovascular follow-up.

OBJECTIVE: To study whether antenatal or neonatal glucocorticoid therapy to reduce the incidence and severity of chronic lung disease in preterm infants is associated with long-term adverse cardiac effects and hypertension. DESIGN: Retrospective matched-cohort study. SETTING: Outpatient clinic of a tertiary care hospital. PARTICIPANTS: One hundred ninety-three children aged 7 to 10 years who had been born prematurely between December 2, 1993, and September 15, 1997. Main Exposure Neonatal treatment with dexamethasone disodium phosphate(n = 48) or the clinically equally effective glucocorticoid hydrocortisone (n = 51), or only antenatal treatment with betamethasone disodium phosphate and betamethasone acetate (n = 51). These 3 groups were compared with a reference group of prematurely born children who had not been exposed to perinatal glucocorticoid therapy (n = 43). MAIN OUTCOME MEASURES: General hemodynamic data (heart rate and blood pressure), cardiovascular function as assessed at echocardiography, intima-media thickness of the carotid arteries, and cardiac biochemical features as early markers of expansion and volume overload of the cardiac left ventricle (B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide). RESULTS: No significant group differences were found for heart rate, blood pressure, biochemical features, intima-media thickness, or systolic or diastolic left ventricular function. CONCLUSIONS: Although no differences were found in blood pressure and cardiovascular function at school age in children antenatally or neonatally treated with glucocorticoids, further cardiovascular follow-up may be advisable because cardiovascular dysfunction may become apparent only later in life.

Comparing brain white matter on sequential cranial ultrasound and MRI in very preterm infants.

INTRODUCTION: Periventricular white matter (WM) echodensities, frequently seen in preterm infants, can be associated with suboptimal neurodevelopment. Major WM injury is well detected on cranial ultrasound (cUS). cUS seems less sensitive for diffuse or more subtle WM injury. Our aim was to assess the value of cUS and magnetic resonance imaging (MRI) for evaluating WM changes and the predictive value of cUS and/or MRI findings for neurodevelopmental outcome in very preterm infants with normal to severely abnormal WM on sequential high-quality cUS. MATERIALS AND METHODS: Very preterm infants (<32 weeks) who had sequential cUS and one MRI within the first three postnatal months were included. Periventricular WM on cUS and MRI was compared and correlated with neurodevelopmental outcome at 2 years corrected age. RESULTS: Forty preterm infants were studied; outcome data were available in 32. WM changes on sequential cUS were predictive of WM changes on MRI. Severely abnormal WM on cUS/MRI was predictive of adverse outcome, and normal-mildly abnormal WM of favorable outcome. Moderately abnormal WM on cUS/MRI was associated with variable outcome. Additional MRI slightly increased the predictive value of cUS in severe WM changes. CONCLUSION: Sequential cUS in preterm infants is reliable for detecting WM changes and predicting favorable and severely abnormal outcome. Conventional and diffusion-weighted MRI sequences before term equivalent age in very preterm infants, suggested on cUS to have mild to moderately abnormal WM, do not seem to be warranted.

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-gamma/interleukin-4 secretion was significantly higher in the dexamethasone group than in the hydrocortisone group. Interferon-gamma production and the ratios of interferon-gamma/interleukin-4 and interferon-gamma/ 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.

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.

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.

Cognitive development of singletons born after intracytoplasmic sperm injection compared with in vitro fertilization and natural conception.

OBJECTIVE: To investigate cognitive development of singletons conceived by intracytoplasmic sperm injection (ICSI) at 5-8 years of age. 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 at the Leiden University Medical Center were compared with matched singletons born after IVF and natural conception (NC). INTERVENTION(S): Mode of conception. MAIN OUTCOME MEASURE(S): Intelligence quotient (IQ) was measured with the Revised Amsterdam Child Intelligence Test (short form). The investigators were blinded to conception mode. RESULT(S): Singletons conceived by ICSI (n = 83) achieved lower IQ scores than IVF singletons (n = 83) (adjusted mean difference IQ: 3.6 [95% confidence interval (CI) -0.8, 8.0]). After categorizing IQ outcomes (<85, 85-115, >115), no significant difference in the distribution of IQ was found. Singletons conceived by ICSI (n = 86) achieved lower IQ scores than NC singletons (n = 85); the adjusted mean difference varied between 5 and 7 points (5.6 [95% CI 0.9, 10.3]; 7.1 [95% CI 1.7, 12.5]) depending on the covariates included in the model. Adjustment for prematurity did not change the results. Percentages in IQ categories <85, 85-115, and >115 were 12%, 64%, and 24% for ICSI and 6%, 54%, and 40% for NC, respectively. CONCLUSION(S): In the relatively limited sample investigated, cognitive development among ICSI singletons was lower than among IVF and NC singletons. Infertility factors or unmeasured confounders may play a role.

Staff opinions regarding the Newborn Individualized Developmental Care and Assessment Program (NIDCAP).

This study explored the opinions of (para)medical and nursing staff in two Dutch Neonatal Intensive Care Units (NICU's). A questionnaire was used that measured: a) the perceived impact of NIDCAP on several NICU conditions, b) attitudes, subjective norm, perceived behavioral control, knowledge and abilities of using the NIDCAP method (based on the Theory of Planned Behavior) and c) training interest, requirements, information sources and the relevance of the NIDCAP method for different groups of NICU patients. Respondents were positive about NIDCAP and felt that using NIDCAP is fulfilling and leads to improvement of the infant's development, health and well-being. However, NIDCAP was also thought to be time-consuming and might worsen job conditions. The nursing staff, compared to the medical staff, had a more positive attitude (p=.004), higher perceived behavioral control (p=.004) and perceived a more positive impact of NIDCAP on NICU conditions (p=.008).

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.

Matched follow-up study of 5-8 year old ICSI-singletons: comparison of their neuromotor development to IVF and naturally conceived singletons.

BACKGROUND: Intracytoplasmic sperm injection (ICSI) is an invasive technique of artificial reproduction. We investigated the effect of ICSI on neuromotor development in 5-8 year old singletons. METHODS: We did a follow-up of ICSI-singletons born between 1996 and 1999 after treatment in the Leiden University Medical Center and compared them with matched controls born after in vitro fertilization (IVF) and natural conception (NC). Children underwent a thorough neurological examination that focused on minor neurological dysfunction (MND). RESULTS: There were no differences in outcome between ICSI (n = 81) and IVF-children (n = 81), all born at term: MND prevalence 66.3% versus 61.3%, prevalence ratio (PR) 1.08 [0.83; 1.29]. MND prevalence among all ICSI-children (n = 87) was higher than among NC-controls (n = 85) (66.3% versus 50.6%, PR 1.31 [1.02; 1.55]). After adjustment for maternal age and parity, the PR remained elevated but was no longer statistically significant (adjusted PR 1.22 [0.86; 1.52]). When comparing only term ICSI and NC-children (n = 81; n = 85), the PR adjusted for maternal age and parity was 1.20 [0.83; 1.51]. CONCLUSIONS: Neuromotor outcome of 5-8 year old singletons born at term after ICSI or IVF was similar; ICSI-children (both the total group and term children only) deviated slightly from NC-controls. Part of this effect was explained by a difference in parity, but not prematurity.

The effect of perinatal risk factors on growth in very preterm infants at 2 years of age: the Leiden Follow-Up Project on Prematurity.

OBJECTIVE: To describe growth in infants <32 weeks GA. To assess the relationship between growth and perinatal factors (like intrauterine growth retardation and the postnatal use of dexamethasone) and neurodevelopmental outcome. DESIGN: Regional, prospective study in two health regions in the Netherlands. Part of the Leiden Follow-Up Project on Prematurity (LFUPP). PATIENTS: 196 live born infants with GA <32 weeks. METHODS: At two years corrected age length, weight and head circumference of 160 of 196 surviving infants (82%) were evaluated. Standard Deviation Scores were calculated and means were compared to Dutch growth references. Mean SDS for length was corrected for the mean SDS for target height. Birth weight (BW)-SDS for gestational age (GA) was calculated according to Swedish references. RESULTS: Length, weight and weight-for-length were equally impaired in both sexes at two years in premature infants compared to Dutch growth charts. Catch-up in length and weight occurred mostly in the first year of life. Intrauterine growth retardation was associated with impairment of all growth parameters. The use of postnatal dexamethasone was associated with shorter length, lower weight, lower weight for length and smaller head circumference; this effect remained after correction for GA, BW and BW-SDS. Growth retardation (length and weight) was associated with an abnormal neurologic examination; smaller head circumference also with mental and psychomotor delay. CONCLUSION: Growth at two years corrected age in children born <32 weeks is impaired. Postnatal dexamethasone is associated with impairment of all growth parameters including head circumference, which may be a significant contributing factor for abnormal neurodevelopmental outcome.

Differences in behavioral outcome and motor development at school age after neonatal treatment for chronic lung disease with dexamethasone versus hydrocortisone.

Neonatal dexamethasone (DEX) for chronic lung disease is associated with adverse outcome. We compared behavioral and motor development at school age of children who neonatally received DEX to children neonatally treated with hydrocortisone (HC) in a retrospective matched cohort study. DEX- and HC-treated groups matched for gestational age, birth weight and year, gender, and severity of respiratory distress syndrome were compared with a reference group (REF) and a group treated only antenatally with betamethasone (BMETH). REF and BMETH groups had a higher gestational age and less severe respiratory distress syndrome. From 192 children (DEX, n = 46; HC, n = 52; REF, n = 43; BMETH, n = 51), the Child Behavioral Checklists from parents and teachers (Teacher's Report Form) and the Movement Assessment Battery for Children to assess neuromotor function were analyzed. DEX girls had a poorer performance on nearly all behavioral scales of the Teacher's Report Form compared with HC girls. DEX boys did not differ from HC boys. The HC boys or girls did not differ from the REF or BMETH groups. Neuromotor development was poorer in DEX than the BMETH and REF groups. The HC group did not differ from REF and BMETH groups. We suggest that neonatal HC may be a "safer" alternative for DEX for the treatment of CLD.

Changes in neonatology: comparison of two cohorts of very preterm infants (gestational age <32 weeks): the Project On Preterm and Small for Gestational Age Infants 1983 and the Leiden Follow-Up Project on Prematurity 1996-1997.

OBJECTIVE: To determine changes in peri- and neonatal care concerning neonatal mortality and morbidity by comparing 2 cohorts of very prematurely born infants (gestational age [GA] <32 weeks), 1 from the 1980s and 1 from the 1990s. METHODS: The Leiden Follow-Up Project on Prematurity (LFUPP-1996/97), a regional, prospective study, includes all infants who were born alive after a GA <32 weeks in 1996 and 1997 in the Dutch health regions Leiden, The Hague, and Delft. The Project On Preterm and Small for Gestational Age Infants (POPS-1983), a national, prospective study from the presurfactant era, includes all liveborn infants <32 weeks' GA and/or <1500 g from 1983 (n = 1338). For comparison, infants from the POPS-1983 cohort with a GA <32 weeks from the same Dutch health regions were selected (n = 102). RESULTS: The absolute number of preterm births in the study region increased by 30%: 102 in 1983 to on average of 133 in 1996-1997. Centralization of perinatal care improved: the percentage of extrauterinely transported infants decreased from 61% in 1983 to 35% in 1996-1997. A total of 182 (73%) of the LFUPP-1996/97 infants were treated antenatally with glucocorticosteroids compared with 6 (6%) of the POPS-1983 infants. A total of 112 (42%) of the LFUPP-1996/97 infants received surfactant. In-hospital mortality decreased from 30% in the 1980s to 11% in the 1990s. Mortality of the extremely preterm infants (<27 weeks) decreased from 76% to 33%. The incidence of respiratory distress syndrome remained the same: approximately 60% in both groups. Mortality from respiratory distress syndrome, however, decreased from 29% to 8%. The incidence of bronchopulmonary dysplasia increased from 6% to 19%. For the surviving infants, the average length of stay in the hospital and the mean number of NICU days stayed approximately the same ( approximately 67 days total admission time and 44 NICU days in both groups); including the infants who died, the mean NICU admission time increased from 27 days in the 1980s to 41 days in the 1990s. Equal percentages of adverse outcome (dead or an abnormal general condition) at the moment of discharge from hospital were found (+/-40% in both groups). CONCLUSIONS: An increase in the absolute number of very preterm births in this study region was found, leading to a greater burden on the regional NICUs. Improvements in peri- and neonatal care have led to an increased survival of especially extremely preterm infants. However, increased survival has resulted in more morbidity, mainly bronchopulmonary dysplasia, at the moment of discharge from the hospital.

Follow up of children after antenatal treatment for alloimmune thrombocytopenia.

OBJECTIVE: To evaluate the long-term follow-up of surviving offspring after antenatal treatment for fetal or neonatal alloimmune thrombocytopenia (FNAIT). PATIENTS: Fifty children at risk of FNAIT were antenatally treated with maternal intravenous immunoglobulins (IVIG) (n=11), IVIG with intrauterine platelet transfusions (IUPT) (n=26) or IUPT alone (n=9). In four cases (n=4), only fetal blood sampling (FBS) was performed. One child died in the neonatal period and one was lost to follow up. METHODS: The remaining 48 children, aged 1.3-11.6 years (median 5.1 years), were given both general and neurological examinations and assessed on their development and susceptibility for infections or atopic constitution. In addition, immunoglobulin levels were measured in 17 infants, aged 5 years and older. RESULTS: Intracranial hemorrhage (ICH) was not observed. The general health and neurodevelopmental outcome in the children was comparable to a normal Dutch population. Children not exposed to maternal IVIG treatment had significantly more infections and hearing problems than children exposed to IVIG treatment or the normal population. Immunoglobulin G, A and M levels were within the normal range, independent of treatment and severity of FNAIT. A high IgE level was more frequently seen in children exposed to IVIG, but did not result in clinical consequences such as allergy or atopy. CONCLUSIONS: Antenatal treatment of children for FNAIT did not affect general health or neurodevelopmental outcome. In particular, exposure to IVIG in utero showed no adverse effect on the clinical outcome of these children.