Risk Of Neurodevelopmental Impairment Research Articles

Risk of neurodevelopmental impairment in Swedish preterm children treated for necrotizing enterocolitis: retrospective cohort study.

As the survival of preterm infants has increased, the management of long-term complications, especially neurodevelopmental impairment, becomes increasingly important. The aim of this study was to investigate the risk of neurodevelopmental disorders in preterm babies receiving medical or surgical treatment for necrotizing enterocolitis, compared with other preterm babies and preterm babies who received abdominal surgery for other indications. In this nationwide Swedish cohort study, including all liveborn preterm babies born between 1998 and 2019, the risk of attention deficit (and hyperactivity) disorder, autism spectrum disorders, cerebral palsy and intellectual disability was assessed by multivariable Cox regression, expressed as hazard ratios and 95% confidence intervals (c.i.). Of the surgically (n = 384) and medically (n = 709) treated preterm infants with necrotizing enterocolitis, neurodevelopmental disorders were present in 32% (HR 2.24, 95% c.i. 1.86 to 2.69) and 22% respectively (HR 1.40, 95% c.i. 1.19 to 1.65), compared with 21% (HR 1.63, 95% c.i. 1.40 to 1.91) in the abdominal surgery group (n = 844) and 13% (reference) among other preterm infants (n = 78 972). The highest relative increases were for intellectual disability (HR 3.60, 95% c.i. 2.65 to 4.89) in the surgical necrotizing enterocolitis group and abdominal surgery group (HR 2.84, 95% c.i. 2.12 to 3.80) compared with the control preterm group, and for cerebral palsy (respectively HR 2.74, 95% c.i. 2.04 to 3.68 and HR 2.54, 95% c.i. 1.87 to 3.44). Medically treated necrotizing enterocolitis was associated with autism (HR 1.67, 95% c.i. 1.34 to 2.08), without significant increases for the other specific outcomes. Both surgically treated groups were also strongly associated with both attention deficit (and hyperactivity) disorder and autism. Surgically treated necrotizing enterocolitis, medically treated necrotizing enterocolitis and abdominal surgery for other indications in preterm infants were all associated with an increased risk of impaired neurodevelopmental outcomes, compared with other preterm infants.

Learning from those who thrive: protective factors and neuroimaging markers in adolescents with complex congenital heart disease and with a favorable neurodevelopmental profile

ABSTRACT Patients with complex congenital heart disease (cCHD) are at risk for neurodevelopmental impairments, yet many patients develop normally. This study investigated associations between a favorable neurodevelopmental profile and protective factors, quality of life (QoL), resilience, and brain development. Adolescents with cCHD (n = 100) were prospectively enrolled. Neurodevelopmental profiles comprised IQ, executive functions, and behavior. Standardized neuropsychological tests and questionnaires were used to assess neurodevelopmental outcomes, family factors, QoL, and resilience. Clinical data were obtained from medical charts. Cerebral MRI was acquired. Specific neurodevelopmental profiles were identified by latent profile analysis and were associated with clinical and family factors, QoL and resilience, and MRI markers. We identified two distinct groups of neurodevelopmental profiles (favorable profile: n = 57, vulnerable profile: n = 43). The favorable profile group had significantly better neurodevelopmental outcome, better family functioning, and better parental mental health compared to the vulnerable profile group. Clinical factors were not significantly associated with profile group. The favorable profile group reported significantly better QoL and resilience and had larger total brain volumes. A positive family environment may be protective for long-term neurodevelopment and may outweigh the role of clinical factors. This study underlines the importance of family-centered care to promote favorable brain development and neurodevelopmental outcome.

Enteral micronutrient supplementation and neurodevelopmental outcomes in preterm or low birth weight infants: A systematic review and meta-analysis.

The association of enteral micronutrient supplementation and the neurodevelopmental outcomes of preterm or low birth weight (LBW) infants is controversial. This research was prospectively registered (CRD42023454034). We searched MEDLINE, Embase, PsycInfo, ClinicalTrials. gov, and the Cochrane Library for randomised clinical trials (RCTs) or quasi-RCTs comparing any enteral micronutrients supplementation with placebo or no supplementation in preterm or LBW infants. The primary outcome was neurodevelopmental impairment (NDI), with secondary outcomes involving various neurodevelopmental tests and disabilities. There was no evidence of an association between enteral micronutrients supplementation and the risk of NDI (RR, 1.03; 95% CI, 0.93-1.14; moderate certainty evidence). There was no evidence that the supplemented groups enhanced cognitive (MD, 0.65; 95% CI, -0.37 to 1.67; low certainty evidence), language (SMD, -0.01; 95% CI, -0.11 to 0.09; moderate certainty evidence), or motor scores (SMD, 0.04; 95% CI, -0.06 to 0.15; very low certainty evidence) or IQ (SMD, -0.20; 95% CI, -0.53 to 0.13; very low certainty evidence). Subgroup analysis showed that multiple micronutrients supplementation improved expressive language score (MD, 1.42; 95% CI, 0.39-2.45), and zinc supplementation enhanced fine motor score (SMD, 1.70; 95% CI, 0.98-2.43). The overall heterogeneity was low. This study demonstrates that enteral micronutrient supplementation is associated with little or no benefits in neurodevelopmental outcomes for preterm or LBW infants. Well-designed RCTs are needed to further ascertain these associations.

Prenatal maternal diabetes, comorbidities, and risk for neurodevelopmental impairment in the first two years.

Maternal diabetes is a known risk for neurodevelopmental delay in offspring, and often presents with comorbid metabolic conditions, such as obesity and hypertension. However, their combined effects on neurodevelopmental outcomes remain unclear. We investigated the independent and combined associations of maternal diabetes and comorbidities with the risk of neurodevelopmental delay in children aged 12 and 24 months. A prospective longitudinal cohort of children from Pregnancy during the COVID-19 Pandemic study. Neurodevelopmental screening at 12 and 24 months was conducted using the Ages and Stages Questionnaire, which assesses domain-specific development. Maternal diabetes was not associated with neurodevelopmental risks either at 12 or 24 months. However, in combined analyses, maternal diabetes and pre-pregnancy overweight were associated with an increased risk of neurodevelopmental delay in personal-social skills (odds ratio [OR], 1.75 [95%CI,1.01-3.01]) at 24 months, though not at 12 months. Maternal diabetes and pre-pregnancy obesity were also associated with an increased risk for neurodevelopmental delay in communication (OR, 1.71 [95%CI,1.01-2.82]) and personal-social skills (OR, 2.01 [95%CI,1.03-3.73]) at 24 months. Furthermore, maternal diabetes and hypertensive disorders of pregnancy (HDP) had higher rates of positive screening for delay in fine-motor skills (OR, 3.54 [95%CI, 1.28-8.41]) at 12 months but not at 24 months. Post-hoc analysis revealed an independent association of maternal pre-pregnancy obesity, but not overweight, with an increased risk of neurodevelopmental delay in communication, fine-motor, and personal-social skills (ORs ranging from 1.44 to 1.71) at 24 months but not 12 months. Similarly, there was an independent association of maternal HDP with an increased risk of neurodevelopmental delay in fine-motor and and personal-social skills (ORs ranging from 2.01 to 2.19) at 24 months. Maternal diabetes with comorbid conditions is likely to increase the risk of neurodevelopmental delay during infancy than individual exposure, suggesting the persistent influence of prenatal exposure on offspring neurodevelopment. 1. Identifying modifiable prenatal risk factors for neurodevelopmental impairment in offspring is crucial for targeted interventions and providing support to mothers during pregnancy, which can lead to improved child health outcomes. 2. Maternal diabetes was not associated with neurodevelopmental delays in children at 12 or 24 months. 3. Maternal diabetes in combination with pre-pregnancy overweight or obesity increased the risk of cognitive delay at 24 months. 4. Maternal pre-pregnancy obesity but not overweight, and hypertensive disorders of pregnancy independently increased risks of cognitive and motor delays at 24 months.

Factors associated with mortality and neurodevelopmental impairment at 12 months in asphyxiated newborns: a retrospective cohort study in rural Tanzania from January 2019 to June 2022

BackgroundWorldwide about 2.3 million newborns still die in the neonatal period and the majority occurs in low- and middle-income countries (LMICs). Intrapartum-related events account for 24% of neonatal mortality. Of these events, intrapartum birth asphyxia with subsequent neonatal encephalopathy is the main cause of child disabilities in LMICs. Data on neurodevelopmental outcome and early risk factors are still missing in LMICs. This study aimed at investigating the factors associated with mortality, risk of neurodevelopmental impairment and adherence to follow-up among asphyxiated newborns in rural Tanzania.MethodsThis retrospective observational cohort study investigated mortality, neurodevelopmental risk and adherence to follow-up among asphyxiated newborns who were admitted to Tosamaganga Hospital (Tanzania) from January 2019 to June 2022. Neurodevelopmental impairment was assessed using standardized Hammersmith neurologic examination. Admission criteria were Apgar score < 7 at 5 min of life and birth weight > 1500 g. Babies with clinically visible congenital malformations were excluded. Comparisons between groups were performed using the Mann-Whitney test, the Chi-square test, and the Fisher test.ResultsMortality was 19.1% (57/298 newborns) and was associated with outborn (p < 0.0001), age at admission (p = 0.02), lower Apgar score at 5 min (p = 0.003), convulsions (p < 0.0001) and intravenous fluids (IV) (p = 0.003). Most patients (85.6%) were lost to follow-up after a median of 1 visit (IQR 0–2). Low adherence to follow-up was associated with female sex (p = 0.005). The risk of neurodevelopmental impairment at the last visit was associated with longer travel time between household and hospital (p = 0.03), female sex (p = 0.04), convulsions (p = 0.007), respiratory distress (p = 0.01), administration of IV fluids (p = 0.04), prolonged oxygen therapy (p = 0.004), prolonged hospital stay (p = 0.0007) and inappropriate growth during follow-up (p = 0.0002).ConclusionsOur findings demonstrated that mortality among asphyxiated newborns in a rural hospital in Tanzania remains high. Additionally, distance from home to hospital and sex of the newborn correlated to higher risks of neurodevelopmental impairment. Educational interventions among the population about the importance of regular health assessment are needed to improve adherence to follow-up and for preventive purposes. Future studies should investigate the role of factors affecting the adherence to follow-up.

Callosal injuries in cytomegalovirus fetopathy: a neurosonographic study.

Introduction - This study aimed to describe the rate and pattern of callosal injury in CMV fetopathy. Methods - This retrospective study included fetuses with confirmed CMV-PCR. Dedicated US including neurosonography was performed. Callosal Length below the 5th centile or morphological abnormalities were considered abnormal. Any additional abnormal findings were reported. Results - Seventy-two patients were included. In 76% infection occurred in the 1stT or periconceptional. In 34.7% a callosal anomaly was observed and it was never isolated. CNS abnormalities included: periventricular hyperechogenicity (PVHE) 55.5%, calcifications 52%, ventriculomegaly 33%, periventricular pseudocysts 31.4%, occipital cysts 22.2%, echogenic precaudate germinal matrix 30.5%, LSV 26.4%, sulcation abnormalities 22.2%, cerebellar findings 18% and HC below -2SD 18%. The most common association with CC insult was PVHE (56%) and calcifications (52%). Conclusion - Although not referred to as a classic brain structure affected by CMV infection, the CC was injured in one-third of our patients, including cases of late infection. The mechanism of disease and the prenatal patterns of callosal involvement in these cases appear to be different from the postnatal patterns and are not reversible. The presence of a callosal injury would imply a worse prognosis and a significant increment in the risk of neurodevelopmental impairment.

Association of Right Ventricular Dysfunction with Risk of Neurodevelopmental Impairment in Infants with Pulmonary Hypertension.

(1) Background: Pulmonary hypertension (PH) increases pulmonary vascular resistance and right ventricular (RV) afterload. Assessment of RV systolic function in PH using RV fractional area change (RV FAC) as a marker directly correlates with mortality and the need for extracorporeal membrane oxygenation (ECMO). However, few studies have assessed neurodevelopmental outcomes. We hypothesize that cardiac RV systolic dysfunction with lower RV FAC is associated with worse neurodevelopmental impairment (NI). (2) Methods: Retrospective study of 42 subjects with PH to evaluate neurodevelopmental outcomes in the first two years of life based on (i) subjective assessment of RV systolic function and (ii) RV FAC, a specific echocardiographic marker for RV function. (3) Results: Subjects from the initial study cohort (n = 135) with PH who had long-term follow-up were divided into RV dysfunction (study, n = 20) and non-RV dysfunction (control, n = 22) groups. RV FAC in the study vs. control group (0.18 vs. 0.25) was lower (p = 0.00017). There was no statistically significant difference in NI either with RV dysfunction or lower RV FAC. Although not significant, RV dysfunction was associated with longer mean duration of mechanical ventilation, time on ECMO, and length of stay. In the initial cohort (135), mortality was 16.3% and the percentage of NI was 62%. (4) Conclusions: Neonatal pulmonary hypertension is associated with a high degree of neurodevelopment impairment. Early RV systolic dysfunction, as identified by RV FAC, was not an optimal predictive biomarker for infants with PH and neurodevelopmental impairment.

Premature newborns with intraventricular hemorrhage do not have vasospasm pattern by cranial Doppler ultrasound: A pilot study.

Preterm neonates are at risk for neurodevelopmental impairment, especially those with intraventricular hemorrhage (IVH). Cerebral vasospasm (VSP) is a common complication after subarachnoid hemorrhage (SAH) in adult population, but it is unknown if preterm neonates with IVH may develop it. We prospectively enrolled premature newborns < 32weeks with IVH and without IVH. All patients received serial transcranial sonography through the temporal window of the middle cerebral artery, anterior cerebral artery, posterior cerebral artery, and the internal carotid artery with transcranial Doppler sonography days 2, 4, and 10 of life. Cerebral blood velocities (CBFVs) were measured including median velocity flow (MV), peak systolic velocity (PSV), and maximum end-diastolic velocity (EDV). Resistance index and pulsatility index were calculated. VSP was defined as an increase of 50% in the baseline velocity per day and/or a Lindegaard ratio higher than 3. Fifty subjects were enrolled. None of the patients with IVH showed elevation of MV or a Lindegaard ratio > 3. There were no differences between IVH and without IVH groups regarding resistance index and pulsatility index. Conclusion: Preterm infants with IVH do not present a pattern of VSP analyzed by Doppler transcranial ultrasound in this pilot study. What is Known: • In adult population with subarachnoid hemorrhage the most treatable cause of cerebral ischemia is due cerebral vasospasm but is unknown if premature newborn may have vasospasm due the extravasation of blood in the context of intraventricular hemorrhage What is New: •In this pilot study we did not find in premature newborn with intraventricular hemorrhage signs of vasoespam measured by transcranial color doppler ultrasound.

Music Therapy in Infancy and Neurodevelopmental Outcomes in Preterm Children

Preterm children are at risk for neurodevelopment impairments. To evaluate the effect of a music therapy (MT) intervention (parent-led, infant-directed singing) for premature children during the neonatal intensive care unit (NICU) stay and/or after hospital discharge on language development at 24 months' corrected age (CA). This predefined secondary analysis followed participants in the LongSTEP (Longitudinal Study of Music Therapy's Effectiveness for Premature Infants and Their Caregivers) randomized clinical trial, which was conducted from August 2018 to April 2022 in 8 NICUs across 5 countries (Argentina, Colombia, Israel, Norway, and Poland) and included clinic follow-up visits and extended interventions after hospital discharge. Participants were children born preterm (<35 weeks' gestation) and their parents. Participants were randomized at enrollment to MT with standard care (SC) or SC alone; they were randomized to MT or SC again at discharge. The MT was parent-led, infant-directed singing tailored to infant responses and supported by a music therapist and was provided 3 times weekly in the NICU and/or in 7 sessions across 6 months after discharge. The SC consisted of early intervention methods of medical, nursing, and social services, without MT. Primary outcome was language development, as measured by the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) language composite score, with the remaining BSID-III composite and subscale scores as the secondary outcomes. Group differences in treatment effects were assessed using linear mixed-effects models using all available data. Of 206 participants (103 female infants [50%]; mean [SD] GA, 30.5 [2.7] weeks), 51 were randomized to MT and 53 to SC at enrollment; at discharge, 52 were randomized to MT and 50 to SC. A total of 112 (54%) were retained at the 24 months' CA follow-up. Most participants (79 [70%] to 93 [83%]) had BSID-III scores in the normal range (≥85). Mean differences for the language composite score were -2.36 (95% CI, -12.60 to 7.88; P = .65) for the MT at NICU with postdischarge SC group, 2.65 (95% CI, -7.94 to 13.23; P = .62) for the SC at NICU and postdischarge MT group, and -3.77 (95% CI, -13.97 to 6.43; P = .47) for the MT group at both NICU and postdischarge. There were no significant effects for cognitive or motor development. This secondary analysis did not confirm an effect of parent-led, infant-directed singing on neurodevelopment in preterm children at 24 months' CA; wide CIs suggest, however, that potential effects cannot be excluded. Future research should determine the MT approaches, implementation time, and duration that are effective in targeting children at risk for neurodevelopmental impairments and introducing broader measurements for changes in brain development. ClinicalTrials.gov Identifier: NCT03564184.

Effects of hemodynamic alterations and oxygen saturation on cerebral perfusion in congenital heart disease

BackgroundPatients with severe congenital heart disease (CHD) are at risk for neurodevelopmental impairment. An abnormal cerebral blood supply caused by the altered cardiac physiology may limit optimal brain development. The aim of this study was to evaluate the effect of a systemic-to-pulmonary shunt, aortic arch obstruction and arterial oxygen saturation on cerebral perfusion in patients with severe CHD.MethodsPatients with severe CHD requiring cardiac surgery within the first six weeks of life, who underwent pre- and/or postoperative brain magnetic resonance imaging (MRI), and healthy controls with one postnatal scan were included. Cerebral perfusion in deep and cortical gray matter was assessed by pseudocontinuous arterial spin labeling MRI.ResultsWe included 59 CHD and 23 healthy control scans. The presence of a systemic-to-pulmonary shunt was associated with decreased perfusion in cortical (p = 0.003), but not in deep gray matter (p = 0.031). No evidence for an effect of aortic arch obstruction and arterial oxygen saturation on cerebral perfusion was found. After adjusting for hemodynamic and oxygen saturation parameters, deep (p = 0.018) and cortical (p = 0.012) gray matter perfusion was increased in patients with CHD compared to controls.ConclusionWe detected regional differences in compensation to the cerebral steal effect in patients with severe CHD.ImpactPatients with severe congenital heart disease (CHD) have altered postnatal brain hemodynamics.A systemic-to-pulmonary shunt was associated with decreased perfusion in cortical gray matter but preserved perfusion in deep gray matter, pointing towards regional differences in compensation to the cerebral steal effect.No effects of aortic arch obstruction and arterial oxygenation on cerebral perfusion were seen.Cerebral perfusion was increased in patients with CHD compared to healthy controls after adjusting for hemodynamic alterations and oxygen saturation.To improve neuroprotection and neurodevelopmental outcomes, it is important to increase our understanding of the factors influencing cerebral perfusion in neonates with severe CHD.

Effect of Placental Transfusion on Long-Term Neurodevelopmental Outcomes in Premature Infants: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

BackgroundThe pathophysiology and the potential risks of placental transfusion (PT) differ substantially in preterm infants, necessitating specific studies in this population. This study aimed to evaluate the safety and efficacy of PT in preterm infants from the perspective of long-term neurodevelopmental outcomes. MethodsWe conducted a systematic literature search using placental transfusion, preterm infant, and its synonyms as search terms. Cochrane Central Register of Controlled Trials, Medline, and Embase were searched until March 07, 2023. Two reviewers independently identified, extracted relevant randomized controlled trials, and appraised the risk of bias. The extracted studies were included in the meta-analysis of long-term neurodevelopmental clinical outcomes using fixed-effects models. ResultsA total of 5612 articles were identified, and seven randomized controlled trials involving 2551 infants were included in our meta-analysis. Compared with immediate cord clamping (ICC), PT may not impact adverse neurodevelopment events. No clear evidence was found of a difference in the risk of neurodevelopmental impairment (risk ratio [RR]: 0.89, 95% confidence interval [CI]: 0.76 to 1.03, P = 0.13, I2 = 0). PT was not associated with the incidence of cerebral palsy (RR: 1.23, 95% CI: 0.59 to 2.57, P = 0.79, I2 = 0). Analyses showed no differences between the two interventions in cognitive, language, and motor domains of neurodevelopment. ConclusionsFrom the perspective of long-term neurodevelopment, PT at preterm birth may be as safe as ICC. Future studies should focus on standardized, high-quality clinical trials and individual participant data to optimize cord management strategies for preterm infants after birth.

Morphine exposure and prematurity affect flash visual evoked potentials in preterm infants

ObjectiveThe present study aimed to explore first the impact of perinatal risk factors on flash-VEP waves and morphology in a group of preterm infants studied at term equivalent age (TEA). Second, to correlate VEP morphology with neurological outcome at 2 years corrected age (CA). MethodsInfants with a gestational age (GA) at birth <32 weeks, without major brain injury, were enrolled. Multivariate regression analyses were performed, and the models were run separately for each dependent variable N2, P2, N3 latencies and P2 amplitude. Logistic regression was applied to study N4 component (present/absent) and VEP morphology (regular/irregular). The predictors were GA, bronchopulmonary dysplasia (BPD), postmenstrual age at VEP registration, cumulative morphine and fentanyl dose, and painful procedures. Lastly, linear regression models were performed to assess the relation between the Bayley-III cognitive and motor scores at 2 years CA and VEP morphology, in relation to GA, BPD, painful procedures and cumulative morphine dose. ResultsEighty infants were enrolled. Morphine was the predictor of N2 (R2 = 0.09, p = 0.006), P2 (R2 = 0.11, p = 0.002), and N3 (R2 = 0.13, p = 0.003) latencies. Younger GA was associated with lower amplitude (R2 = 0.05, p = 0.029). None of the independent variables predicted the presence of N4 component, nor VEP morphology in the logistic analysis. VEP morphology was not associated with cognitive and motor scores at 2 years. ConclusionsMorphine treatment and prematurity were risk factors for altered VEPs parameters at TEA. In our cohort VEP morphology did not predict neurological outcome. SignificanceMorphine administration should be evaluated according to potential risks and benefits, and dosage individually accustomed, according to pain and comfort scores, considering the possible risk for neurodevelopmental impairment.

Impact of moderate-to-late preterm birth on neurodevelopmental outcomes in young children: Results from retrospective longitudinal follow-up with nationally representative data.

This study investigated the relationship between moderate-to-late preterm (MLPT) birth and the risk of neurodevelopmental impairments (NIs) in young children compared with the risks associated with very preterm (VPT) and full-term (FT) birth based on nationally representative large-scale population data. Retrospective follow-up was conducted over 71 months for 738,733 children who were born and participated in the Korean National Health Screening Program for Infants and Children (NHSPIC) between 2011 and 2013. Using a data linkage between the NHSPIC and Korean healthcare claim information, data on birth year, sex, delivery type, birth weight, growth abnormality, gestational age, breastfeeding history, maternal age, NIs, multiple gestation, preterm labor, premature rupture of membranes (PROM), gestational diabetes, gestational hypertension, smoking during pregnancy, and socioeconomic status were collected and included in the final analysis. Cox proportional hazards models were applied to identify the impact of gestational age on NI risk, with all variables adjusted as appropriate. Overall, 0.9% and 3.8% rates of VPT and MLPT births were identified, respectively. NI incidence was highest among VPT children (34.7%), followed by MLPT (23.9%) and FT (18.2%) children. Both VPT (hazard ratio [HR], 1.45; 95% confidence interval [CI], 1.03 to 2.05) and MLPT (HR, 1.21; 95% CI, 1.04 to 1.41) births were associated with increased NI risk. Low birth weight, PROM, and smoking during pregnancy were also associated with increased NI risk, while longer breastfeeding and higher socioeconomic status were associated with decreased risk. Special attention must be given to NIs for both VPT and MLPT children.

Neurodevelopmental outcomes at age 3 years after moderate preterm, late preterm and early term birth: the Japan Environment and Children’s Study

ObjectiveTo assess the association between gestational age classification at birth and the risk of neurodevelopmental impairments at age 3 years.DesignCohort study using the Japan Environment and Children’s Study database.PatientsA total...

Trends in neonatal mortality and morbidity in very-low-birth-weight (VLBW) infants over a decade: Singapore national cohort study.

Very preterm infants are at risk for neurodevelopmental impairment because of postnatal morbidities. This study aims to (1) compare the outcomes of very-low-birth-weight (VLBW) infants in Singapore during two time periods over a decade; 2) compare performances among Singaporean neonatal intensive care units (NICUs); and 3) compare a Singapore national cohort with one from the Australian and New Zealand Neonatal Network (ANZNN). Singapore national data on VLBW infants born during two periods, 2007-2008 (SG2007, n=286) and 2015-2017 (SG2017, n=905) were extracted from patient medical records. The care practices and clinical outcomes among three Singapore NICUs were compared using SG2017 data. Third, using data from the ANZNN2017 annual report, infants with gestational age (GA) ≤29 weeks in SG2017 were compared with their Oceania counterparts. SG2017 had 9.9% higher usage of antenatal steroids (p<0.001), 8% better survival for infants ≤26 weeks (p=0.174), and used 12.7% lesser nonsteroidal anti-inflammatory drugs for patent ductus arteriosus closure (p<0.001) than those of SG2007 cohort. Rate of late-onset sepsis (LOS) was almost halved (7.4% vs. 14.0%, p<0.001), and exclusive human milk feeding after discharge increased threefold (p<0.001). SG2017, in contrast, had a higher rate of chronic lung disease (CLD) (20.0% vs. 15.1%, p=0.098). Within SG2017, the rates of LOS, CLD, and human milk feeding varied significantly between the three NICUs. When compared with ANZNN2017, SG2017 had significantly lower rates of LOS for infants ≤25 weeks (p=0.001), less necrotizing enterocolitis for infants ≤27 weeks (p=0.002), and less CLD across all GA groups. Postnatal morbidities and survival rates for VLBW infants in Singapore have improved over a decade. Outcomes for VLBW infants varied among three Singapore NICUs, which provide a rationale for collaboration to improve clinical quality. The outcomes of Singaporean VLBW infants were comparable to those of their ANZNN counterparts.

Neurodevelopmental Outcome of Preterm Infants with Hypothyroidism

Background: Hypothyroidism is one of the most common causes of preventable intellectual disability and is common in preterm infants. Some studies have reported that developmental delay is still high in these patients despite appropriate treatment. Objectives: This study aimed to investigate the short-term neurodevelopmental outcome of preterm infants with thyroid dysfunction. Methods: This cohort study included 50 preterm infants with thyroid dysfunction requiring levothyroxine treatment (case group) and 50 age- and sex-matched healthy preterm infants with normal thyroid tests (control group). The patients were followed, and Ages and Stages Questionnaires (ASQ) (including five domains) were filled out at 6 and 12 months to evaluate the short-term neurodevelopmental outcome. Results: There was no statistically significant difference in gestational age, sex, and birth weight between the two groups (P-values = 0.648, 0.756, and 0.866, respectively). A total number of 4 (8%) and 7 (14%) of the case group and 1 (2.85%) and 2 (5.71%) of the control group had a possible neurodevelopmental delay based on the low score in at least one domain of ASQ at 6 and 12 months of age (P-values = 0.321 and 0.222, respectively). Treated hypothyroidism was not significantly associated with higher impaired neurodevelopmental outcomes (P-value = 0.236, Odd Ratio: 2.686, 95% CI: 0.523 - 13.787). Conclusions: In this study, the risk of neurodevelopmental impairment in preterm infants with hypothyroidism was similar to that of healthy preterm infants. Thus, these findings may confirm the adequacy of levothyroxine replacement therapy in preventing neurodevelopmental delay.

Effects of preterm birth and postnatal exposure to metal mixtures on neurodevelopment in children at 24 months of age.

The effects of early-life metal exposure on neurodevelopment in very low birth weight preterm (VLBMP) children (with a birth weight of <1500 g and a gestational age of <37 weeks) have not been clearly established. We aimed to investigate associations of childhood exposure to multiple metals and preterm low birth weight with neurodevelopment among children at 24 months of corrected age. VLBWP children (n = 65) and normal birth weight term (NBWT) children (n = 87) were enrolled from Mackay Memorial Hospital in Taiwan between December 2011 and April 2015. Lead (Pb), cadmium (Cd), arsenic (As), methylmercury (MeHg), and selenium (Se) concentrations in the hair and fingernails were analyzed as biomarkers for metal exposure. The Bayley Scale of Infant and Toddler Development, Third Edition, was used to determine neurodevelopment levels. VLBWP children had significantly lower scores in all development domains compared to NBWT children. We also investigated preliminary exposure levels of VLBWP children to metals as reference values for future epidemiological and clinical survey. Fingernails are a useful biomarker for metal exposure to evaluate the effects on neurological development. A multivariable regression analysis revealed that fingernail Cd concentrations were significantly negatively associated with cognition (β = -0.63, 95% confidence interval (CI): -1.17 to -0.08) and receptive language function (β = -0.43, 95% CI: -0.82 to -0.04) among VLBWP children. VLBWP children with a 10-μg/g increase in the As concentration in their nails had a 8.67-point lower composite score in cognitive ability and a 1.82-point lower score in gross-motor functions. Effects of preterm birth and postnatal exposure to Cd and As were associated with poorer cognitive, receptive language, and gross-motor abilities. VLBWP children are at risk for neurodevelopmental impairments when exposed to metals. Further large-scale studies are needed assess to the risk of neurodevelopmental impairments when vulnerable children are exposed to metal mixtures.

2130. Neonatal Immune Phenotypes and Neurodevelopmental Outcomes in Infants with Congenital Cytomegalovirus Infection (cCMV)

Abstract Background Infants with congenital cytomegalovirus infection (cCMV) are at risk for neurodevelopmental impairment (NDI). Antiviral therapy has been shown to improve neurodevelopmental outcomes but is not recommended for all infected infants. There are currently no predictive markers for NDI in infants with cCMV. Our objective was to compare neonatal T cell differentiation and memory phenotypes in CMV-infected infants with and without subsequent NDI. Methods Blood samples were collected from infants with cCMV and age-matched healthy controls. Peripheral blood mononuclear cells were analyzed by flow cytometry for CD4 and CD8 T cells expressing CD28, CD57, PD, CD45RA/RO, and CCR7. Demographic and clinical data were collected. NDI was defined as Bayley III/IV testing below the average range in at least one domain in infants for whom this developmental testing was available or based on diagnosis by infectious disease physician or primary care provider. Outcomes for infants with follow-up at least 6 months of age were included. Infants with isolated speech delay associated with hearing loss were not considered to have NDI. Results Samples were analyzed from 18 infants (Table 1) at time of diagnosis (≤ 60 days of age) and 5 uninfected age-matched controls. The frequencies of CD8+ T cells expressing CD28low (differentiation), CD57+ (terminal differentiation/senescence), PD1hi (inhibitory or exhausted phenotype) and CD45RO± (memory) phenotypes were higher for the cCMV group without NDI compared to that with NDI (Figure 1). The cCMV group without NDI had lower proportions of naïve (CCR7+/CD45RA+) effector memory, TEM (CCR7-/CD45RA-), and effector memory RA, TEMRA (CCR7-/CD45RA+) CD8+ T cells than those with NDI (Figure 2). There was no difference in memory distribution or surface marker expression of CD4+ T cells. Table 1 Demographic and clinical characteristics of the infants with congenital cytomegalovirus infection (cCMV) with and without neurodevelopmental impairment (NI) and age-matched controls. Continuous variables are compared using the Mann Whitney U test and categorical variables with the Fischer’s Exact test. There were no significant differences between infants with and without NI. Figure 1.CD8+ T cell phenotypes in cCMV groups with and without Neurodevelopmental Impairment (NDI) Frequencies of CD8+ T cells lacking expression of CD28 (A), or expressing CD57 (B), PD-1 (C), or CD45RO (D) are shown at age ≤ 60 days. Infants with congenital CMV (cCMV) and normal neurodevelopmental outcome are shown in blue, infants with neurodevelopmental impairment are shown in red, and uninfected age-matched controls are shown in black. Data are shown as medians [interquartile range]. Groups were compared using the Mann Whitney U Test. Infants with no NDI had significantly higher frequencies of CD28- (p = 0.002), CD57+ (p = 0.001), PD-1+ (p = 0.01) and CD45RO+ (p = 0.01) CD8 T cells. * p ≤ 0.05; ** p ≤ 0.01. Figure 2.T cell memory subset distributions among cCMV groups and uninfected controls Proportions of CD4+ (A) and CD8+ (B) naïve (CCR7+/CD45RA+), central memory, TCM (CCR7+/CD45RA-), effector memory, TEM (CCR7-, CD45RA-), and effector memory RA, TEMRA (CCR7-/CD45RA+) T cells. Infants with congenital CMV (cCMV) and normal neurodevelopmental outcome are shown in blue, infants with neurodevelopmental impairment (NI) are shown in red while uninfected age-matched controls are shown in black and gray. Comparisons between T cell groups were made using the Mann Whitney U test. Infants with cCMV without NI had significantly fewer naïve (p = 0.0001), greater TEM (p = 0.0001), and TEMRA (p = 0.005) CD8+ T cells than those with NI. The distributions of CD4+ T cells were not significantly different. Conclusion In this small cohort of infants infected with CMV, these data suggest that a more differentiated memory CD8+ T cell phenotype in the neonatal period may correlate with normal neurodevelopmental outcomes. Disclosures Alexandra K. Medoro, MD, Merck: Grant/Research Support.

COVID-19 Pandemic and Infant Neurodevelopmental Impairment

Primary studies proposed that aberrant maternal antiviral immunity and/or giving birth in quarantine, such as during the ongoing COVID-19 pandemic, may be associated with the risk of neurodevelopmental impairment (NDI) in offspring. To evaluate the associations of birth and being raised during the COVID-19 pandemic with risk of NDI among infants and to assess the association of gestational exposure to SARS-CoV-2 with risk of NDI. PubMed, Web of Science, Scopus, Embase, and preprint servers were systematically searched from inception to March 25, 2022. Studies evaluating the neurodevelopment of infants born during the SARS-CoV-2 pandemic were included in this systematic review and meta-analysis. Studies using Ages and Stages Questionnaires, Third Edition (ASQ-3), were used for quantitative meta-analysis. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses, a random-effects model meta-analysis was used to pool the proportion and odds ratios (ORs) of overall NDI, as well as each developmental domain on ASQ-3 with the corresponding 95% CI. The primary outcome was the risk of overall NDI among infants screened during the pandemic vs prepandemic. The secondary outcome was the comparison of NDI by ASQ-3 domain among infants born to women with known gestational exposure to SARS-CoV-2 vs no exposure. A total of 8 studies were included, including 21 419 infants (11 438 screened in pandemic and 9981 in prepandemic period). NDI was present in 330 of 8992 infants (7%; 95% CI, 4%-10%) screened during the COVID-19 pandemic from January 2020 to January 2021. Among the pandemic cohort, the prevalence of NDI among infants with gestational exposure to SARS-CoV-2 was 77 of 691 (12%; 95% CI, 6%-18%). Compared with the prepandemic cohort (2015-2019), the pandemic cohort was more likely to have communication impairment (OR, 1.70; 95% CI, 1.37-2.11; P < .001), without significant differences in other ASQ-3 domains (eg, gross motor, fine motor, personal-social, and problem-solving). In contrast, maternal SARS-CoV-2 infection was not associated with significant differences in any neurodevelopment domain in offspring, except for increasing the odds of fine motor impairment (OR, 3.46; 95% CI, 1.43-8.38; P < .001). In this systematic review and meta-analysis examining the association between COVID-19 pandemic and the risk of NDI, findings suggest that overall neurodevelopment in the first year of life was not changed by either being born or raised during the SARS-CoV-2 pandemic or by gestational exposure to SARS-CoV-2. Interestingly, the first year of life during the COVID-19 pandemic, regardless of maternal infection, was significantly associated with the risk of communication delay among the offspring.

Short-term and long-term risk of mortality and neurodevelopmental impairments after bacterial meningitis during infancy in children in Denmark and the Netherlands: a nationwide matched cohort study

SummaryBackgroundFew studies have reported the long-term consequences of bacterial meningitis during infancy, and studies that have been done usually do not include a comparison cohort. We aimed to assess short-term and long-term risk of mortality, neurodevelopmental impairment (NDI), and health-care use and household income in cohorts of children with and without a history of bacterial meningitis during infancy in Denmark and the Netherlands.MethodsIn this nationwide cohort study, infants with a history of bacterial meningitis before age 1 year were identified through the Danish Medical Birth Registry and Danish National Patient Registry using International Classification of Diseases (ICD)-10 codes and through the Netherlands Reference Laboratory for Bacterial Meningitis. Infants were matched (1:10) by sex and birth month and year to a comparison cohort of the general population without a history of bacterial meningitis. We analysed mortality using Cox proportional hazards regression. In Denmark, diagnoses of NDIs were based on ICD-10 codes; in the Netherlands, special educational needs were used as a functional NDI outcome. Risk ratios (RRs) of NDIs were estimated using modified Poisson regression. We also analysed long-term health-care use in Denmark and household income in both countries. All regression analyses were adjusted for sex and year of birth, and stratified by pathogen whenever sample size allowed.FindingsWe included 2216 children with a history of bacterial meningitis (570 [25·7%] in Denmark between Jan 1, 1997, and Dec 31, 2018, and 1646 [74·3%] in the Netherlands between Jan 1, 1995, and Dec 31, 2018), matched to 22 127 comparison cohort members. Median age at diagnosis was 2·8 months (IQR 0·4–7·1) in Denmark and 4·3 months (0·7–7·4) in the Netherlands. Mortality risks within 3 months after disease onset were 3·9% (95% CI 2·6–5·8%) in Denmark and 5·9% (4·7–7·0) in the Netherlands, compared with 0·0% (p<0·0001) and 0·1% (p<0·0001) in the comparison cohorts. Survivors had an increased risk of moderate or severe NDIs at age 10 years (RR 5·0 [95% CI 3·5–7·1] in Denmark and 4·9 [4·0–6·2] in the Netherlands) compared to children in the comparison cohort, particularly after pneumococcal and group B streptococcal meningitis. In Denmark, a history of bacterial meningitis was associated with increased health-care use in the 10 years following diagnosis (rate ratio 4·5 [95% CI 3·9–5·2] for outpatient visits and 4·1 [3·6–4·7] for hospital admissions).InterpretationOur study shows increased risk of mortality in the short and long term, a five times increase in risk of NDIs, and increased health-care use after bacterial meningitis during infancy. Together with context-specific incidence data, our results can advance pathogen-specific estimation of the meningitis burden and inform service provision at the individual and population level.FundingBill & Melinda Gates Foundation, the Stichting Remmert Adriaan Laan Fonds, and the Netherlands Organisation for Health Research and Development.