Identifying effect modifiers of systemic hydrocortisone treatment initiated 7-14 days after birth in ventilated very preterm infants on long-term outcome: secondary analysis of a randomised controlled trial.

OBJECTIVE: To explore clinical effect modifiers of systemic hydrocortisone in ventilated very preterm infants for survival and neurodevelopmental outcome at 2 years' corrected age (CA). DESIGN: Secondary analysis of a randomised placebo-controlled trial. SETTING: Dutch and Belgian neonatal intensive care units. PATIENTS: Infants born <30 weeks' gestational age (GA), ventilator-dependent in the second week of postnatal life. INTERVENTION: Infants were randomly assigned to systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). MAIN OUTCOME MEASURES: The composite of death or neurodevelopmental impairment (NDI) at 2 years' CA and its components. Candidate effect modifiers (GA, small for GA, respiratory index, sex, multiple births, risk of moderate/severe bronchopulmonary dysplasia or death) were analysed using regression models with interaction terms and subpopulation treatment effect pattern plots. RESULTS: The composite outcome was available in 356 (96.0%) of 371 patients (one consent withdrawn). For this outcome, treatment effect heterogeneity was seen across GA subgroups (<27 weeks: hydrocortisone (n=141) vs placebo (n=156), 54.6% vs 66.2%; OR 0.61 (95% CI 0.38 to 0.98); ≥27 weeks: hydrocortisone (n=30) vs placebo (n=31), 66.7% vs 45.2%; OR 2.43 (95% CI 0.86 to 6.85); p=0.02 for interaction). This effect was also found for the component death (<27 weeks: 20.1% vs 32.1%; OR 0.53 (95% CI 0.32 to 0.90); ≥27 weeks: 28.1% vs 16.1%; OR 2.04 (95% CI 0.60 to 6.95); p=0.049 for interaction) but not for the component NDI. No differential treatment effects were observed across other subgroups. CONCLUSION: This secondary analysis suggests that in infants <27 weeks' GA, systemic hydrocortisone may improve the outcome death or NDI, mainly driven by its component death. There was insufficient evidence for other selected candidate effect modifiers.

Risk factors for cerebral palsy and movement difficulties in 5-year-old children born extremely preterm.

BACKGROUND: Motor impairment is common after extremely preterm (EPT, <28 weeks' gestational age (GA)) birth, with cerebral palsy (CP) affecting about 10% of children and non-CP movement difficulties (MD) up to 50%. This study investigated the sociodemographic, perinatal and neonatal risk factors for CP and non-CP MD. METHODS: Data come from a European population-based cohort of children born EPT in 2011-2012 in 11 countries. We used multinomial logistic regression to assess risk factors for CP and non-CP MD (Movement Assessment Battery for Children - 2nd edition ≤5th percentile) compared to no MD (>15th percentile) among 5-year-old children. RESULTS: Compared to children without MD (n = 366), young maternal age, male sex and bronchopulmonary dysplasia were similarly associated with CP (n = 100) and non-CP MD (n = 224) with relative risk ratios (RRR) ranging from 2.3 to 3.6. CP was strongly related to severe brain lesions (RRR >10), other neonatal morbidities, congenital anomalies and low Apgar score (RRR: 2.4-3.3), while non-CP MD was associated with primiparity, maternal education, small for GA (RRR: 1.6-2.6) and severe brain lesions, but at a much lower order of magnitude. CONCLUSION: CP and non-CP MD have different risk factor profiles, with fewer clinical but more sociodemographic risk factors for non-CP MD. IMPACT: Young maternal age, male sex and bronchopulmonary dysplasia similarly increased risks of both cerebral palsy and non-cerebral palsy movement difficulties. Cerebral palsy was strongly related to clinical risk factors including severe brain lesions and other neonatal morbidities, while non-cerebral palsy movement difficulties were more associated with sociodemographic risk factors. These results on the similarities and differences in risk profiles of children with cerebral palsy and non-cerebral palsy movement difficulties raise questions for etiological research and provide a basis for improving the identification of children who may benefit from follow-up and early intervention.

Behavioral and neurodevelopmental outcome of children after maternal allopurinol administration during suspected fetal hypoxia: 5-year follow up of the ALLO-trial.

OBJECTIVE: To evaluate the long-term neurodevelopmental and behavioral outcome of antenatal allopurinol treatment during suspected fetal hypoxia. STUDY DESIGN: We studied children born from women who participated in a randomized double-blind placebo controlled multicenter study (ALLO-trial). Labouring women in whom the fetus was suspected to have fetal hypoxia were randomly allocated to receive allopurinol or placebo. At 5 years of age, the children were assessed with 2 parent reported questionnaires, the Ages and Stages Questionnaire (ASQ) and the Child Behavior Checklist (CBCL). A child was marked abnormal for ASQ if it scored below 2 standard deviation under the normative mean of a reference population in at least one domain. For CBCL, a score above the cut-off value (95th percentile for narrowband scale, 85th percentile for broadband scale) in at least one scale was marked as abnormal. RESULTS: We obtained data from 138 out of the original 222 mildly asphyxiated children included in the ALLO-trial (response rate 62%, allopurinol n = 73, placebo n = 65). At 5 years of age, the number of children that scored abnormal on the ASQ were 11 (15.1%) in the allopurinol group versus 11 (9.2%) in the placebo group (relative risk (RR) 1.64, 95% confidence interval (CI): 0.64 to 4.17, p = 0.30). On CBCL 21 children (30.4%) scored abnormal in de allopurinol group versus 12 children (20.0%) in the placebo group (RR 1.52, 95% CI: 0.82 to 2.83, p = 0.18). CONCLUSION: We found no proof that allopurinol administered to labouring women with suspected fetal hypoxia improved long-term developmental and behavioral outcome. These findings are limited due to the fact that the study was potentially underpowered. TRIAL REGISTRATION: NCT00189007 Dutch Trial Register NTR1383.

Diffusion-weighted imaging changes in cerebral watershed distribution following neonatal encephalopathy are not invariably associated with an adverse outcome.

AIM: Patterns of injury in term-born infants with neonatal encephalopathy following hypoxia-ischaemia are seen earlier and are more conspicuous on diffusion-weighted magnetic resonance imaging (DW-MRI) than on conventional imaging. Although the prognostic value of DW-MRI in infants with basal ganglia and thalamic damage has been established, data in infants in whom there is extensive injury in a watershed distribution are limited. The aim of this study was to assess cognitive and functional motor outcome in a cohort of infants with changes in a predominantly watershed distribution injury on neonatal cerebral MRI, including DWI. METHOD: DW-MRI findings in infants with neonatal encephalopathy following hypoxia-ischaemia were evaluated retrospectively. Twenty-two infants in whom DWI changes exhibited a predominantly watershed distribution were enrolled in the study (10 males, 12 females; mean birthweight 3337 g, 2830-3900 g; mean gestational age 40.5 wks, 37.9-42.1 wks). Follow-up MRI data at the age of 3 months (n=15) and over the age of 18 months (n=7) were analysed. In survivors, neurodevelopmental outcome was assessed with the Griffiths Mental Development Scales at the age of at least 18 months. Amplitude-integrated electroencephalography was used to score background patterns and the occurrence of epileptiform activity. RESULTS: DW-MRI revealed abnormalities that were bilateral in all infants and symmetrical in 10. The posterior regions were more severely affected in five infants and the anterior regions in three. Watershed injury occurred in isolation in 10 out of 22 infants and was associated with involvement of the basal ganglia and thalami in the other 12, of whom seven died. Cystic evolution, seen on MRI at age 3 months, occurred in three of the 15 surviving infants. Neurodevelopmental assessment of the surviving infants was performed at a median age of 35 months (range 18-48 mo). Of the five survivors with basal ganglia and thalamic involvement, two developed cerebral palsy, one had a developmental quotient of less than 85, and two had a normal outcome. Of the 10 infants with isolated watershed injury, nine had an early normal motor and cognitive outcome. In all infants with a favourable outcome, background recovery was seen on amplitude integrated EEG within 48 hours after birth. CONCLUSION: Extensive DWI changes in a watershed distribution in term-born neonates are not invariably associated with adverse sequelae, even in the presence of cystic evolution. Associated lesions of the basal ganglia and thalami are a better predictor of adverse sequelae than the extent and severity of the watershed abnormalities seen on DW-MRI.

Urine viral load and correlation with disease severity in infants with congenital or postnatal cytomegalovirus infection.

BACKGROUND: A correlation between cytomegalovirus (CMV) load in urine and severity of disease in congenitally infected infants has previously been reported. CMV load in postnatally infected infants has not been studied before. OBJECTIVE: To investigate CMV load in urine of infants with postnatal or congenital infection and correlate this with clinical symptoms of CMV disease and cerebral abnormalities. STUDY DESIGN: Infants admitted to our NICU between July 2000 and February 2010, and diagnosed with congenital or postnatal CMV infection were included. Clinical symptoms of CMV infection, cranial ultrasonography (cUS) and magnetic resonance imaging (MRI) findings were evaluated. CMV urine loads of postnatally infected infants were analyzed and compared with CMV urine loads of congenitally infected infants. RESULTS: Seventeen infants with congenital CMV infection and 45 infants with postnatal CMV infection were included. Thirteen/17 (76%) congenitally infected infants had clinical symptoms of CMV infection at birth and 11/17 (65%) had cerebral abnormalities diagnosed by neuro-imaging. None of the four asymptomatic infants had cerebral abnormalities. Of the postnatally infected infants 43/45 (96%) did not develop any clinical symptoms of CMV infection, but in 23/45 (51%) cerebral abnormalities such as lenticulostriate vasculopathy and germinolytic cysts were identified. The median CMV load in postnatally infected infants was significantly lower than in congenitally infected infants (1.0×10(5)copies/ml versus 8.5×10(6)copies/ml, p<0.001, respectively). CONCLUSIONS: CMV load in urine is significantly lower in infants with postnatal CMV infection than in infants with congenital CMV infection irrespective of clinical symptoms of CMV infection or cerebral abnormalities.

Early end-tidal carbon monoxide levels and neurodevelopmental outcome at 3 years 6 months of age in preterm infants.

AIM: Increased end-tidal carbon monoxide (ETCOc) and cytokines in preterm infants are related to bronchopulmonary dysplasia and intraventricular haemorrhages. The aim was to study the predictive value of ETCOc and cytokine levels for long-term outcome. METHODS: This study comprised 105 very preterm infants (57 males, 48 females; gestational age range 25 wks 5d-31 wks 4d; birthweight 610-2100 g) who were admitted to a neonatal intensive care unit between 1 February and 31 December 2002. ETCOc, plasma tumour necrosis factor alpha (TNF-α) and interleukins (IL) 6 and 8, and malondialdehyde (MDA, a marker of lipid peroxidation), were measured at days 1, 3, and 5 of life and related to outcome at 3 years 6 months of age (Griffiths Mental Developmental Scales). RESULTS: Of the 105 infants, 69 were eligible for follow-up (37 males; 32 females; bronchopulmonary dysplasia, n = 12). ETCOc at 0 to 24 hours was higher in infants with adverse outcome (Griffiths developmental quotient <85, n = 15) compared with favourable outcome (2.7SD 0.7 vs 2.0SD 0.5; p < 0.05). MDA and cytokines did not differ between groups. Regression analysis with bootstrapping of independent variables (gestational age, birthweight, ETCOc, TNF-α, IL-6, IL-8, and bronchopulmonary dysplasia) showed that ETCOc was the only parameter that correlated with outcome. The sensitivity and negative predictive value of ETCOc for adverse outcome were 93% and 85% respectively. INTERPRETATION: Adverse neurodevelopmental outcome is associated with increased endogenous carbon monoxide. ETCOc less than 2.0 ppm during the first day indicates a favourable outcome.

Long-term neurodevelopmental outcome of monochorionic and matched dichorionic twins.

BACKGROUND: Monochorionic (MC) twins are at increased risk for perinatal mortality and serious morbidity due to the presence of placental vascular anastomoses. Cerebral injury can be secondary to haemodynamic and hematological disorders during pregnancy (especially twin-to-twin transfusion syndrome (TTTS) or intrauterine co-twin death) or from postnatal injury associated with prematurity and low birth weight, common complications in twin pregnancies. We investigated neurodevelopmental outcome in MC and dichorionic (DC) twins at the age of two years. METHODS: This was a prospective cohort study. Cerebral palsy (CP) was studied in 182 MC infants and 189 DC infants matched for weight and age at delivery, gender, ethnicity of the mother and study center. After losses to follow-up, 282 of the 366 infants without CP were available to be tested with the Griffiths Mental Developmental Scales at 22 months corrected age, all born between January 2005 and January 2006 in nine perinatal centers in The Netherlands. Due to phenotypic (un)alikeness in mono-or dizygosity, the principal investigator was not blinded to chorionic status; perinatal outcome, with exception of co-twin death, was not known to the examiner. FINDINGS: Four out of 182 MC infants had CP (2.2%) - two of the four CP-cases were due to complications specific to MC twin pregnancies (TTTS and co-twin death) and the other two cases of CP were the result of cystic PVL after preterm birth - compared to one sibling of a DC twin (0.5%; OR 4.2, 95% CI 0.5-38.2) of unknown origin. Follow-up rate of neurodevelopmental outcome by Griffith's test was 76%. The majority of 2-year-old twins had normal developmental status. There were no significant differences between MC and DC twins. One MC infant (0.7%) had a developmental delay compared to 6 DC infants (4.2%; OR 0.2, 95% 0.0-1.4). Birth weight discordancy did not influence long-term outcome, though the smaller twin had slightly lower developmental scores than its larger co-twin. CONCLUSIONS: There were no significant differences in occurrence of cerebral palsy as well as neurodevelopmental outcome between MC and DC twins. Outcome of MC twins seems favourable in the absence of TTTS or co-twin death.