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.

Movement Difficulties at Age Five Among Extremely Preterm Infants.

BACKGROUND AND OBJECTIVES: Children born extremely preterm (EPT), <28 weeks' gestational age, face higher risks of movement difficulties than their term-born peers. Studies report varying prevalence estimates and prognostic factors identifying children who could benefit from early intervention are inconsistent. This study investigated the prevalence of movement difficulties in children born EPT and associated risk factors. METHODS: Data come from a population-based EPT birth cohort in 2011 and 2012 in 11 European countries. Children without cerebral palsy were assessed at 5 years of age (N = 772) with the Movement Assessment Battery for Children-Second Edition, which classifies movement difficulties as none (>15th percentile), at risk (6th-15th percentile) and significant (≤5th percentile). Associations with sociodemographic, perinatal, and neonatal characteristics collected from obstetric and neonatal medical records and parental questionnaires were estimated using multinomial logistic regression. RESULTS: We found 23.2% (n = 179) of children were at risk for movement difficulties and 31.7% (n = 244) had significant movement difficulties. Lower gestational age, severe brain lesions, and receipt of postnatal corticosteroids were associated with significant movement difficulties, whereas male sex and bronchopulmonary dysplasia were associated with being at risk and having significant movement difficulties. Children with younger, primiparous, less educated, and non-European-born mothers were more likely to have significant movement difficulties. Differences in prevalence between countries remained after population case-mix adjustments. CONCLUSIONS: This study confirms a high prevalence of movement difficulties among EPT children without cerebral palsy, which are associated with perinatal and neonatal risk factors as well as sociodemographic characteristics and country.

Profiles of Functioning in 5.5-Year-Old Very Preterm Born Children in France: The EPIPAGE-2 Study.

OBJECTIVE: Very preterm born children are at risk for impairments in multiple neurodevelopmental domains, but outcomes vary between individuals. The present study aimed to distinguish subgroups with distinct profiles of functioning across motor, cognitive, behavioral, and psychosocial domains. These profiles were related to neonatal and social/environmental factors. METHOD: The sample included 1977 children born very preterm (<32 weeks' gestation) in 2011 from the French population-based EPIPAGE-2 cohort. Using latent profile analysis, subgroups of children were distinguished based on their functioning at 5.5 years. The relation between outcome profiles and neonatal and social/environmental factors was tested using multivariable multinomial logistic regression analysis. RESULTS: Four subgroups with distinct outcome profiles were distinguished: no deficit in any domain (45%); motor and cognitive deficits without behavioral/psychosocial deficits (31%); primarily behavioral and psychosocial deficits (16%); and deficits in multiple domains (8%). Male sex (odds ratio [OR] = 2.1-2.7), bronchopulmonary dysplasia (OR = 2.1-2.8), low parental education level (OR = 1.8-2.1), and parental non-European immigrant status (OR = 2.3-3.0) were independently associated with higher odds for all suboptimal outcome profiles compared to the favorable outcome profile. CONCLUSION: Among 5.5-year-old very preterm born children, subgroups can be distinguished with distinct outcome profiles that vary in severity, type, and combinations of deficits. This information is important for the development of interventions that are tailored to the needs of large subgroups of children across multiple domains of functioning. General neonatal and social/environmental factors may be useful for early identification of very preterm born children at risk for general rather than domain-specific impairments.

Bronchopulmonary Dysplasia and Risk of Developmental Delay: An EPIPAGE-2 Cohort Study.

BACKGROUND: Overall and respiratory management of preterm children are constantly evolving, which might have changed both the pathophysiology and neurodevelopmental consequences of bronchopulmonary dysplasia (BPD). OBJECTIVES: The objective of this study is to determine whether the previously shown association between BPD and risk of developmental delay persists. METHODS: The study population was children born before 32 weeks' gestation from the French prospective cohort EPIPAGE-2. The exposure was BPD assessed at 36 weeks' postmenstrual age. The main outcome was risk of developmental delay defined by an Age & Stages Questionnaires (ASQ) score below threshold at 24 months' corrected age. RESULTS: The analyzed population included 2,706 children. Among those with available ASQ score, 196/1,587 had BPD and 671/1,587 had an ASQ score below threshold. BPD was associated with an ASQ score below threshold (odds ratio 1.52, 95% confidence interval 1.11-2.08; p = 0.008). CONCLUSIONS: BPD was strongly associated with risk of developmental delay.

Screening for Retinopathy of Prematurity in Very Preterm Children: The EPIPAGE-2 Cohort Study.

INTRODUCTION: Retinopathy of prematurity (ROP) is a blinding disease that requires screening by retinal examination. Screening practices are rarely evaluated. We aimed to determine the prevalence of ROP screening in very preterm infants and individual- and center-related factors associated with ROP screening. METHODS: Data were extracted from the EPIPAGE-2 cohort, a French prospective population-based study of premature births in 2011. Children born before 32 weeks' gestation (WG) without severe malformation and alive at the recommended time for ROP screening were included. Outcome measures were achievement of ROP screening and compliance with recommended screening timeline. Individual- and center-related factors associated with both measures were studied using mixed models. RESULTS: Among 3,077 eligible infants, 2,169 (70.5%) had a ROP screening, ranging from 96% at 24 WG to 50% at 31 WG. Large variability among units was observed. Individual characteristics associated with screening were low gestational age, low birth weight, severe bronchopulmonary dysplasia or neurological lesions, and transfer between neonatal units during the screening period. Odds of screening were higher in neonatal units using wide-angle imaging (odds ratio 2.65 [95% confidence interval 1.17-6.01]) but decreased in units without a local protocol for ROP screening (0.03 [0.01-0.09]). Among screened children, 1,641/2,169 (75.7%) were screened according to recommended timeline. Delayed screening was associated with low gestational age, severe bronchopulmonary dysplasia or necrotizing enterocolitis, and absence of local protocol for ROP screening. DISCUSSION/CONCLUSIONS: In this large cohort study of infants born very preterm, almost one-third were not screened for ROP. Children most at risk for ROP were the best screened but often with delay. The higher compliance of neonatal units using wide-angle imaging systems supports its use.

Survival and morbidity of preterm children born at 22 through 34 weeks' gestation in France in 2011: results of the EPIPAGE-2 cohort study.

IMPORTANCE: Up-to-date estimates of the health outcomes of preterm children are needed for assessing perinatal care, informing parents, making decisions about care, and providing evidence for clinical guidelines. OBJECTIVES: To determine survival and neonatal morbidity of infants born from 22 through 34 completed weeks' gestation in France in 2011 and compare these outcomes with a comparable cohort in 1997. DESIGN, SETTING, AND PARTICIPANTS: The EPIPAGE-2 study is a national, prospective, population-based cohort study conducted in all maternity and neonatal units in France in 2011. A total of 2205 births (stillbirths and live births) and terminations of pregnancy at 22 through 26 weeks' gestation, 3257 at 27 through 31 weeks, and 1234 at 32 through 34 weeks were studied. Cohort data were collected from January 1 through December 31, 1997, and from March 28 through December 31, 2011. Analyses for 1997 were run for the entire year and then separately for April to December; the rates for survival and morbidities did not differ. Data are therefore presented for the whole year in 1997 and the 8-month and 6-month periods in 2011. MAIN OUTCOMES AND MEASURES: Survival to discharge and survival without any of the following adverse outcomes: grade III or IV intraventricular hemorrhage, cystic periventricular leukomalacia, severe bronchopulmonary dysplasia, retinopathy of prematurity (stage 3 or higher), or necrotizing enterocolitis (stages 2-3). RESULTS: A total of 0.7% of infants born before 24 weeks' gestation survived to discharge: 31.2% of those born at 24 weeks, 59.1% at 25 weeks, and 75.3% at 26 weeks. Survival rates were 93.6% at 27 through 31 weeks and 98.9% at 32 through 34 weeks. Infants discharged home without severe neonatal morbidity represented 0% at 23 weeks, 11.6% at 24 weeks, 30.0% at 25 weeks, 47.5% at 26 weeks, 81.3% at 27 through 31 weeks, and 96.8% at 32 through 34 weeks. Compared with 1997, the proportion of infants surviving without severe morbidity in 2011 increased by 14.4% (P < .001) at 25 through 29 weeks and 6% (P < .001) at 30 through 31 weeks but did not change appreciably for those born at less than 25 weeks. The rates of antenatal corticosteroid use, induced preterm deliveries, cesarean deliveries, and surfactant use increased significantly in all gestational-age groups, except at 22 through 23 weeks. CONCLUSIONS AND RELEVANCE: The substantial improvement in survival in France for newborns born at 25 through 31 weeks' gestation was accompanied by an important reduction in severe morbidity, but survival remained rare before 25 weeks. Although improvement in survival at extremely low gestational age may be possible, its effect on long-term outcomes requires further studies. The long-term results of the EPIPAGE-2 study will be informative in this regard.

Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population-based cohort study.

AIM: The aim of this study was to assess the independent role of cerebral lesions on ultrasound scan, and several other neonatal and obstetric factors, as potential predictors of cerebral palsy (CP) in a large population-based cohort of very preterm infants. METHOD: As part of EPIPAGE, a population-based prospective cohort study, perinatal data and outcome at 5 years of age were recorded for 1812 infants born before 33 weeks of gestation in nine regions of France in 1997. RESULTS: The study group comprised 942 males (52%) and 870 females with a mean gestational age of 30 weeks (SD 2 wks; range 24-32 wks) and a mean birthweight of 1367 g (SD 393 g; range 450-2645 g). CP was diagnosed at 5 years of age in 159 infants (prevalence 9%; 95% confidence interval [CI] 7-10%), 97 males and 62 females, with a mean gestational age of 29 weeks (SD 2 wks; range 24-32 wks) and a mean birthweight of 1305 g (SD 386 g; range 500-2480 g). Among this group, 67% walked without aid, 14% walked with aid, and 19% were unable to walk. Spastic, ataxic, and dyskinetic CP accounted for 89%, 7%, and 4% of cases respectively. The prevalence of CP was 61% among infants with cystic periventricular leukomalacia, 50% in infants with intraparenchymal haemorrhage, 8% in infants with grade I intraventricular haemorrhage, and 4% in infants without a detectable cerebral lesion. After controlling for cerebral lesions and obstetric and neonatal factors, only male sex (odds ratio [OR] 1.52; 95% CI 1.03-2.25) and preterm premature rupture of membranes or preterm labour (OR 1.72; 95% CI 0.95-3.14) were predictors of the development of CP in very preterm infants. INTERPRETATION: Cerebral lesions were the most important predictor of CP in very preterm infants. In addition, infant sex and preterm premature rupture of membranes or preterm labour were also independent predictors of CP.

Neonatal and 5-year outcomes after birth at 30-34 weeks of gestation.

OBJECTIVE: To evaluate the rates of in-hospital death, neonatal complications, and 5-year outcomes of infants born at 30-34 weeks of gestation. METHODS: In nine regions of France, all 2,020 stillbirths and live births at 30, 31, and 32 weeks in 1997 and all 457 births at 33 and 34 weeks in April and October 1997 were recorded. Survivors were evaluated at 5 years of age. RESULTS: Increasing gestational age from 30 to 34 weeks was associated with progressive decreases in in-hospital mortality (from 8.1% to 0.4%) and neonatal complications (respiratory distress syndrome, 43.8% to 2.6%; maternofetal infections, 7.2% to 2.6%; and severe white matter injury, 5.5% to 1.3%). Although infants at 33 and 34 weeks of gestation rarely experienced necrotizing enterocolitis, bronchopulmonary dysplasia, or nosocomial infections, they still required endotracheal ventilation, antibiotics, or parenteral nutrition. At 5 years of age, older gestational age was associated with significant decreases in rates of cerebral palsy (6.3% at 30 weeks and 0.7% at 34 weeks) and mild to severe cognitive impairments (35.3% at 30 weeks and 23.9% at 34 weeks). In singletons, preterm rupture of membranes or preterm labor carried an increased risk of cerebral palsy but not of cognitive impairment. CONCLUSION: Neonates born at 30-34 weeks experienced substantial morbidity and often required admission to neonatal intensive care units. These outcomes suggest that prolonging pregnancies beyond 34 weeks may be desirable whenever possible. Infants born at 30-34 weeks should be carefully monitored to ensure prompt detection and management of neurodevelopmental impairment.

Resting energy expenditure in children with neonatal chronic lung disease and obstruction of the airways.

Children with history of broncho-pulmonary dysplasia (BPD) often suffer from growth failure and lung sequelae. The main objective of this study was to test the role of pulmonary obstruction on resting energy expenditure (REE) and nutritional status in BPD. Seventy-one children with BPD (34 boys and 37 girls) and 30 controls (20 boys and 10 girls) aged 4-8 years were enrolled. Body composition was assessed by bio-impedancemetry measurements; REE was measured by indirect calorimetry. Predicted REE was calculated using the Schofield equation. The population of children with BPD was divided into three groups: children without obstruction of the airways, children with moderate obstruction of the airways, and children with severe obstruction. Children with BPD were significantly smaller and leaner than controls. Altered body composition (reduction of fat mass) was observed in BPD children that suffered from airway obstruction. REE was significantly lower in children with BPD compared to controls, but when adjusted for weight and fat-free mass no significant difference was observed irrespective of pulmonary status. Airway obstruction in children with BPD does not appear to be associated with an increased REE. Moreover altered REE could not explain the altered nutritional status that is still observed in BPD in later childhood. This supports the hypothesis that body composition and pulmonary function in BPD in later childhood are fixed sequelae originating from the neonatal period.

Nutritional status at 2 years in former infants with bronchopulmonary dysplasia influences nutrition and pulmonary outcomes during childhood.

Improved survival rates for extreme prematurity have been accompanied by an increase in the incidence of bronchopulmonary dysplasia (BPD). The objective of this study was to assess factors associated with long-term nutritional and pulmonary function outcomes. The study was a cross-sectional study of 52 children who had been born prematurely, had experienced BPD, and were 4-8 y old at the time of the study. Undernutrition was defined as a Z score for weight-for-height of <-2 SD. Body composition and lung function were evaluated. Resting energy expenditure (REE) was measured using indirect calorimetry. Stepwise logistic regression was used to test for factors associated with undernutrition and pulmonary function. Eighteen children (35%) with BPD, predominantly girls, were undernourished. Undernutrition occurred within the first months of life and was associated with high REE. Multivariate analysis showed that factors significantly associated with undernutrition were female sex and undernutrition at age 2 y. Thirty-one children (60%) had abnormal lung function tests. Multivariate analysis showed that undernutrition at age 2 y was the only factor associated with the risk of developing distension of the airways. Nutritional status at age 2 y in children who had BPD in infancy influences nutritional and pulmonary outcomes in childhood.

Cerebral palsy among very preterm children in relation to gestational age and neonatal ultrasound abnormalities: the EPIPAGE cohort study.

OBJECTIVE: To estimate the prevalence of cerebral palsy at 2 years of age among children born very preterm, according to gestational age, infant gender, plurality, and neonatal cranial ultrasound abnormalities. METHODS: All infants born between 22 and 32 weeks of gestation in 9 regions of France in 1997 were included in this prospective, population-based, cohort study. The main outcome measure was cerebral palsy prevalence at 2 years. Of the 2364 survivors eligible for follow-up evaluation, 1954 (83%) were assessed at 2 years of age. RESULTS: Among the 1954 children assessed at 2 years, 8.2% had cerebral palsy. Bilateral spastic cerebral palsy, hemiplegia, and monoplegia accounted for 72%, 9%, and 10% of cases, respectively. Fifty percent of the children with cerebral palsy walked independently at the age of 2, 31% were unable to walk but could sit independently, and 19% could not sit (unable to maintain head and trunk control). The prevalence of cerebral palsy was 20% at 24 to 26 weeks of gestation, compared with 4% at 32 weeks. On the basis of ultrasound findings in the neonatal period, we found that 17% of children with isolated grade III intraventricular hemorrhage and 25% of children with white matter damage (ie, ventricular dilation, persistent echodensities, or cystic periventricular leukomalacia) had cerebral palsy, compared with 4% of children with normal ultrasound scans. CONCLUSIONS: Despite recent improvements in survival rates, cerebral palsy remains highly prevalent among very preterm children. Severe cranial ultrasound abnormalities predict motor disability strongly, but one third of infants with cerebral palsy had no ultrasound abnormalities.

Are maternal hypertension and small-for-gestational age risk factors for severe intraventricular hemorrhage and cystic periventricular leukomalacia? Results of the EPIPAGE cohort study.

OBJECTIVE: The purpose of this study was to examine the relationships between different causes of preterm delivery (eg, maternal hypertension, small-for-gestational age [SGA], other) and cerebral damage (eg, cystic periventricular leukomalacia [c-PVL], grade III intraventricular hemorrhage [IVH], and intra-parenchymal hemorrhage [IPH]). STUDY DESIGN: This study included 1902 very preterm singletons who were transferred to neonatal intensive care units in 9 French regions. We used logistic regression models to compare the risk of cerebral injury associated with maternal hypertension, SGA, and all other causes of preterm delivery. RESULTS: We found that the risk of c-PVL and grade III IVH was higher in infants born after preterm premature rupture of membranes (PPROM) with short latency or idiopathic preterm labor than in infants born to hypertensive mothers. We show that SGA and antepartum maternal hemorrhage significantly increase the risk of IPH. CONCLUSION: Our results show that infants born to hypertensive mothers have a lower risk of cerebral injuries than infants born following idiopathic preterm labor and PPROM because they are less exposed to prenatal infection.

Traumatic intracranial hemorrhage in newborns.

INTRODUCTION: Neonatal traumatic head injuries (NTHI) can be life-threatening and require aggressive treatment. The indications, techniques, and results of brain decompression are not well defined in the literature. METHODS: We studied prospectively cases of NTHI with intracranial traumatic lesions; skull fractures without underlying lesions were not included. We treated 17 cases of NTHI: 7 patients had a subdural hematoma, 3 had an extradural hematoma, and the others had subarachnoid hemorrhage. Surgical evacuation of intracranial clots was performed in 7 cases, by needle aspiration in 5 and by craniotomy in 2 patients with extradural hematomas. RESULTS: The outcome was favorable in all but one patient, who had hemophilia A, and died of rebleeding at the age of 2 months. CONCLUSION: Surgical decompression of intracranial hematomas due to NTHI is often unnecessary; however, it may be required in emergency because of poor clinical tolerance. Whenever possible, percutaneous needle aspiration is the treatment of choice.

White matter damage and intraventricular hemorrhage in very preterm infants: the EPIPAGE study.

OBJECTIVE: To evaluate the prevalence of cranial ultrasound abnormalities in very preterm infants as a function of gestational age, plurality, intrauterine growth restriction, and death before discharge. STUDY DESIGN: A prospective, population-based cohort of 2667 infants born between 22 and 32 weeks of gestation in 1997 in nine regions of France, transferred to a neonatal intensive care unit, for whom at least one cranial ultrasound scan was available. RESULTS: The frequencies of white matter damage (WMD), major WMD, cystic periventricular leukomalacia (PVL), periventricular parenchymal hemorrhagic involvement, and intraventricular hemorrhage with ventricular dilatation were 21%, 8%, 5%, 3%, and 3%, respectively. The risk of WMD increased with decreasing gestational age. Mean age at diagnosis of cystic PVL was older for the most premature infants. Intraventricular hemorrhage with ventricular dilatation was associated with a higher risk of cystic PVL. Intrauterine growth restriction was not associated with a lower prevalence of cystic PVL. CONCLUSION: The frequency of WMD is high in very preterm babies and is strongly related to gestational age. The incidence of cystic PVL did not differ between babies with intrauterine growth restriction and babies who were appropriate for gestational age.

Outcome at 2 years of infants with congenital diaphragmatic hernia: a population-based study.

BACKGROUND: Management of neonates with congenital diaphragmatic hernia (CDH) has undergone many changes associated with increased survival of high-risk CDH. However, little is known about the long-term outcome of CDH infants. METHODS: Follow-up was performed in 85 newborn infants with CDH admitted in our neonatal intensive care unit between January 1991 and December 1998. Early (< 2 months) and late mortality (> or = 2 months), and respiratory, nutritional, musculoskeletal, and neurosensory outcome at 2 years were recorded. RESULTS: Surgical repair was performed in 59 infants (69%) at a median postnatal age of 124 (range, 38 to 246) hours. Extracorporeal membrane oxygenation was used in 26 (30%) newborn infants. Survival at 2 years was 51 of 85 (60%) (early death, 28/85 [33%]; late death, 6/85 [7%]). Late deaths occurred because of persistent pulmonary hypertension or iatrogenic complications. Twelve of 51 (24%) newborn infants were oxygen dependant at the postnatal age of 28 days, and 1 of 51 (1.9%) was still oxygen dependant at 2 years. Growth failure was noted in 9 of 51 (18%), mainly related to severe gastroesophageal reflux and oral aversion. Scoliosis was diagnosed in 2 infants. Neurologic examination at 2 years was normal in 45 of 51 (88%). Cerebral palsy and developmental delay were observed in 2 and 4 infants, respectively. Four infants (8%) experienced associated problems. Respiratory, nutritional, and musculoskeletal morbidity was higher in infants treated by extracorporeal membrane oxygenation (p < 0.05). CONCLUSIONS: CDH infants are at risk for adverse nutritional and respiratory outcome. Despite severe respiratory failure at birth, prolonged oxygen therapy above 2 years of age is uncommon. Conversely, failure to thrive related at least in part to gastroesophageal reflux and oral dysfunction remains the major problem at 2 years of age. However, both nutritional and respiratory problems tend to improve with age.