ABSTRACT
Streptococcus agalactiae (Group B Streptococcus; GBS) is a common cause of sepsis in neonates. Previous work detected GBS DNA in the placenta in ~5% of women before the onset of labour, but the clinical significance of this finding is unknown. Here we re-analysed this dataset as a case control study of neonatal unit (NNU) admission. Of 436 infants born at term (≥37 weeks of gestation), 7/30 with placental GBS and 34/406 without placental GBS were admitted to the NNU (odds ratio (OR) 3.3, 95% confidence interval (CI) 1.3-7.8). We then performed a validation study using non-overlapping subjects from the same cohort. This included a further 239 cases of term NNU admission and 686 term controls: 16/36 with placental GBS and 223/889 without GBS were admitted to the NNU (OR 2.4, 95% CI 1.2-4.6). Of the 36 infants with placental GBS, 10 were admitted to the NNU with evidence of probable but culture-negative sepsis (OR 4.8, 95% CI 2.2-10.3), 2 were admitted with proven GBS sepsis (OR 66.6, 95% CI 7.3-963.7), 6 were admitted and had chorioamnionitis (inflammation of the foetal membranes) (OR 5.3, 95% CI 2.0-13.4), and 5 were admitted and had funisitis (inflammation of the umbilical cord) (OR 6.7, 95% CI 12.5-17.7). Foetal cytokine storm (two or more pro-inflammatory cytokines >10 times median control levels in umbilical cord blood) was present in 36% of infants with placental GBS DNA and 4% of cases where the placenta was negative (OR 14.2, 95% CI 3.6-60.8). Overall, ~1 in 200 term births had GBS detected in the placenta, which was associated with infant NNU admission and morbidity.
Subject(s)
Sepsis , Streptococcal Infections , Infant, Newborn , Humans , Pregnancy , Infant , Female , Placenta , Streptococcus agalactiae/genetics , Case-Control Studies , InflammationABSTRACT
BACKGROUND: Genetic risk variants and preterm birth are early and potent risk factors for later neuropsychiatric disorders. To understand the interrelationships between these factors, a large-scale genetic study of very preterm (VPT, <32 weeks gestation) infants with prospective follow-up is required. In this paper, we describe a streamlined study approach, using efficient processes for biological and clinical data collection, to feasibly establish such a cohort. METHODS: We sought to recruit 500 VPT families within a 1 year period from neonatal units. Treating clinical teams recruited eligible participants, obtained parent consent, collected blood samples and posted specimens to the research laboratory. We extracted all clinical data from the National Neonatal Research Database, an existing UK resource that captures daily patient-level data on all VPT infants. RESULTS: Between May 2017 and June 2018, we established a cohort of 848 VPT infants and their parents from 60 English neonatal units. The study population (median (IQR), gestation: 28.9 (26-30) weeks; birth weight: 1120 (886-1420) g) represented 18.9% of eligible infants born at the study sites during the recruitment period (n=4491). From the subset of 521 complete family trios, we successfully completed genotyping for 510 (97.9%) trios. Of the original 883 infants whose parents consented to participate, the parents of 796 (90.1%) infants agreed to future data linkage and 794 (89.9%) agreed to be recalled. CONCLUSION: We demonstrate the feasibility and acceptability of streamlined strategies for genetic, neonatal and longitudinal data collection and provide a template for future cost-effective and efficient cohort development.
ABSTRACT
OBJECTIVE: To describe the cognitive, language and motor developmental trajectories of children born very preterm and to identify perinatal factors that predict the trajectories. DESIGN: Data from a cohort of 1142 infants born at <30 weeks' gestation who were prospectively assessed on the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III) at 3, 6, 12 and 24 months corrected age, were analysed using the Super Imposition by Translation and Rotation (SITAR) growth curve analysis model. MAIN OUTCOME MEASURES: Developmental trajectory SITAR models for Bayley-III cognitive, language (receptive and expressive communication subscales) and motor (fine and gross motor subscales) scores. RESULTS: The successfully fitted SITAR models explained 62% of variance in cognitive development, 68% in receptive communication, 53% in fine motor and 68% in the gross motor development. There was too much variation in the expressive communication subscale to fit a SITAR model. The rate of development (gradient of the curve) best explains the variation in trajectories of development in all domains. Lower gestational age, lower birth weight and male sex significantly predicted a slower rate of development. CONCLUSION: The rate of development, rather than single time point developmental assessment, best predicts the very preterm infant's developmental trajectory and should be the focus for monitoring and early intervention.
Subject(s)
Child Language , Cognition/physiology , Infant, Extremely Premature/growth & development , Birth Weight , Female , Follow-Up Studies , Gestational Age , Humans , Infant, Newborn , Male , Neuropsychological Tests , Reference Values , Retrospective Studies , Sex FactorsABSTRACT
BACKGROUND: The genomic contribution to adverse health sequelae in babies born very preterm (<32 weeks' gestation) is unknown. We conducted an investigation of rare CNVs in infants born very preterm as part of a study to determine the feasibility and acceptability of a larger, well-powered genome-wide investigation in the UK, with follow-up using linked National Health Service records and DNA storage for additional research. METHODS: We studied 488 parent-offspring trios. We performed genotyping using Illumina Infinium OmniExpress Arrays. CNV calling and quality control (QC) were undertaken using published protocols. We examined de novo CNVs in infants and the rate of known pathogenic variants in infants, mothers and fathers and compared these with published comparator data. We defined rare pathogenic CNVs as those consistently reported to be associated with clinical phenotypes. RESULTS: We identified 14 de novo CNVs, representing a mutation rate of 2.9%, compared with 2.1% reported in control populations. The median size of these CNV was much higher than in comparator data (717 kb vs 255 kb). The rate of pathogenic CNVs was 4.3% in infants, 2.7% in mothers and 2% in fathers, compared with 2.3% in UK Biobank participants. CONCLUSION: Our findings suggest that the rate of de novo CNVs, especially rare pathogenic CNVs, could be elevated in those born very preterm. However, we will need to conduct a much larger study to corroborate this conclusion.
Subject(s)
DNA Copy Number Variations/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Premature Birth/genetics , Female , Gestational Age , Humans , Infant, Extremely Premature/growth & development , Infant, Newborn , Male , Pregnancy , Premature Birth/pathologyABSTRACT
Preterm birth is associated with short- and long-term impairments affecting physical, cognitive, and neuropsychiatric health. These sequelae, together with a rising preterm birth rate and increased survival, make prematurity a growing public health issue because of the increased number of individuals with impaired health throughout the life span. Although a major contribution to preterm birth comes from environmental factors, it is also modestly heritable. Little is known about the architecture of this genetic contribution. Studies of common and of rare genetic variation have had limited power, but recent findings implicate variation in both the maternal and fetal genome. There is some evidence risk alleles in mothers may be enriched for processes related to immunity and inflammation, and in the preterm infant, processes related to brain development. Overall genomic discoveries for preterm birth lag behind progress for many other multifactorial diseases and traits. Investigations focusing on gene-environment interactions may also provide insights, but these studies still have a number of limitations. Adequately sized genetic studies of preterm birth are a priority for the future especially given the breadth of its negative health impacts across the life span and the current interest in newborn genome sequencing.
Subject(s)
Premature Birth/genetics , Alleles , DNA Copy Number Variations , Gene-Environment Interaction , Genome-Wide Association Study , Humans , Infant, Premature , Twin Studies as Topic , Exome Sequencing , Whole Genome SequencingABSTRACT
OBJECTIVE: To determine the validity of assessing and recording the neurodevelopmental outcome of very preterm infants during routine clinical follow-up in England. DESIGN: Children born <30 weeks gestation, attending routine clinical follow-up at post-term ages 20-28 months, were recruited. Data on neurodevelopmental outcomes were recorded by the reviewing clinician in a standardised format in the child's electronic patient record, based on a set of key questions designed to be used without formal training or developmental testing. Using a predefined algorithm, each participant was classified as having 'no', 'mild/moderate' or 'severe' impairment in cognitive, communication and motor domains. All participants also received a research assessment by a single assessor using the Bayley Scales of Infant Development, third edition (Bayley-III). The sensitivity and specificity of routine data in capturing impairment (any Bayley-III score <85) or severe impairment (any Bayley-III score <70) was calculated. RESULTS: 190 children participated. The validity of routine assessments in identifying children with no impairment and no severe impairment was high across all domains (specificities 83.9%-100.0% and 96.6%-100.0%, respectively). However, identification of impairments, particularly in the cognitive (sensitivity 69.7% (55.1%-84.3%)) and communication (sensitivity (53.2% (42.0%-64.5%)) domains, was poor. CONCLUSIONS: Neurodevelopmental status determined during routine clinical assessment lacks adequate sensitivity in cognitive and communication domains. It is uncertain whether this reflects the assessment or/and the recording of findings. As early intervention may improve education and social outcomes, this is an important area for healthcare quality improvement research.
Subject(s)
Child Development , Developmental Disabilities , Neurologic Examination , Developmental Disabilities/diagnosis , Developmental Disabilities/epidemiology , Developmental Disabilities/etiology , Electronic Health Records/statistics & numerical data , England/epidemiology , Female , Follow-Up Studies , Humans , Infant , Infant, Extremely Premature/growth & development , Infant, Newborn , Male , Neurologic Examination/methods , Neurologic Examination/statistics & numerical data , Reproducibility of Results , Sensitivity and Specificity , Severity of Illness IndexABSTRACT
CONTEXT: Developmental outcomes of very preterm (gestational age ≤32 weeks) or very low birth weight (<1500 g) children are commonly reported before age 3 years although the predictive validity for later outcomes are uncertain. OBJECTIVE: To determine the validity of early developmental assessments in predicting school-age cognitive deficits. DATA SOURCES: PubMed. STUDY SELECTION: English-language studies reporting at least 2 serial developmental/cognitive assessments on the same population, 1 between ages 1 and 3 years and 1 at ≥5 years. DATA EXTRACTION: For each study, we calculated the sensitivity, specificity, and positive and negative predictive values of early assessment for cognitive deficit (defined as test scores 1 SD below the population mean). Pooled meta-analytic sensitivity and specificity were estimated by using a hierarchical summary receiver operator characteristic curve. RESULTS: We included 24 studies (n = 3133 children). Early assessments were conducted at 18 to 40 months and generally involved the Bayley Scales of Infant Development or the Griffiths Mental Development Scales; 11 different cognitive tests were used at school-age assessments at 5 to 18 years. Positive predictive values ranged from 20.0% to 88.9%, and negative predictive vales ranged from 47.8% to 95.5%. The pooled sensitivity (95% confidence interval) of early assessment for identifying school-age cognitive deficit was 55.0% (45.7%-63.9%) and specificity was 84.1% (77.5%-89.1%). Gestational age, birth weight, age at assessment, and time between assessments did not explain between-study heterogeneity. LIMITATIONS: The accuracy of aggregated data could not be verified. Many assessment tools have been superseded by newer editions. CONCLUSIONS: Early developmental assessment has poor sensitivity but good specificity and negative predictive value for school-age cognitive deficit.
Subject(s)
Child Development , Cognition Disorders/epidemiology , Child, Preschool , Cognition Disorders/diagnosis , Humans , Infant , Infant, Premature , Predictive Value of Tests , Reproducibility of ResultsABSTRACT
OBJECTIVES: To characterize early childhood social-communication skills and autistic traits in children born very preterm using the Quantitative Checklist for Autism in Toddlers (Q-CHAT) and explore neonatal and sociodemographic factors associated with Q-CHAT scores. STUDY DESIGN: Parents of children born before 30 weeks gestation and enrolled in a study evaluating routinely collected neurodevelopmental data between the post-menstrual ages of 20 and 28 months were invited to complete the Q-CHAT questionnaire. Children with severe neurosensory disabilities and cerebral palsy were excluded. Participants received neurodevelopmental assessments using the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III). Q-CHAT scores of this preterm cohort were compared with published general population scores. The association between Bayley-III cognitive and language scores and neonatal and sociodemographic factors with Q-CHAT scores were examined. RESULTS: Q-CHAT questionnaires were completed from 141 participants. At a mean post-menstrual age of 24 months, the Q-CHAT scores of the preterm cohort (mean 33.7, SD 8.3) were significantly higher than published general population scores (mean 26.7; SD 7.8), indicating greater social-communication difficulty and autistic behavior. Preterm children received higher scores, particularly in the categories of restricted, repetitive, stereotyped behavior, communication, and sensory abnormalities. Lower Bayley-III language scores and non-white ethnicity were associated with higher Q-CHAT scores. CONCLUSIONS: Preterm children display greater social-communication difficulty and autistic behavior than the general population in early childhood as assessed by the Q-CHAT. The implications for longer-term outcome will be important to assess.
Subject(s)
Autistic Disorder/psychology , Checklist , Child Development , Cognition/physiology , Infant, Premature , Mass Screening/methods , Social Behavior , Autistic Disorder/epidemiology , Female , Follow-Up Studies , Humans , Incidence , Infant , Infant, Newborn , Male , Retrospective Studies , Surveys and Questionnaires , United Kingdom/epidemiologyABSTRACT
OBJECTIVES: To report on retinopathy of prematurity (ROP) screening compliance against a national guideline, factors associated with non-compliance and effect on ROP treatment. DESIGN: National cohort study using operational NHS data from the National Neonatal Research Database (NNRD) for the period 2009-2011. SETTING: 161 (94%) neonatal units in England. POPULATION: Infants born below 32 weeks' gestation and/or with a birth weight below 1501 g. MAIN OUTCOME MEASURES: ROP screening status ('on-time', 'early', 'late', 'unknown') and associated infant and neonatal unit characteristics, ROP treatment. RESULTS: The proportion of infants screened on-time increased over the study period (p<0.001). Of 19 821 eligible infants, 7602 (38.4%) were recorded to have received ROP screening in accordance with the national guideline; 7474 (37.8%) received screening outside the recommended time period; data were missing for 4745 (16.7%) infants. For 16 411 infants in neonatal care during the recommended screening period, late screening was significantly associated with lower gestational age (relative risk ratio (RRR) (95% credible interval) for late versus on-time screening 0.83 (0.80 to 0.86) for each increased week of gestation) and care in a neonatal unit providing less than 500 days of intensive care per annum (2.48 (0.99 to 4.99)). Infants screened late were almost 40% more likely to receive ROP treatment (OR (95% CI) 1.36 (1.05 to 1.76)). CONCLUSIONS: Understanding organisational differences between neonatal units may help improve ROP screening. Patient-level electronic NHS clinical data offer opportunity for future rapid, low cost, population-based evaluations but require improved data entry.
Subject(s)
Guideline Adherence/statistics & numerical data , Infant, Premature, Diseases/diagnosis , Intensive Care Units, Neonatal/statistics & numerical data , Neonatal Screening/standards , Retinopathy of Prematurity/diagnosis , Bayes Theorem , Cohort Studies , England , Female , Gestational Age , Humans , Infant, Newborn , Infant, Premature , Infant, Premature, Diseases/therapy , Intensive Care Units, Neonatal/organization & administration , Male , Odds Ratio , Practice Guidelines as Topic , Retinopathy of Prematurity/therapy , State Medicine , Time FactorsABSTRACT
The effect of socio-economic status (SES) on the cognitive outcome of preterm-born children is unknown. The objectives of this study were to systematically review the published literature and to report the strength and consistency of the effect of SES on the cognitive outcomes of preterm children, across different SES indicators. We conducted a literature search on MEDLINE, EMBASE, PsycINFO and Social Science Citation Index to identify English-language cohort or case-control studies published after 1990 that had reported the effect of at least one SES indicator on cognitive outcome in children born <37 weeks gestation. Fifteen studies (from a total 4,162 identified) were included. Thirteen SES indicators were evaluated [categorized as: "individual-level" (6 indicators), "family-structure" (3), "contextual" (2) and "composite" (2)]. Maternal educational level was the most frequently evaluated SES indicator (by 11/15 studies) and was most consistently associated with cognitive outcome. Maternal education below high school level was associated with severe cognitive deficiency [reported odds ratios (95 % CI) range: OR = 1.4 (1.0-1.9) to OR = 2.3 (1.2-4.5)]. A meta-analytic measure of the effect of SES was not calculated due to heterogeneity in studies. SES appears to confound the association between preterm birth and cognitive deficit and should be adjusted for in studies reporting cognitive outcome.