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OBJECTIVE: To document the prevalence of self-reported postpartum hemorrhage (PPH) in Ga East, Accra, Ghana, and examine the demographic, biological, and social risk factors for PPH. METHODS: The present study was a cross-sectional secondary analysis of data collected during 2010-2012 from the Ghana Essential Health Interventions Program, a quasi-experimental interventional study surveying households in the urban Ga East Municipal District. The analysis included data from randomly selected parous women of childbearing age (15-49\u00a0years), excluding those with a history of abortion (spontaneous or induced) or stillbirth. The \u03c72 test and logistic regression were used to identify significant risk factors for self-reported PPH. RESULTS: The current analysis included 2136 women. Self-reported PPH was recorded for 95 (4.4%) participants. The maternal age at delivery, the duration of labor, and the number of skilled delivery providers were significantly associated with self-reported PPH. Prolonged labor (odds ratio 3.70, 95% confidence interval 2.27-5.94; P<0.001) and maternal age (odds ratio 0.96, 95% confidence interval 0.94-0.99; P=0.020) were predictors of self-reported PPH. CONCLUSION: Prolonged labor and younger maternal age were related to a higher burden of reported PPH. These findings were congruent with global and regional data on the prevalence and risk factors for objectively measured PPH and could help focus intervention strategies to high-risk groups, particularly in resource-limited settings.
\n \n\n \n \nAngelman syndrome (AS), an early-onset neurodevelopmental disorder characterized by abnormal gait, intellectual disabilities, and seizures, occurs when the maternal allele of the UBE3A gene is disrupted, since the paternal allele is silenced in neurons by the UBE3A antisense (UBE3A-AS) transcript. Given the importance of early treatment, we hypothesized that prenatal delivery of an antisense oligonucleotide (ASO) would downregulate the murine Ube3a-AS, resulting in increased UBE3A protein and functional rescue. Using a mouse model with a Ube3a-YFP allele that reports on-target ASO activity, we found that in utero, intracranial (IC) injection of the ASO resulted in dose-dependent activation of paternal Ube3a, with broad biodistribution. Accordingly, in utero injection of the ASO in a mouse model of AS also resulted in successful restoration of UBE3A and phenotypic improvements in treated mice on the accelerating rotarod and fear conditioning. Strikingly, even intra-amniotic (IA) injection resulted in systemic biodistribution and high levels of UBE3A reactivation throughout the brain. These findings offer a novel strategy for early treatment of AS using an ASO, with two potential routes of administration in the prenatal window. Beyond AS, successful delivery of a therapeutic ASO into neurons has implications for a clinically feasible prenatal treatment for numerous neurodevelopmental disorders.
\n \n\n \n \nDysfunction in sodium channels and their ankyrin scaffolding partners have both been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). In particular, the genes SCN2A, which encodes the sodium channel NaV1.2, and ANK2, which encodes ankyrin-B, have strong ASD association. Recent studies indicate that ASD-associated haploinsufficiency in Scn2a impairs dendritic excitability and synaptic function in neocortical pyramidal cells, but how NaV1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the dendritic membrane of mouse neocortical neurons and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a+/\u2212 conditions. These results establish a direct, convergent link between two major ASD risk genes and reinforce an emerging framework suggesting that neocortical pyramidal cell dendritic dysfunction can contribute to neurodevelopmental disorder pathophysiology.
\n \n\n \n \nOBJECTIVE: To determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus (cCMV(-associated sensorineural hearing loss (SNHL). STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled phase 2 trial of 6 weeks of oral valganciclovir at United States (n=12) and United Kingdom (n=9) sites. Patients ages1 month through 3 years with baseline SNHL were enrolled. The primary outcome was change in total ear hearing between baseline and study month 6. Secondary outcome measures included change in best ear hearing and reduction in CMV viral load in blood, saliva, and urine. RESULTS: Of 54 participants enrolled, 35 were documented to have cCMV infection and were randomized (active group: 17; placebo group: 18). Mean age at enrollment was 17.8 \u00b1 15.8 months (valganciclovir) versus 19.5 \u00b1 13.1 months (placebo). Twenty (76.9%) of the 26 ears from subjects in the active treatment group did not have worsening of hearing, compared with 27 (96.4%) of 28 ears from subjects in the placebo group (p= 0.09). All other comparisons of total ear or best ear hearing outcomes were also not statistically significant. Saliva and urine viral loads decreased significantly in the valganciclovir group but did not correlate with change in hearing outcome. CONCLUSIONS: In this randomized controlled trial, initiation of antiviral therapy beyond the first month of age did not improve hearing outcomes in children with cCMV-associated SNHL.
\n \n\n \n \nBackground: Adults <55 years comprise a quarter of all acute coronary syndromes (ACS) hospitalisations. There is a paucity of data characterising this group, particularly sex differences. This study aimed to compare the clinical and risk profile of patients with ACS aged <55 with older counterparts, and measure short-term outcomes by age and sex. Method: The study population comprised patients with ACS enrolled in the AUS-Global Registry of Acute Coronary Events (GRACE), Cooperative National Registry of Acute Coronary Syndrome Care (CONCORDANCE) and SNAPSHOT ACS registries. We compared clinical features and combinations of major modifiable risk factors (hypertension, smoking, dyslipidaemia, and diabetes) by sex and age group (20\u201354, 55\u201374, 75\u201394 years). All-cause mortality and major adverse events were identified in-hospital and at 6-months. Results: There were 16,658 patients included (22.3% aged 20\u201354 years). Among them, 20\u201354 year olds had the highest proportion of ST-elevation myocardial infarction compared with sex-matched older age groups. Half of 20\u201354 year olds were current smokers, compared with a quarter of 55\u201374 year olds, and had the highest prevalence of no major modifiable risk factors (14.2% women, 12.7% men) and of single risk factors (27.6% women, 29.0% men), driven by smoking. Conversely, this age group had the highest proportion of all four modifiable risk factors (6.6% women, 4.7% men). Mortality at 6 months in 20\u201354 year olds was similar between men (2.3%) and women (1.7%), although lower than in older age groups. Conclusions: Younger adults with ACS are more likely to have either no risk factor, a single risk factor, or all four modifiable risk factors, than older patients. Targeted risk factor prevention and management is warranted in this age group.
\n \n\n \n \nBACKGROUND: Data on SARS-CoV-2 infection in pregnancy and infancy has accumulated throughout the course of the pandemic, though evidence regarding asymptomatic SARS-CoV-2 infection and adverse birth outcomes are scarce. Limited information is available from countries in sub-Saharan Africa (SSA). The pregnant woman and infant COVID in Africa study (PeriCOVID Africa) is a South-South-North partnership involving hospitals and health centres in five countries: Malawi, Uganda, Mozambique, The Gambia, and Kenya. The study leveraged data from three ongoing prospective cohort studies: Preparing for Group B Streptococcal Vaccines (GBS PREPARE), SARS-CoV-2 infection and COVID-19 in women and their infants in Kampala and Mukono (COMAC) and Pregnancy Care Integrating Translational Science Everywhere (PRECISE). In this paper we describe the seroepidemiology of SARS-CoV-2 infection in pregnant women enrolled in sites in Uganda and Malawi, and the impact of SARS-CoV-2 infection on pregnancy and infant outcomes. OUTCOME: Seroprevalence of SARS-CoV-2 antibodies in maternal blood, reported as the proportion of seropositive women by study site and wave of COVID-19 within each country. METHODS: The PeriCOVID study was a prospective mother-infant cohort study that recruited pregnant women at any gestation antenatally or on the day of delivery. Maternal and cord blood samples were tested for SARS-CoV-2 antibodies using Wantai and Euroimmune ELISA. In periCOVID Uganda and Malawi nose and throat swabs for SARS-Cov-2 RT-PCR were obtained. RESULTS: In total, 1379 women were enrolled, giving birth to 1387 infants. Overall, 63% of pregnant women had a SARS-CoV-2 positive serology. Over subsequent waves (delta and omicron), in the absence of vaccination, seropositivity rose from 20% to over 80%. The placental transfer GMR was 1.7, indicating active placental transfer of anti-spike IgG. There was no association between SARS-CoV-2 antibody positivity and adverse pregnancy or infancy outcomes.
\n \n\n \n \nZika virus (ZIKV) is a mosquito-borne, single-stranded DNA flavivirus that is teratogenic and neurotropic. Similar to the teratogenic effects of other TORCH infections, ZIKV infection during pregnancy can have an adverse impact on fetal and neonatal development. Epilepsy is detected in 48-96% of children with Congenital Zika Syndrome (CZS) and microcephaly. Early epilepsy surveillance is needed in children with prenatal ZIKV exposure; yet, most ZIKV-endemic regions do not have specialist epilepsy care. Here, we describe the demographic, clinical, imaging, and EEG characteristics of a 2-year-old child with CZS and microcephaly who presented with focal epileptiform activity, suboptimal growth, and severe neurodevelopmental delays. Administration of a brief seizure questionnaire by allied health professionals to the patient's caregiver helped to characterize the child's seizure semiology and differentiate focal from generalized seizure features. A telemedicine EEG interpretation platform provided valuable diagnostic information for the patient's local pediatrician to integrate into her treatment plan. This case illustrates that CZS can present with focal epilepsy features and that a telemedicine approach can be used to bridge the gap between epilepsy specialists and local care providers in resource limited ZIKV-endemic regions to achieve better seizure control in children with CZS.
\n \n\n \n \nBACKGROUND: The INTER-NDA is a novel assessment of early child development measuring cognition, language, motor skills, behaviour, attention, and socio-emotional reactivity in 2 year olds in 15 minutes. Here, we present the results of an evaluation of the INTER-NDA against the Bayley Scales of Infant Development III edition (BSID-III), its sensitivity and specificity and its psychometric properties. METHODS: Eighty-one infants from Oxford, UK, aged 23.1-28.3 months, were evaluated using the INTER-NDA and the BSID-III. The agreement between the INTER-NDA and the BSID-III was assessed using interclass correlations (for absolute agreement), Bland-Altman analyses (for bias and limits of agreement), and sensitivity and specificity analyses (for accuracy). The internal consistency of the INTER-NDA and uni-dimensionality of its subscales were also determined. RESULTS: The interclass correlation coefficients between the BSID-III and the INTER-NDA cognitive, motor and behaviour scores ranged between 0.745 and 0.883 (p<0.001). The Bland-Altman analysis showed little to no bias in the aforementioned subscales. The sensitivity and specificity of INTER-NDA cognitive scores \u22641 SD below the mean are 66.7% and 98.6% respectively, with moderate agreement between INTER-NDA and BSID-III classifications (\u03ba = 0.72, p<0.001). The sensitivity and specificity of INTER-NDA scores <2 SD below the mean, in predicting low BSID-III scores (<70), are 100% each for cognition, and 25% and 100% respectively for language. More than 97% of children who scored in the normal range of the INTER-NDA (<1SD below mean) also scored in the normal range in the BSID-III (\u226585). The INTER-NDA demonstrates satisfactory internal consistency and its subscales demonstrate good unidimensionality. CONCLUSION: The INTER-NDA shows good agreement with the BSID-III, and demonstrates satisfactory psychometric properties, for the assessment of ECD at 22-28 months.
\n \n\n \n \nBACKGROUND: The International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) Project is a population-based, longitudinal study describing early growth and development in an optimally healthy cohort of 4607 mothers and newborns. At 24 months, children are assessed for neurodevelopmental outcomes with the INTERGROWTH-21st Neurodevelopment Package. This paper describes neurodevelopment tools for preschoolers and the systematic approach leading to the development of the Package. METHODS: An advisory panel shortlisted project-specific criteria (such as multi-dimensional assessments and suitability for international populations) to be fulfilled by a neurodevelopment instrument. A literature review of well-established tools for preschoolers revealed 47 candidates, none of which fulfilled all the project's criteria. A multi-dimensional assessment was, therefore, compiled using a package-based approach by: (i) categorizing desired outcomes into domains, (ii) devising domain-specific criteria for tool selection, and (iii) selecting the most appropriate measure for each domain. RESULTS: The Package measures vision (Cardiff tests); cortical auditory processing (auditory evoked potentials to a novelty oddball paradigm); and cognition, language skills, behavior, motor skills and attention (the INTERGROWTH-21st Neurodevelopment Assessment) in 35-45 minutes. Sleep-wake patterns (actigraphy) are also assessed. Tablet-based applications with integrated quality checks and automated, wireless electroencephalography make the Package easy to administer in the field by non-specialist staff. The Package is in use in Brazil, India, Italy, Kenya and the United Kingdom. CONCLUSIONS: The INTERGROWTH-21st Neurodevelopment Package is a multi-dimensional instrument measuring early child development (ECD). Its developmental approach may be useful to those involved in large-scale ECD research and surveillance efforts.
\n \n\n \n \nBACKGROUND: The 2005-06 chikungunya virus (CHIKV) outbreak in La R\u00e9union suggested that mothers could transmit CHIKV to their neonates while viremic during the intrapartum period, and more than half of the infected neonates showed impaired neurodevelopment at two years of age. However, data sparsity precluded an overview of the developmental impact of vertical infection within the whole prenatal period. OBJECTIVE & METHODS: The current study assessed two-year old children born to mothers who were infected during the 2014 CHIKV outbreak in Grenada to determine the neurodevelopmental impact of perinatal CHIKV infection throughout gestation. Mother and child infection status were confirmed by serologic testing (IgG and IgM) for CHIKV. Cognitive, fine motor, gross motor, language and behavioral outcomes were assessed at two years of age on the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA). RESULTS: No differences in neurodevelopmental outcomes were observed between two-year-old children born to mothers infected with CHIKV during gestation (n = 149) and those born to mothers not infected with CHIKV (n = 161). No differences were found in INTER-NDA scores between children infected with CHIKV (n = 47) and children not infected with CHIKV (n = 592). Likewise, there were no differences between children infected with CHIKV post-partum (n = 19) versus children not infected with CHIKV (n = 592). CONCLUSION: Our findings suggest that children exposed and/or infected with CHIKV outside of the intrapartum period experience no significant neurodevelopmental delay at two years of age, as measured by the INTER-NDA, compared to their unexposed and/or uninfected peers. These results complement those of previous studies which showed a neurodevelopmental risk only for children infected during the intrapartum period, while the mother was highly viremic. These results might be reassuring for women of childbearing age and public health officials in CHIKV-endemic regions.
\n \n\n \n \nBACKGROUND: Maternal depression during pregnancy is associated with an increased risk of adverse child outcomes. One potential mechanism is the influence of antenatal depression on the foetal hypothalamic-pituitary-adrenal axis. This can be observed as disturbances in baseline cortisol secretion during childhood. The influence of antenatal depression on infant cortisol reactivity to a stressor may provide further insight into this association. In addition, the dose-response relationship between foetal exposure to antenatal depression and infant cortisol reactivity is unclear. METHODS: A consecutive sample of 133 pregnant women in their third trimester was recruited from an antenatal clinic in Karnataka, South India. Women were assessed for depression before and after birth on the Edinburgh Postnatal Depression Scale (EPDS) and the Kessler 10 Scale. Salivary cortisol response to immunization was measured in 58 infants at 2 months of age. We aimed (i) to investigate the association between antenatal depression and infant cortisol reactivity to immunization and (ii) to explore whether the relationship is dose-dependent. RESULTS: Exposure to antenatal depression independently predicted elevated infant cortisol responses to immunization (\u03b2 = 0.53, P = 0.04). The association was found to be U-shaped, for antenatal depression measured on the EPDS, with the infants exposed to the highest and lowest levels of maternal antenatal EPDS scores during intra-uterine life showing elevated cortisol responses to immunization (R(2) = 0.20, P = 0.02). Infants exposed to moderate levels of maternal antenatal depression showed the lowest cortisol response to immunization. CONCLUSIONS: These findings suggest that the association between antenatal depression and infant cortisol reactivity is dose-dependent and U-shaped, implying that infants exposed to both low and high levels of maternal depression showed greater reactivity. The study provides the first evidence of such an association from a low-income setting.
\n \n\n \n \nBACKGROUND: Cross-cohort comparison is an established method for improving causal inference. This study compared 2 cohorts, 1 from a high-income country and another from a middle-income country, to (1) establish whether birth exposures may play a causal role in the development of childhood attention problems; and (2) identify whether confounding structures play a different role in parent-reported attention difficulties compared with attention deficit hyperactivity disorder (ADHD) diagnoses. METHODS: Birth exposures included low birth weight (LBW), small-for-gestational age (SGA), small head circumference (HC) and preterm birth (PTB)). Outcomes of interest were attention difficulties (Strengths and Difficulties Questionnaire, SDQ) and ADHD (Development and Well-Being Assessment, DAWBA). Associations between exposures and outcomes were compared between 7-year-old children from the Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK (N=6849) and the 2004 Pelotas cohort in Brazil (N=3509). RESULTS: For attention difficulties (SDQ), the pattern of association with birth exposures was similar between cohorts: following adjustment, attention difficulties were associated with SGA (OR=1.59, 95% CI 1.20 to 2.19) and small HC (OR=1.64, 95% CI 1.11 to 2.41) in ALSPAC and SGA (OR=1.35, 95% CI 1.04 to 1.75) in Pelotas. For ADHD, however, the pattern of association following adjustment differed markedly between cohorts. In ALSPAC, ADHD was associated with LBW (OR=2.29, 95% CI 1.09 to 4.80) and PTB (OR=2.33, 95% CI 1.23 to 4.42). In the Pelotas cohort, however, ADHD was associated with SGA (OR=1.69, 95% CI 1.02 to 2.82). CONCLUSIONS: The findings suggest that fetal growth impairment may play a causal role in the development of attention difficulties in childhood, as similar associations were identified across both cohorts. Confounding structures, however, appear to play a greater role in determining whether a child meets the full diagnostic criteria for ADHD.
\n \n\n \n \nBACKGROUND: Neurodevelopmental disorders are increasingly believed to originate from intrauterine growth restriction (IUGR). Current reviews exploring the neurodevelopmental effects of IUGR, however, are mostly based on birthweight, an inadequate proxy. OBJECTIVE: We aimed to examine the association between IUGR documented in utero, and neurodevelopmental outcomes during childhood. SEARCH STRATEGY: Medline, CINAHL, PsycInfo and Scopus were searched for relevant studies published after 1970. SELECTION CRITERIA: The analysis included studies that identified IUGR in utero, with follow-up assessments between 1 month and 12 years of age. DATA COLLECTION AND ANALYSIS: Data was extracted for cognitive, behavioural, language, motor, hearing, vision or sleep outcomes. Studies were summarised separately for children born at <35 and \u226535 weeks gestation. MAIN RESULTS: Of 28 876 titles identified, 38 were suitable for inclusion. IUGR children born \u226535 weeks gestation scored on average 0.5 SD lower than non-IUGR children across all neurodevelopmental assessments. IUGR children born <35 weeks of gestation scored approximately 0.7 SD lower than non-IUGR children across all neurodevelopmental assessments. IUGR children with evidence of fetal circulatory redistribution (preferential perfusion of the brain) had more severe neurodevelopmental impairments than those born IUGR alone. CONCLUSIONS: IUGR increases the risk of neurodevelopmental impairment during childhood differentially across domains. IUGR children born preterm or with evidence of fetal circulatory redistribution are more severely affected. TWEETABLE ABSTRACT: IUGR is associated with an overall risk for neurodevelopmental delay in a range of neurodevelopmental domains.
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