Karin J. Rademaker

Structural and functional brain development after hydrocortisone treatment for neonatal chronic lung disease

Objective. There is much concern about potential neurodevelopmental impairment after neonatal corticosteroid treatment for chronic lung disease. Dexamethasone is the corticosteroid most often used in this clinical setting, and it has been shown to impair cortical growth among preterm infants. This study evaluated long-term effects of prematurity itself and of neonatal hydrocortisone treatment on structural and functional brain development using three-dimensional MRI with advanced image-processing and neurocognitive assessments. Methods. Sixty children born preterm, including 25 children treated with hydrocortisone and 35 children not treated with hydrocortisone, and 21 children born at term were evaluated, at a mean age of 8 years, with quantitative MRI and neurocognitive assessments (Wechsler Intelligence Scales for Children-Revised [WISC-R]). Automatic image segmentation was used to determine the tissue volumes of cerebral gray matter, white matter, and cerebrospinal fluid. In addition, the volume of the hippocampus was determined manually. WISC-R scores were recorded as mean intelligence scores at evaluation. Neonatal hydrocortisone treatment for chronic lung disease consisted of a starting dose of 5 mg/kg per day tapered over a minimum of 3 weeks. Results. Cerebral gray matter volume was reduced among preterm children (regardless of hydrocortisone treatment), compared with children born at term (preterm: 649 ± 4.4 mL; term: 666 ± 7.3 mL). Birth weight was shown to correlate with gray matter volume at 8 years of age in the preterm group (r = 0.421). Cerebrospinal fluid volume was increased among children born preterm, compared with children born at term (preterm: 228 ± 4.9 mL; term: 206 ± 8.2 mL). Total hippocampal volume tended to be lower among children born preterm, with a more pronounced reduction of hippocampal volume among boys (preterm: 6.1 ± 0.13 mL; term: 6.56 ± 0.2 mL). The WISC-R score was lower for children born preterm, compared with children born at term (preterm: 99.4 ± 12.4; term: 109.6 ± 8.8). Children treated with neonatal hydrocortisone had very similar volumes of gray matter (preterm with hydrocortisone: 650 ± 7.0 mL; preterm without hydrocortisone: 640 ± 5.6 mL), white matter (preterm with hydrocortisone: 503 ± 6.1 mL; preterm without hydrocortisone: 510 ± 4.9 mL), and cerebrospinal fluid (preterm with hydrocortisone: 227 ± 7.4 mL; preterm without hydrocortisone: 224 ± 6.0 mL), compared with untreated infants. The hippocampal volumes were similar in the 2 groups (preterm with hydrocortisone: 5.92 ± 0.15 mL; preterm without hydrocortisone: 5.81 ± 0.12 mL). The WISC-R score assessments were within the normal range for both groups, with no difference between the groups (preterm with hydrocortisone: 100.8 ± 13; preterm without hydrocortisone: 98.6 ± 12.3). Conclusions. Prematurity is associated with mild brain structural differences that persist at 8 years of age, with associated lower scores in neurocognitive assessments. The data suggest that perinatal hydrocortisone given at the described dosage has no long-term effects on either neurostructural brain development or neurocognitive outcomes.

Neurodevelopmental Outcome of Preterm Infants with Severe Intraventricular Hemorrhage and Therapy for Post-Hemorrhagic Ventricular Dilatation

OBJECTIVE To evaluate the neurodevelopmental outcome of preterm infants with a grade III or IV hemorrhage and to assess the effect of routine low-threshold therapy of post-hemorrhagic ventricular dilatation (PHVD) on neurodevelopmental outcome. STUDY DESIGN Of the 214 preterm infants (< or = 34 weeks gestational age), 94 (44%) had a grade III intraventricular hemorrhage (IVH), and 120 (56%) had a grade IV hemorrhage. We evaluated the natural evolution of IVH, the need for intervention for PHVD, and neurodevelopmental outcome at 24 months corrected age. RESULTS PHVD developed significantly more often in the surviving infants with a grade III hemorrhage (53/68, 78%) than in infants with a grade IV hemorrhage (40/76, 53%; P = .002). Intervention for PHVD was required significantly more often in the grade III group, than in the grade IV group (P < .001). In the grade III group, cerebral palsy developed in 5 of the 68 surviving infants (7.4%), compared with 37 of the 76 infants (48.7%) with a grade IV hemorrhage (P < .001). The mean developmental quotient (DQ) in the grade III group was 99, and in the grade IV-group it was 95 at 24 months corrected age. CONCLUSIONS Short-term neurodevelopmental outcome of preterm infants with grade III or IV hemorrhage was better than reported earlier. Requiring intervention for PHVD only had a negative effect on DQ in infants with a grade IV hemorrhage. Infants with cerebral palsy had significantly lower DQs, irrespective of the severity of IVH.

Neonatal cranial ultrasound versus MRI and neurodevelopmental outcome at school age in children born preterm

Aim: To examine the correlation between neonatal cranial ultrasound and school age magnetic resonance imaging (MRI) and neurodevelopmental outcome. Methods: In a prospective 2 year cohort study, 221 children (gestational age ⩽32 weeks and/or birth weight ⩽1500 g) participated at a median age of 8.1 years (inclusion percentage 78%). Conventional MRI, IQ (subtests of the WISC), and motor performance (Movement Assessment Battery for Children) at school age were primary outcome measurements. Results: Overall, there was poor correspondence between ultrasound group classifications and MRI group classifications, except for the severe group (over 70% agreement). There was only a 1% chance of the children with a normal cranial ultrasound having a major lesion on MRI. Mean IQ (standard deviation) was significantly lower in children with major ultrasound or MRI lesions, but was also lower in children with minor lesions on MRI compared to children with a normal MRI (91±16, 100±13, 104±13 for major lesions, minor lesions, and normal MRI, respectively). Median total impairment score (TIS) was significantly higher in children with major lesions on ultrasound or MRI as well as in children with minor lesions on MRI (TIS 4.0 and 6.25 for normal and minor lesions on MRI, respectively; p<0.0001). Conclusions: A normal neonatal cranial ultrasound excluded a severe lesion on MRI in 99% of cases. MRI correlated more strongly with mean IQ and median TIS than ultrasound. Subtle white matter lesions are better detected with MRI which could explain the stronger correlation of MRI with IQ and motor performance.

Early versus late treatment of posthaemorrhagic ventricular dilatation: results of a retrospective study from five neonatal intensive care units in The Netherlands.

Posthaemorrhagic ventricular dilatation (PHVD) in very preterm infants carries a poor prognosis. As earlier studies have failed to show a benefit of early intervention, it is recommended that PHVD be first treated when head circumference is rapidly increasing and/or when symptoms of raised intracranial pressure develop. Infants with PHVD, admitted to 5 of the 10 Dutch neonatal intensive care units were studied retrospectively, to investigate whether there was a difference in the time of onset of treatment of PHVD and, if so, whether this was associated with a difference in the requirement of a ventriculo‐peritoneal (VP) shunt and/or neurodevelopmental outcome. The surviving infants with a gestational age ≤34 wk, born between 1992 and 1996, diagnosed as having a grade III haemorrhage according to Papile on cranial ultrasound and who developed PHVD were included in the study. PHVD was defined as a ventricular index (VI) exceeding the 97th percentile according to Levene (1981), and severe PHVD as a VI crossing the p 97 + 4 mm line. Ninety‐five infants met the entry criteria. Intervention was not deemed necessary in 22 infants, because of lack of progression. In 31 infants lumbar punctures (LP) were done before the p 97 + 4 mm line was crossed (early intervention). In 20/31 infants, stabilization occurred. In 9 a subcutaneous reservoir was placed, with subsequent stabilization in 6. In 5/31 infants a VP shunt was eventually inserted. In 42 infants treatment was started once the p 97 + 4 mm line was crossed (late intervention). In 30 infants LPs were performed and in 17 of these a VP shunt was eventually inserted. In 11 infants a subcutaneous reservoir was immediately inserted and in 8 of these infants a VP shunt was needed. In one infant a VP shunt was immediately inserted, without any other form of treatment. Infants with late intervention crossed the p 97+ 4 mm earlier (p 0.03) and needed a shunt (26/42; 62%) more often than those with early intervention (5/31; 16%). Early LP was associated with a strongly reduced risk of VP‐shunting (odds ratio = 0.22, 95% confidence interval: 0.08–0.62). The number of infants who developed a moderate or severe handicap was also higher (11/42; 26%) in the late intervention group, compared with those not requiring any intervention (3/22; 14%) or treated early (5/31; 16%).

Antenatal onset of haemorrhagic and/or ischaemic lesions in preterm infants: prevalence and associated obstetric variables

AIM To assess the prevalence of an antenatal onset of haemorrhagic and/or ischaemic lesions in preterm infants; to identify possibly related obstetric risk factors. METHODS A prospective cohort study was made of 1332 infants born at less than 34 completed weeks, using cranial ultrasound, for the presence of antenatal brain lesions (group A) involving the periventricular white matter (PVWM) or central grey matter. Entry criteria were presence of (i) cysts in the PVWM < 7 days; (ii) increased PVWM echogenicity < 6 hours, confirmed to be white matter necrosis at post mortem examination; (iii) a unilateral porencephalic cyst < 3 days; (iv) an intraventricular haemorrhage with unilateral parenchymal involvement < 6 hours; and (v) symmetrical areas of increased echogenicity in the thalami, confirmed to be areas of calcification on post mortem examination. Group B consisted of infants with a normal early neonatal ultrasound scan with subsequent development of the lesions mentioned above. RESULTS Twenty four cases met the entry criteria for group A: 17 died and five of the seven survivors developed cerebral palsy at follow up. Of the whole cohort, 156 (11.7%) infants died and in 63 (40.3%) of these a large ultrasound lesion was present. In 17 (26.9%) cases this lesion was considered to be of antenatal onset. Sixty eight of the 1176 (5.8%) survivors developed cerebral palsy and this was attributed to antenatal onset in five (7.3%). A comparison of the obstetric risk factors between the infants in group A and B, who either died or developed cerebral palsy, showed a significant difference in gestational age between the two groups (30.9vs 28.9 weeks; p<0.001). Prolonged rupture of membranes was significantly more common in group B (p=0.03), while an ominous cardiotachogram was significantly more common in group A (p=0.01), and this remained significant following logistic regression analysis. CONCLUSIONS Although these data suggest that most preterm infants did not develop their brain lesions in utero, an antenatal onset was not uncommon, especially in those with PVWM lesions, who did not survive the neonatal period.

Unilateral haemorrhagic parenchymal lesions in the preterm infant: shape, site and prognosis

Rademaker KJ, Groenendaal F, Jansen GH, Eken P, de Vries LS. Unilateral haemorrhagic parenchymal lesions in the preterm infant: shape, site and prognosis. Acta Pædiatr 1994;83:602–8. Stockholm. ISSN 0803–5253

Subependymal pseudocysts : ultrasound diagnosis and findings at follow-up

During a two‐year period, subependymal pseudocysts were diagnosed in 24 infants using cranial ultrasound: 8 were located at the external angle of the lateral ventricle and 16 at the caudothalamic notch. Associated congenital anomalies were present in six infants and CMV was isolated in one case. Four of the eight infants with pseudocysts at the external angle were one half of twins. As all but one of the surviving infants with pseudocysts were normal at follow‐up (at 3–24 months of age), it is important to make a distinction between pseudocysts and extensive cystic periventricular leukomalacia, as the latter condition invariably leads to cerebral palsy and/or visual impairment.

Ultrasound measurements of the lateral ventricles in neonates: why, how and when? A systematic review

Germinal matrix‐intraventricular haemorrhage and subsequent post‐haemorrhagic ventricular dilatation (PHVD) are frequently encountered complications in preterm neonates. As progressive dilatation of the lateral ventricles may be associated with elevated intracranial pressure, ultrasound measurements of ventricular size play a major role in the evaluation of neonates at risk of ventricular dilatation as well as in assessing the effect of intervention for PHVD. A systematic search was carried out in Medline and Embase to identify neonatal and foetal ultrasound studies on lateral ventricular size. This review presents an overview of the available data concerning neonatal reference values for lateral ventricular size, the influence of gender, ventricular asymmetry and the effect of the mode of delivery on the phenomenon of ventricular reopening following birth.

Postnatal hydrocortisone treatment for chronic lung disease in the preterm newborn and long-term neurodevelopmental follow-up.

The benefits versus the risks of postnatal administration of steroids in preterm-born infants are still debatable. This review examines the literature on postnatal hydrocortisone treatment for chronic lung disease (CLD) in preterm-born infants with a particular focus on the effects of such treatment on long-term neurodevelopmental outcomes. Quantitative published evidence does not point to a clear advantage of treatment with hydrocortisone over dexamethasone with regard to the impact on long-term neurological outcomes. However, in the absence of a randomised comparison, a consensus may soon have to be reached on the basis of the best available evidence whether hydrocortisone should replace dexamethasone in the treatment of CLD.

Incidence of infections of ventricular reservoirs in the treatment of post-haemorrhagic ventricular dilatation: a retrospective study (1992-2003).

Background: Since 1992, infants with progressive posthaemorrhagic ventricular dilatation (PHVD) have been treated in the Neonatal Intensive Care Unit, Wilhelmina Children’s Hospital, Utrecht, The Netherlands, with a ventricular reservoir. Objective: To retrospectively study the incidence of infection using this invasive procedure. Methods: Between January 1992 and December 2003, 76 preterm infants were treated with a ventricular reservoir. Infants admitted during two subsequent periods were analysed: group 1 included infants admitted during 1992–7 (n = 26) and group 2 those admitted during 1998–2003 (n = 50). Clinical characteristics and number of reservoir punctures were evaluated. The incidence of complications over time was assessed, with a focus on the occurrence of infection of the reservoir. Results: The number of punctures did not change during both periods. Infection was significantly less common during the second period (4% (2/50) v 19.2% (5/26), p = 0.029). Conclusion: The use of a ventricular reservoir is a safe treatment to ensure adequate removal of cerebrospinal fluid in preterm infants with PHVD. In experienced hands, the incidence of infection of the ventricular reservoir or major complications remains within acceptable limits.