Neil Marlow

Neurologic and developmental disability after extremely preterm birth

Background Small studies show that many children born as extremely preterm infants have neurologic and developmental disabilities. We evaluated all children who were born at 25 or fewer completed weeks of gestation in the United Kingdom and Ireland from March through December 1995 at the time when they reached a median age of 30 months. Methods Each child underwent a formal assessment by an independent examiner. Development was evaluated with use of the Bayley Scales of Infant Development, and neurologic function was assessed by a standardized examination. Disability and severe disability were defined by predetermined criteria. Results At a median age of 30 months, corrected for gestational age, 283 (92 percent) of the 308 surviving children were formally assessed. The mean (±SD) scores on the Bayley Mental and Psychomotor Developmental Indexes, referenced to a population mean of 100, were 84±12 and 87±13, respectively. Fifty-three children (19 percent) had severely delayed development (with scores more t...

Moderate Hypothermia to Treat Perinatal Asphyxial Encephalopathy

BACKGROUND Whether hypothermic therapy improves neurodevelopmental outcomes in newborn infants with asphyxial encephalopathy is uncertain. METHODS We performed a randomized trial of infants who were less than 6 hours of age and had a gestational age of at least 36 weeks and perinatal asphyxial encephalopathy. We compared intensive care plus cooling of the body to 33.5 degrees C for 72 hours and intensive care alone. The primary outcome was death or severe disability at 18 months of age. Prespecified secondary outcomes included 12 neurologic outcomes and 14 other adverse outcomes. RESULTS Of 325 infants enrolled, 163 underwent intensive care with cooling, and 162 underwent intensive care alone. In the cooled group, 42 infants died and 32 survived but had severe neurodevelopmental disability, whereas in the noncooled group, 44 infants died and 42 had severe disability (relative risk for either outcome, 0.86; 95% confidence interval [CI], 0.68 to 1.07; P=0.17). Infants in the cooled group had an increased rate of survival without neurologic abnormality (relative risk, 1.57; 95% CI, 1.16 to 2.12; P=0.003). Among survivors, cooling resulted in reduced risks of cerebral palsy (relative risk, 0.67; 95% CI, 0.47 to 0.96; P=0.03) and improved scores on the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development II (P=0.03 for each) and the Gross Motor Function Classification System (P=0.01). Improvements in other neurologic outcomes in the cooled group were not significant. Adverse events were mostly minor and not associated with cooling. CONCLUSIONS Induction of moderate hypothermia for 72 hours in infants who had perinatal asphyxia did not significantly reduce the combined rate of death or severe disability but resulted in improved neurologic outcomes in survivors. (Current Controlled Trials number, ISRCTN89547571.)

The EPICure Study: Outcomes to Discharge From Hospital for Infants Born at the Threshold of Viability

Objective. To evaluate the outcome for all infants born before 26 weeks of gestation in the United Kingdom and the Republic of Ireland. This report is of survival and complications up until discharge from hospital. Methodology. A prospective observational study of all births between March 1, 1995 and December 31, 1995 from 20 to 25 weeks of gestation. Results. A total of 4004 births were recorded, and 811 infants were admitted for intensive care. Overall survival was 39% (n = 314). Male sex, no reported chorioamnionitis, no antenatal steroids, persistent bradycardia at 5 minutes, hypothermia, and high Clinical Risk Index for Babies (CRIB) score were all independently associated with death. Of the survivors, 17% had parenchymal cysts and/or hydrocephalus, 14% received treatment for retinopathy of prematurity (ROP), and 51% needed supplementary oxygen at the expected date of delivery. Failure to administer antenatal steroids and postnatal transfer for intensive care within 24 hours of birth were predictive of major scan abnormality; lower gestation was predictive of severe ROP, while being born to a black mother was protective. Being of lower gestation, male sex, tocolysis, low maternal age, neonatal hypothermia, a high CRIB score, and surfactant therapy were all predictive of oxygen dependency. Intensive care was provided in 137 units, only 8 of which had >5 survivors. There was no difference in survival between institutions when divided into quintiles based on their numbers of extremely preterm births or admissions. Conclusions. This study provides outcome data for this geographically defined cohort; survival and neonatal morbidity are consistent with previous data from the United Kingdom and facilitate comparison with other geographically based data.

Perinatal and maternal outcomes by planned place of birth for healthy women with low risk pregnancies: The Birthplace in England national prospective cohort study

Objective To compare perinatal outcomes, maternal outcomes, and interventions in labour by planned place of birth at the start of care in labour for women with low risk pregnancies. Design Prospective cohort study. Setting England: all NHS trusts providing intrapartum care at home, all freestanding midwifery units, all alongside midwifery units (midwife led units on a hospital site with an obstetric unit), and a stratified random sample of obstetric units. Participants 64 538 eligible women with a singleton, term (≥37 weeks gestation), and “booked” pregnancy who gave birth between April 2008 and April 2010. Planned caesarean sections and caesarean sections before the onset of labour and unplanned home births were excluded. Main outcome measure A composite primary outcome of perinatal mortality and intrapartum related neonatal morbidities (stillbirth after start of care in labour, early neonatal death, neonatal encephalopathy, meconium aspiration syndrome, brachial plexus injury, fractured humerus, or fractured clavicle) was used to compare outcomes by planned place of birth at the start of care in labour (at home, freestanding midwifery units, alongside midwifery units, and obstetric units). Results There were 250 primary outcome events and an overall weighted incidence of 4.3 per 1000 births (95% CI 3.3 to 5.5). Overall, there were no significant differences in the adjusted odds of the primary outcome for any of the non-obstetric unit settings compared with obstetric units. For nulliparous women, the odds of the primary outcome were higher for planned home births (adjusted odds ratio 1.75, 95% CI 1.07 to 2.86) but not for either midwifery unit setting. For multiparous women, there were no significant differences in the incidence of the primary outcome by planned place of birth. Interventions during labour were substantially lower in all non-obstetric unit settings. Transfers from non-obstetric unit settings were more frequent for nulliparous women (36% to 45%) than for multiparous women (9% to 13%). Conclusions The results support a policy of offering healthy women with low risk pregnancies a choice of birth setting. Women planning birth in a midwifery unit and multiparous women planning birth at home experience fewer interventions than those planning birth in an obstetric unit with no impact on perinatal outcomes. For nulliparous women, planned home births also have fewer interventions but have poorer perinatal outcomes.

The EPICure study: associations and antecedents of neurological and developmental disability at 30 months of age following extremely preterm birth

Aims: To describe perinatal factors associated with later morbidity among extremely preterm children at 30 months of age corrected for prematurity. Population: Of 308 surviving children born at ⩽25 weeks gestation in the United Kingdom and Ireland from March to December 1995, 283 (92%) were evaluated at 30 months of age corrected for prematurity. Methods: Cerebral palsy, severe motor disability, and Bayley scores were used as dependent variables in sequential multiple regression analyses to identify factors associated with adverse outcomes. Results: Adverse outcomes were consistently more common in boys. Factors related to perinatal illness, ultrasound evidence of brain injury, and treatment (particularly postnatal steroids) were associated with adverse motor outcomes (cerebral palsy, disability or Bayley psychomotor development index). Increasing duration of postnatal steroid treatment was associated with poor motor outcomes. A score was developed for severe motor disability with good negative predictive value. In contrast, mental development was associated with a broader range of factors: ethnic group, maternal educational level, the use of antenatal steroids, and prolonged rupture of membranes in addition to chronic lung disease. Conclusion: Male sex is a pervasive risk factor for poor outcome at extremely low gestations. Avoidable or effective treatment factors are identified, which may indicate the potential for improving outcome.

Lung function and respiratory symptoms at 11 years in children born extremely preterm: the EPICure study.

RATIONALE The long-term respiratory sequelae of infants born extremely preterm (EP) and now graduating from neonatal intensive care remains uncertain. OBJECTIVES To assess the degree of respiratory morbidity and functional impairment at 11 years in children born EP (i.e., at or less than 25 completed weeks of gestation) in relation to neonatal determinants and current clinical status. METHODS Pre- and postbronchodilator spirometry were undertaken at school in children born EP and classroom control subjects. Physical examination and respiratory health questionnaires were completed. Multivariable regression was used to estimate the predictive power of potential determinants of lung function. MEASUREMENTS AND MAIN RESULTS Spirometry was obtained in 182 of 219 children born EP (129 with prior bronchopulmonary dysplasia [BPD]) and 161 of 169 classmates, matched for age, sex, and ethnic group. Children born EP had significantly more chest deformities and respiratory symptoms than classmates, with twice as many (25 vs. 13%; P < 0.01) having a current diagnosis of asthma. Baseline spirometry was significantly reduced (P < 0.001) and bronchodilator responsiveness was increased in those born EP, the changes being most marked in those with prior BPD. EP birth, BPD, current symptoms, and treatment with beta-agonists are each associated independently with lung function z-scores (adjusted for age, sex, and height) at 11 years. Fifty-six percent of children born EP had abnormal baseline spirometry and 27% had a positive bronchodilator response, but less than half of those with impaired lung function were receiving any medication. CONCLUSIONS After extremely preterm birth, impaired lung function and increased respiratory morbidity persist into middle childhood, especially among those with BPD. Many of these children may not be receiving appropriate treatment.

Cognitive and educational outcome of very‐low‐birthweight children in early adolescence

A cohort of 138 very‐low‐birthweight (VLBW) 12‐year‐old children and matched control children were assessed on objective cognitive and educational measures. School performance was rated by teachers and by the children themselves. VLBW children were shown to have lower IQ scores, and poorer scores on all objective educational measures compared with control children. Controlling for IQ differences, mathematics and reading‐comprehension scores remained significantly lower for VLBW children. Teachers rated VLBW children lower in all curriculum areas. Significantly more VLBW children were found to be ‘failing’ in one or more subject and an increased proportion compared with the control children had received remedial education. The VLBW group showed no evidence of ‘catch up’ between 6 and 12 years of age. Multiple regression analyses were used to identify predictors of cognitive and educational outcome. The duration of mechanical ventilation in the neonatal period was inversely related to outcome. Full‐Scale IQ at 6 years, motor‐skills score at 6 years, and head circumference at 12 years all predicted outcome at 12 years, as did maternal education, family income and size. Individually, many VLBW children perform satisfactorily, but as a group VLBW children appear to be at a long‐term disadvantage to peers in the areas of cognitive and educational performance.

Academic attainment and special educational needs in extremely preterm children at 11 years of age: the EPICure Study

Aim: To assess academic attainment and special educational needs (SEN) in extremely preterm children in middle childhood. Methods: Of 307 extremely preterm (⩽25 weeks) survivors born in the UK and Ireland in 1995, 219 (71%) were re-assessed at 11 years of age and compared to 153 classmates born at term, using standardised tests of cognitive ability and academic attainment and teacher reports of school performance and SEN. Multiple imputation was used to correct for selective dropout. Results: Extremely preterm children had significantly lower scores than classmates for cognitive ability (−20 points; 95% CI −23 to −17), reading (−18 points; −22 to −15) and mathematics (−27 points; −31 to −23). Twenty nine (13%) extremely preterm children attended special school. In mainstream schools, 105 (57%) extremely preterm children had SEN (OR 10; 6 to 18) and 103 (55%) required SEN resource provision (OR 10; 6 to 18). Teachers rated 50% of extremely preterm children as having below average attainment compared with 5% of classmates (OR 18; 8 to 41). Extremely preterm children who entered compulsory education an academic year early due to preterm birth had similar academic attainment but required more SEN support (OR 2; 1.0 to 3.6). Conclusions: Extremely preterm survivors remain at high risk for learning impairments and poor academic attainment in middle childhood. A significant proportion require full-time specialist education and over half of those attending mainstream schools require additional health or educational resources to access the national curriculum. The prevalence and impact of SEN are likely to increase as these children approach the transition to secondary school.

Autism spectrum disorders in extremely preterm children.

OBJECTIVES To investigate the prevalence, correlates, and antecedents of autism spectrum disorders (ASD) in extremely preterm children. STUDY DESIGN We conducted a prospective study of all births <26 weeks gestation in the United Kingdom and Ireland in 1995. Of 307 survivors at 11 years, 219 (71%) were assessed and compared with 153 term-born classmates. Parents completed the Social Communication Questionnaire (SCQ) to assess autism spectrum symptoms, and ASD were diagnosed by using a psychiatric evaluation. An IQ test and clinical evaluation were also administered. Longitudinal outcome data were available for extremely preterm children. RESULTS Extremely preterm children had significantly higher SCQ scores than classmates (mean difference, 4.6 points; 95% CI, 3.4-5.8). Sixteen extremely preterm children (8%) were assigned an ASD diagnosis, compared with none of the classmates. By hospital discharge, male sex, lower gestation, vaginal breech delivery, abnormal cerebral ultrasound scanning results, and not having had breast milk were independently associated with autism spectrum symptoms. By 6 years, independent associates were cognitive impairment, inattention and peer problems, withdrawn behavior at 2.5 years, and not having had breast milk. CONCLUSIONS Extremely preterm children are at increased risk for autism spectrum symptoms and ASD in middle childhood. These symptoms and disorders were associated with neurocognitive outcomes, suggesting that ASD may result from abnormal brain development in this population.

Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial

BACKGROUND The ORACLE II trial compared the use of erythromycin and/or amoxicillin-clavulanate (co-amoxiclav) with that of placebo for women in spontaneous preterm labour and intact membranes, without overt signs of clinical infection, by use of a factorial randomised design. The aim of the present study--the ORACLE Children Study II--was to determine the long-term effects on children after exposure to antibiotics in this clinical situation. METHODS We assessed children at age 7 years born to the 4221 women who had completed the ORACLE II study and who were eligible for follow-up with a structured parental questionnaire to assess the childs health status. Functional impairment was defined as the presence of any level of functional impairment (severe, moderate, or mild) derived from the mark III Multi-Attribute Health Status classification system. Educational outcomes were assessed with national curriculum test results for children resident in England. FINDINGS Outcome was determined for 3196 (71%) eligible children. Overall, a greater proportion of children whose mothers had been prescribed erythromycin, with or without co-amoxiclav, had any functional impairment than did those whose mothers had received no erythromycin (658 [42.3%] of 1554 children vs 574 [38.3%] of 1498; odds ratio 1.18, 95% CI 1.02-1.37). Co-amoxiclav (with or without erythromycin) had no effect on the proportion of children with any functional impairment, compared with receipt of no co-amoxiclav (624 [40.7%] of 1523 vs 608 [40.0%] of 1520; 1.03, 0.89-1.19). No effects were seen with either antibiotic on the number of deaths, other medical conditions, behavioural patterns, or educational attainment. However, more children whose mothers had received erythromycin or co-amoxiclav developed cerebral palsy than did those born to mothers who received no erythromycin or no co-amoxiclav, respectively (erythromycin: 53 [3.3%] of 1611 vs 27 [1.7%] of 1562, 1.93, 1.21-3.09; co-amoxiclav: 50 [3.2%] of 1587 vs 30 [1.9%] of 1586, 1.69, 1.07-2.67). The number needed to harm with erythromycin was 64 (95% CI 37-209) and with co-amoxiclav 79 (42-591). INTERPRETATION The prescription of erythromycin for women in spontaneous preterm labour with intact membranes was associated with an increase in functional impairment among their children at 7 years of age. The risk of cerebral palsy was increased by either antibiotic, although the overall risk of this condition was low. FUNDING UK Medical Research Council.