Elaine M. Boyle

Effects of gestational age at birth on health outcomes at 3 and 5 years of age: population based cohort study

Objective To investigate the burden of later disease associated with moderate/late preterm (32-36 weeks) and early term (37-38 weeks) birth. Design Secondary analysis of data from the Millennium Cohort Study (MCS). Setting Longitudinal study of infants born in the United Kingdom between 2000 and 2002. Participants 18 818 infants participated in the MCS. Effects of gestational age at birth on health outcomes at 3 (n=14 273) and 5 years (n=14 056) of age were analysed. Main outcome measures Growth, hospital admissions, longstanding illness/disability, wheezing/asthma, use of prescribed drugs, and parental rating of their children’s health. Results Measures of general health, hospital admissions, and longstanding illness showed a gradient of increasing risk of poorer outcome with decreasing gestation, suggesting a “dose-response” effect of prematurity. The greatest contribution to disease burden at 3 and 5 years was in children born late/moderate preterm or early term. Population attributable fractions for having at least three hospital admissions between 9 months and 5 years were 5.7% (95% confidence interval 2.0% to 10.0%) for birth at 32-36 weeks and 7.2% (1.4% to 13.6%) for birth at 37-38 weeks, compared with 3.8% (1.3% to 6.5%) for children born very preterm (<32 weeks). Similarly, 2.7% (1.1% to 4.3%), 5.4% (2.4% to 8.6%), and 5.4% (0.7% to 10.5%) of limiting longstanding illness at 5 years were attributed to very preterm birth, moderate/late preterm birth, and early term birth. Conclusions These results suggest that health outcomes of moderate/late preterm and early term babies are worse than those of full term babies. Additional research should quantify how much of the effect is due to maternal/fetal complications rather than prematurity itself. Irrespective of the reason for preterm birth, large numbers of these babies present a greater burden on public health services than very preterm babies.

Early term and late preterm birth are associated with poorer school performance at age 5 years: a cohort study

Objective To compare school performance at age 5 years in children born at full term (39–41 weeks gestation) with those born at early term (37–38 weeks gestation), late preterm (34–36 weeks gestation), moderately preterm (32–33 weeks gestation) and very preterm (<32 weeks gestation). Design Population-based cohort (UK Millennium Cohort Study). Participants Seven thousand six hundred and fifty children born in 2000–2001 and attending school in England in 2006. Methods School performance was measured using the foundation stage profile (FSP), a statutory assessment by teachers at the end of the childs first school year. The FSP comprises 13 assessment scales (scored from 1 to 9). Children who achieve an average of 6 points per scale and at least 6 in certain scales are classified as ‘reaching a good level of overall achievement’. Results Fifty-one per cent of full term children had not reached a good level of overall achievement; this proportion increased with prematurity (55% in early term, 59% in late preterm, 63% in moderately preterm and 66% in very preterm children). Compared with full term children, an elevated risk remained after adjustment, even in early term (adjusted RR 1.05, 95% 1.00 to 1.11) and late preterm children (adjusted RR 1.12, 95% CI 1.04 to 1.22). Similar effects were noted for ‘not working securely’ in mathematical development, physical development and creative development. The effects of late preterm and early term birth were small in comparison with other risk factors. Conclusions Late preterm and early term birth are associated with an increased risk of poorer educational achievement at age 5 years.

Neurodevelopmental outcomes following late and moderate prematurity: a population-based cohort study

Objective There is a paucity of data relating to neurodevelopmental outcomes in infants born late and moderately preterm (LMPT; 32+0–36+6 weeks). This paper present the results of a prospective, population-based study of 2-year outcomes following LMPT birth. Design 1130 LMPT and 1255 term-born children were recruited at birth. At 2 years corrected age, parents completed a questionnaire to assess neurosensory (vision, hearing, motor) impairments and the Parent Report of Childrens Abilities-Revised to identify cognitive impairment. Relative risks for adverse outcomes were adjusted for sex, socio-economic status and small for gestational age, and weighted to account for over-sampling of term-born multiples. Risk factors for cognitive impairment were explored using multivariable analyses. Results Parents of 638 (57%) LMPT infants and 765 (62%) controls completed questionnaires. Among LMPT infants, 1.6% had neurosensory impairment compared with 0.3% of controls (RR 4.89, 95% CI 1.07 to 22.25). Cognitive impairments were the most common adverse outcome: LMPT 6.3%; controls 2.4% (RR 2.09, 95% CI 1.19 to 3.64). LMPT infants were at twice the risk for neurodevelopmental disability (RR 2.19, 95% CI 1.27 to 3.75). Independent risk factors for cognitive impairment in LMPT infants were male sex, socio-economic disadvantage, non-white ethnicity, preeclampsia and not receiving breast milk at discharge. Conclusions Compared with term-born peers, LMPT infants are at double the risk for neurodevelopmental disability at 2 years of age, with the majority of impairments observed in the cognitive domain. Male sex, socio-economic disadvantage and preeclampsia are independent predictors of low cognitive scores following LMPT birth.

Sucrose and non-nutritive sucking for the relief of pain in screening for retinopathy of prematurity: a randomised controlled trial

Background: Screening is necessary for infants at risk of retinopathy of prematurity. Despite local anaesthetic drops, infants find eye examinations distressing, displaying behavioural and physiological changes indicating acute pain. Oral sucrose and non-nutritive sucking reduce pain responses associated with invasive procedures. Objective: To evaluate the use of oral sucrose and/or pacifier for reducing pain responses during eye examinations. Methods: Forty infants <32 weeks gestation or <1500 g birth weight, in two neonatal units, were randomised to one of four interventions administered two minutes before their first screening examination: 1 ml sterile water as placebo (group 1, n  =  10), 1 ml 33% sucrose solution (group 2, n  =  10), 1 ml sterile water with pacifier (group 3, n  =  9), or 1 ml 33% sucrose solution with pacifier (group 4, n  =  11). Examinations were videotaped. Two observers, blind to the intervention, assessed recordings. Pain responses were scored using the premature infant pain profile (PIPP). Results: The groups were similar in gestation, birth weight, and age at examination. Mean PIPP scores were 15.3, 14.3, 12.3, and 12.1 for groups 1, 2, 3, and 4 respectively. Analysis of variance showed a significant difference in PIPP score between groups (p  =  0.023). Infants randomised to pacifiers scored lower than those without pacifiers (p  =  0.003). There was no difference between groups receiving sucrose and those receiving water (p  =  0.321). Conclusions: Non-nutritive sucking reduced distress responses in infants undergoing screening for retinopathy of prematurity. The difference in response was large enough to be detected by a validated assessment tool. No synergistic effect of sucrose and pacifier was apparent in this group.

Guidelines for the Management of Extremely Premature Deliveries: A Systematic Review.

BACKGROUND AND OBJECTIVES: Available data on survival rates and outcomes of extremely low gestational age (GA) infants (22–25 weeks’ gestation) display wide variation by country. Whether similar variation is found in statements by national professional bodies is unknown. The objectives were to perform a systematic review of management from scientific and professional organizations for delivery room care of extremely low GA infants. METHODS: We searched Embase, PubMed, and Google Scholar for management guidelines on perinatal care. Countries were included if rated by the United Nations Development Programme’s Human Development Index as “very highly developed.” The primary outcome was rating of recommendations from “comfort care” to “active care.” Secondary outcomes were specifying country-specific survival and considering potential for 3 biases: limitations of GA assessment; bias from different definitions of stillbirths and live births; and bias from the use of different denominators to calculate survival. RESULTS: Of 47 highly developed countries, 34 guidelines from 23 countries and 4 international groups were identified. Of these, 3 did not state management recommendations. Of the remaining 31 guidelines, 21 (68%) supported comfort care at 22 weeks’ gestation, and 20 (65%) supported active care at 25 weeks’ gestation. Between 23 and 24 weeks’ gestation, much greater variation was seen. Seventeen guidelines cited national survival rates. Few guidelines discussed potential biases: limitations in GA (n = 17); definition bias (n = 3); and denominator bias (n = 7). CONCLUSIONS: Although there is a wide variation in recommendations (especially between 23 and 24 weeks’ GA), there is general agreement for comfort care at 22 weeks’ GA and active care at 25 weeks’ GA.

Assessment of persistent pain or distress and adequacy of analgesia in preterm ventilated infants

Abstract Indicators of persistent pain in preterm neonates are poorly defined. In the setting of a double blind, placebo‐controlled trial investigating morphine use in ventilated preterm infants (NEOPAIN Trial) we aimed to identify factors that may be useful in assessing persistent pain. Twenty‐two babies (morphine 12; placebo 10) were assessed for comfort, pain or distress and clinical staff described the factors they had considered. This assessment was performed during the first period of duty with the baby. Based on this, they stated which study drug they believed the infant was receiving. Eighty‐nine assessments were made in total (1–14 per baby). The drug was correctly identified on 71% of occasions. Staff considered one or more of the following factors: infant activity; response to routine care; known pain‐related behaviours; posture/quality of movements; respiratory effort; synchrony with ventilator; blood pressure and heart rate. Four factors most frequently identified babies receiving placebo: facial expressions of pain, high activity levels, poor response to handling and poor synchrony with ventilation. Absence of pain‐related behaviour was less discriminating. Observation of a good response to handling, good synchrony with ventilation, a “settled” baby, normal blood pressure and heart rate were poor discriminators. Hypotension and poor respiratory drive were noted exclusively in babies receiving morphine infusions. Facial expressions of pain, high activity levels, poor response to routine care, and poor ventilator synchrony were associated with placebo versus morphine therapy, and may be considered useful markers for persistent pain in preterm infants.

Use of evidence based practices to improve survival without severe morbidity for very preterm infants: results from the EPICE population based cohort

Objectives To evaluate the implementation of four high evidence practices for the care of very preterm infants to assess their use and impact in routine clinical practice and whether they constitute a driver for reducing mortality and neonatal morbidity. Design Prospective multinational population based observational study. Setting 19 regions from 11 European countries covering 850 000 annual births participating in the EPICE (Effective Perinatal Intensive Care in Europe for very preterm births) project. Participants 7336 infants born between 24+0 and 31+6 weeks’ gestation in 2011/12 without serious congenital anomalies and surviving to neonatal admission. Main outcome measures Combined use of four evidence based practices for infants born before 28 weeks’ gestation using an “all or none” approach: delivery in a maternity unit with appropriate level of neonatal care; administration of antenatal corticosteroids; prevention of hypothermia (temperature on admission to neonatal unit ≥36°C); surfactant used within two hours of birth or early nasal continuous positive airway pressure. Infant outcomes were in-hospital mortality, severe neonatal morbidity at discharge, and a composite measure of death or severe morbidity, or both. We modelled associations using risk ratios, with propensity score weighting to account for potential confounding bias. Analyses were adjusted for clustering within delivery hospital. Results Only 58.3% (n=4275) of infants received all evidence based practices for which they were eligible. Infants with low gestational age, growth restriction, low Apgar scores, and who were born on the day of maternal admission to hospital were less likely to receive evidence based care. After adjustment, evidence based care was associated with lower in-hospital mortality (risk ratio 0.72, 95% confidence interval 0.60 to 0.87) and in-hospital mortality or severe morbidity, or both (0.82, 0.73 to 0.92), corresponding to an estimated 18% decrease in all deaths without an increase in severe morbidity if these interventions had been provided to all infants. Conclusions More comprehensive use of evidence based practices in perinatal medicine could result in considerable gains for very preterm infants, in terms of increased survival without severe morbidity.

Gestational Age and Cognitive Ability in Early Childhood: a Population-based Cohort Study

BACKGROUND Recent studies suggest that children born at late preterm (34-36 weeks gestation) and early term (37-38 weeks) may have poorer developmental outcomes than children born at full term (39-41 weeks). We examined how gestational age is related to cognitive ability in early childhood using the U.K. Millennium Cohort Study. METHODS Cognitive development was assessed using Bracken School Readiness Assessment at age 3 years, British Ability Scales II at ages 3, 5 and 7 years and Progress in Mathematics at age 7 years. Sample size varied according to outcome between 12,163 and 14,027. Each gestational age group was compared with the full-term group using differences in z-scores and risk ratios for scoring more than -1 SD below the mean. RESULTS Children born at <32 weeks gestation scored lower (P < 0.05) than the full-term group on all scales with unadjusted z-score differences ranging between -0.8 to -0.2 SD. In all groups, there was an increased risk (P < 0.05) of scoring less than -1 SD below the mean compared with the full-term group for some of the tests: those born at < 32 weeks had a 40-140% increased risk in seven tests, those born at 32-33 weeks had a 60-80% increased risk in three tests, those born at 34-36 weeks had a 30-40% increased risk in three tests, and those born at 37-38 weeks had a 20% increased risk in two tests. CONCLUSIONS Cognitive ability is related to the entire range of gestational age, including children born at 34-36 and 37-38 weeks gestation.

Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study

BACKGROUND Neonates who are in pain or are stressed during care in the intensive care unit (ICU) are often given sedation or analgesia. We investigated the current use of sedation or analgesia in neonatal ICUs (NICUs) in European countries. METHODS EUROPAIN (EUROpean Pain Audit In Neonates) was a prospective cohort study of the management of sedation and analgesia in patients in NICUs. All neonates admitted to NICUs during 1 month were included in this study. Data on demographics, methods of respiration, use of continuous or intermittent sedation, analgesia, or neuromuscular blockers, pain assessments, and drug withdrawal syndromes were gathered during the first 28 days of admission to NICUs. Multivariable linear regression models and propensity scores were used to assess the association between duration of tracheal ventilation (TV) and exposure to opioids, sedatives-hypnotics, or general anaesthetics in neonates (O-SH-GA). This study is registered with ClinicalTrials.gov, number NCT01694745. FINDINGS From Oct 1, 2012, to June 30, 2013, 6680 neonates were enrolled in 243 NICUs in 18 European countries. Mean gestational age of these neonates was 35.0 weeks (SD 4.6) and birthweight was 2384 g (1007). 2142 (32%) neonates were given TV, 1496 (22%) non-invasive ventilation (NIV), and 3042 (46%) were kept on spontaneous ventilation (SV). 1746 (82%), 266 (18%), and 282 (9%) neonates in the TV, NIV, and SV groups, respectively, were given sedation or analgesia as a continuous infusion, intermittent doses, or both (p<0.0001). In the participating NICUs, the median use of sedation or analgesia was 89.3% (70.0-100) for neonates in the TV group. Opioids were given to 1764 (26%) of 6680 neonates and to 1589 (74%) of 2142 neonates in the TV group. Midazolam was given to 576 (9%) of 6680 neonates and 536 (25%) neonates of 2142 neonates in the TV group. 542 (25%) neonates in the TV group were given neuromuscular blockers, which were administered as continuous infusions to 146 (7%) of these neonates. Pain assessments were recorded in 1250 (58%) of 2138, 672 (45%) of 1493, and 916 (30%) of 3017 neonates in the TV, NIV, and SV groups, respectively (p<0.0001). In the univariate analysis, neonates given O-SH-GA in the TV group needed a longer duration of TV than did those who were not given O-SH-GA (mean 136.2 h [SD 173.1] vs 39.8 h [94.7] h; p<0.0001). Multivariable and propensity score analyses confirmed this association (p<0.0001). INTERPRETATION Wide variations in sedation and analgesia practices occur between NICUs and countries. Widespread use of O-SH-GA in intubated neonates might prolong their need for mechanical ventilation, but further research is needed to investigate the therapeutic and adverse effects of O-SH-GA in neonates, and to develop new and safe approaches for sedation and analgesia. FUNDING European Communitys Seventh Framework Programme.

Infants born late/moderately preterm are at increased risk for a positive autism screen at 2 years of age.

OBJECTIVES To assess the prevalence of positive screens using the Modified Checklist for Autism in Toddlers (M-CHAT) questionnaire and follow-up interview in late and moderately preterm (LMPT; 32-36 weeks) infants and term-born controls. STUDY DESIGN Population-based prospective cohort study of 1130 LMPT and 1255 term-born infants. Parents completed the M-CHAT questionnaire at 2-years corrected age. Parents of infants with positive questionnaire screens were followed up with a telephone interview to clarify failed items. The M-CHAT questionnaire was re-scored, and infants were classified as true or false positives. Neurosensory, cognitive, and behavioral outcomes were assessed using parent report. RESULTS Parents of 634 (57%) LMPT and 761 (62%) term-born infants completed the M-CHAT questionnaire. LMPT infants had significantly higher risk of a positive questionnaire screen compared with controls (14.5% vs 9.2%; relative risk [RR] 1.58; 95% CI 1.18, 2.11). After follow-up, significantly more LMPT infants than controls had a true positive screen (2.4% vs 0.5%; RR 4.52; 1.51, 13.56). This remained significant after excluding infants with neurosensory impairments (2.0% vs 0.5%; RR 3.67; 1.19, 11.3). CONCLUSIONS LMPT infants are at significantly increased risk for positive autistic screen. An M-CHAT follow-up interview is essential as screening for autism spectrum disorders is especially confounded in preterm populations. Infants with false positive screens are at risk for cognitive and behavioral problems.