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Phosphorylation of 'SDT-like' motifs in ATRX mediates its interaction with the MRN complex and is important for ALT pathway suppression.
Approximately 10-15% of human cancers are telomerase-negative and maintain their telomeres through a recombination-based process known as the alternative lengthening of telomeres (ALT) pathway. Loss of the alpha-thalassemia/mental retardation, X-linked (ATRX) chromatin remodeller is a common event in ALT-positive cancers, but is generally insufficient to drive ALT induction in isolation. We previously demonstrated that ATRX binds to the MRN complex, which is also known to be important in the ALT pathway, but the molecular basis of this interaction remained elusive. Here, we demonstrate that the interaction between ATRX and MRN is dependent on the N-terminal forkhead-associated and BRCA1 C-terminal domains of NBS1, analogous to the previously reported NBS1-MDC1 interaction. A number of conserved 'SDT-like' motifs (serine and threonine residues with aspartic/glutamic acid residues at proximal positions) in the central unstructured region of ATRX were found to be crucial for the ATRX-MRN interaction. Furthermore, treatment with a casein kinase 2 inhibitor prevented the ability of ATRX to bind MRN, suggesting that phosphorylation of these residues by casein kinase 2 is also important for the interaction. Finally, we show that a functional ATRX-MRN interaction is important for the ability of ATRX to prevent induction of ALT hallmarks in the presence of chemotherapeutically induced DNA-protein crosslinks, and might also have implications for individuals with ATR-X syndrome.
Biomarkers of vaccine safety and efficacy in vulnerable populations: Lessons from the fourth international precision vaccines conference
Vaccination has been a cornerstone of public health, substantially reducing the global burden of infectious diseases, notably evident during the COVID-19 pandemic caused by SARS-CoV-2. However, vulnerable populations (VPs), including those in extreme age groups and those with underlying health conditions, have borne a disproportionate burden of morbidity and mortality from infectious diseases. Understanding vaccine immunogenicity in these populations is crucial for developing effective vaccines. Characterizing vaccine responses in VPs presents unique challenges due to under-vaccination, sub-optimal vaccine responses, and distinct mechanisms of vaccine-induced protection. To address these challenges, experts convened at the 4th International Precision Vaccines Conference in Rome. Co-hosted by the Precision Vaccines Program of Boston Children's Hospital and Ospedale Pediatrico Bambino Gesù, the conference focused on biomarkers of vaccine safety and efficacy in vulnerable populations. Discussions at the conference emphasized the need for multidisciplinary strategies and international collaborations to optimize vaccine development. Key areas of focus included assessing vaccine safety, defining biomarkers for vaccine immunogenicity, developing human in vitro assay models, and accelerating the selection of novel vaccine formulations and adjuvants tailored for vulnerable populations. The conference provided a platform for experts from diverse fields, including immunology, paediatrics, and vaccinology, to exchange ideas and advance research in precision vaccines. This manuscript highlights key concepts discussed at the conference and underscores the importance of precision vaccines in addressing the unique needs of vulnerable populations.
Immunogenicity of MVA-BN vaccine deployed as mpox prophylaxis: a prospective cohort study and analysis of transcriptomic predictors of response
Background: Since 2022, mpox has emerged as a global health threat, with two clades (I and II) causing outbreaks of international public health concern. The third generation smallpox vaccine modified vaccinia Ankara, manufactured by Bavarian Nordic (MVA-BN), has emerged as a key component of mpox prevention. To date, the immunogenicity of this vaccine, including determinants of response has been incompletely described, especially when MVA-BN has been administered intradermally at 1/5th the registered dose (‘fractionated dosing’), as recommended as a dose-sparing strategy. The aim of this study was to explore the immunogenicity of MVA-BN, and baseline determinants of vaccine response in an observational public-health response setting. Methods: We conducted a prospective cohort study and immunological analysis of responses to MVA-BN in patients attending a sexual health vaccination clinic in Oxford, UK. Blood samples were taken at baseline, day 14, and day 28 after first vaccine, and 28 and 90 days following a second vaccine. A sub-cohort had additional blood samples collected day 1 following their first vaccine (optional timepoint). We assessed IgG responses to mpox/vaccinia antigens using Luminex assay (‘MpoxPlex’) via generalised linear mixed modelling, and T-cell responses using interferon- enzyme linked immunospot and activation induced marker assay. Associations between blood transcriptomic signatures (baseline, day 1) and immunogenicity were assessed using differential expression analysis and gene set enrichment methods. Findings: We recruited 34 participants of whom 33 received fractionated dosing. Of those without prior smallpox vaccination (n=30), 50% seroconverted by day 28, and while this increased to 89% by day 90 post second vaccination, individuals seronegative on day 28 demonstrated persistently lower responses compared to day 28 seropositive individuals. Serological response on day 28 positively associated with type I and II interferon signatures day one post-vaccination (n=18 samples) but negatively associated with these signatures at baseline. Interpretation: Baseline inflammatory states may inhibit MVA-BN serological immunogenicity by inhibiting the upregulation of MVA-induced innate immune signalling. If confirmed mechanistically these insights may inform improved vaccination strategies against mpox in diverse geographic and demographic settings. Given the likelihood of vaccine supply limitations in the current context and in future outbreak settings, the utility of dose-sparing vaccine strategies as a general approach to maximising population benefit warrants further study
The Epidemiology, Clinical, and Economic Burdens of Respiratory Syncytial Virus Infections Amongst Hospitalized Children Under 5 Years of Age in Jordan: A National Multi-Center Cross-Sectional Study
Respiratory syncytial virus (RSV) has been recognized as a highly important cause of morbidity and mortality among children and adults. A cross-sectional study at representative sites in Jordan was undertaken to provide an assessment of the epidemiology and health and economic burdens of RSV and influenza infections in Jordan amongst hospitalized children under 5 years old for the period between 15 November 2022 and 14 April 2023. This study involved 1000 patients with a mean age of 17.10 (SD: 16.57) months. Of these, half (n = 506, 50.6%) had positive results for RSV. Furthermore, 33% and 17.4% of the participants had positive results for RSV-B and RSV-A, respectively. The findings underscore the severity of RSV infections, where a significant proportion of the children experienced severe respiratory distress, which led to bronchiolitis and pneumonia. This study meticulously documented the clinical outcomes, including the need for intensive care, mechanical ventilation, and prolonged hospital stays. There was no statistically significant difference in the financial burdens between the RSV-positive and RSV-negative patients. This study revealed the urgent need for preventive measures to control the substantial burden of RSV among children under 5 years old in Jordan.
COVID-19 testing and reporting behaviours in England across different sociodemographic groups: a population-based study using testing data and data from community prevalence surveillance surveys.
BACKGROUND: Understanding underlying mechanisms of heterogeneity in test-seeking and reporting behaviour during an infectious disease outbreak can help to protect vulnerable populations and guide equity-driven interventions. The COVID-19 pandemic probably exerted different stresses on individuals in different sociodemographic groups and ensuring fair access to and usage of COVID-19 tests was a crucial element of England's testing programme. We aimed to investigate the relationship between sociodemographic factors and COVID-19 testing behaviours in England during the COVID-19 pandemic. METHODS: We did a population-based study of COVID-19 testing behaviours with mass COVID-19 testing data for England and data from community prevalence surveillance surveys (REACT-1 and ONS-CIS) from Oct 1, 2020, to March 30, 2022. We used mass testing data for lateral flow device (LFD; data for approximately 290 million tests performed and reported) and PCR (data for approximately 107 million tests performed and returned from the laboratory) tests made available for the general public and provided by date and self-reported age and ethnicity at the lower tier local authority (LTLA) level. We also used publicly available data on mean population size estimates for individual LTLAs, and data on ethnic groups, age groups, and deprivation indices for LTLAs. We did not have access to REACT-1 or ONS-CIS prevalence data disaggregated by sex or gender. Using a mechanistic causal model to debias the PCR testing data, we obtained estimates of weekly SARS-CoV-2 prevalence by both self-reported ethnic groups and age groups for LTLAs in England. This approach to debiasing the PCR (or LFD) testing data also estimated a testing bias parameter defined as the odds of testing in infected versus not infected individuals, which would be close to zero if the likelihood of test seeking (or seeking and reporting) was the same regardless of infection status. With confirmatory PCR data, we estimated false positivity rates, sensitivity, specificity, and the rate of decline in detection probability subsequent to reporting a positive LFD for PCR tests by sociodemographic groups. We also estimated the daily incidence, allowing us to calculate the fraction of cases captured by the testing programme. FINDINGS: From March, 2021 onwards, individuals in the most deprived regions reported approximately half as many LFD tests per capita as individuals in the least deprived areas (median ratio 0·50 [IQR 0·44-0·54]). During the period October, 2020, to June, 2021, PCR testing patterns showed the opposite trend, with individuals in the most deprived areas performing almost double the number of PCR tests per capita than those in the least deprived areas (1·8 [1·7-1·9]). Infection prevalences in Asian or Asian British individuals were considerably higher than those of other ethnic groups during the alpha (B.1.1.7) and omicron (B.1.1.529) BA.1 waves. Our estimates indicate that the England Pillar 2 COVID-19 testing programme detected 26-40% of all cases (including asymptomatic cases) over the study period with no consistent differences by deprivation levels or ethnic groups. Testing biases for PCR were generally higher than those for LFDs, in line with the general policy of symptomatic and asymptomatic use of these tests. Deprivation and age were associated with testing biases on average; however, the uncertainty intervals overlapped across deprivation levels, although the age-specific patterns were more distinct. We also found that ethnic minorities and older individuals were less likely to use confirmatory PCR tests through most of the pandemic and that delays in reporting a positive LFD test were possibly longer in populations self-reporting as "Black; African; Black British or Caribbean". INTERPRETATION: Differences in testing behaviours across sociodemographic groups might be reflective of the higher costs of self-isolation to vulnerable populations, differences in test accessibility, differences in digital literacy, and differing perceptions about the utility of tests and risks posed by infection. This study shows how mass testing data can be used in conjunction with surveillance surveys to identify gaps in the uptake of public health interventions both at fine-scale levels and across sociodemographic groups. It provides a framework for monitoring local interventions and yields valuable lessons for policy makers in ensuring an equitable response to future pandemics. FUNDING: UK Health Security Agency.
Cognitive function and skeletal size and mineral density at age 6-7 years: Findings from the Southampton Women's Survey.
INTRODUCTION: Poor cognitive function and osteoporosis commonly co-exist in later life. In women, this is often attributed to post-menopausal estrogen loss. However, a common early life origin for these conditions and the associations between cognitive function and bone mineral density (BMD) in childhood have not previously been explored. We examined these relationships at age 6-7 years in the Southampton Women's Survey (SWS) mother-offspring cohort. METHODS: Child occipitofrontal circumference (OFC), a proxy for brain volume, intelligence quotient (IQ) [Wechsler Abbreviated Scale of Intelligence] and visual recognition and working memory [CANTAB® Delayed Matching to Sample (DMS) and Spatial Span Length (SSP), respectively] were assessed. Whole-body-less-head (WBLH) and lumbar spine dual-energy X-ray absorptiometry [Hologic Discovery] (DXA) were performed to measure bone area (BA), bone mineral content (BMC), BMD and bone mineral apparent density (BMAD). Linear regression was used to examine associations between age and sex standardized variables (β represent standard deviation (SD) difference per SD of cognitive function). RESULTS: DXA was performed in 1331 children (mean (SD) age 6.8 (0.33) years, 51.5 % male), with OFC, IQ, DMS and SSP assessed in 1250, 551, 490 and 460, respectively. OFC (β = 0.25 SD/SD, 95%CI 0.20,0.30), IQ (β = 0.11 SD/SD, 95%CI 0.02,0.19), and DMS (β = 0.11, SD/SD, 95%CI 0.01,0.20) were positively associated with WBLH BA, with similar associations for lumbar spine BA. OFC and DMS were also positively associated with WBLH BMC, but only OFC was associated with BMD (WBLH: β = 0.38 SD/SD, 95%CI 0.33,0.43; LS: β = 0.19 SD/SD, 95%CI 0.13,0.24). CONCLUSION: Childhood brain volume was positively associated with measures of skeletal size and BMD, whereas IQ and memory were associated only with skeletal size. These findings suggest that common early life determinants for skeletal growth and BMD and cognitive function should be explored to identify potential early-life approaches to preventing osteoporosis and cognitive decline.
Focal epilepsy features in a child with Congenital Zika Syndrome.
Zika 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.
Evaluation of the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) in 2 year-old children.
BACKGROUND: 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 ≤1 SD below the mean are 66.7% and 98.6% respectively, with moderate agreement between INTER-NDA and BSID-III classifications (κ = 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 (≥85). 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.
The INTERGROWTH-21st Project Neurodevelopment Package: a novel method for the multi-dimensional assessment of neurodevelopment in pre-school age children.
BACKGROUND: 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.
Pre and postnatal exposure to Chikungunya virus does not affect child neurodevelopmental outcomes at two years of age.
BACKGROUND: The 2005-06 chikungunya virus (CHIKV) outbreak in La Réunion 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.
Foetal exposure to maternal depression predicts cortisol responses in infants: findings from rural South India.
BACKGROUND: 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 (β = 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.
Are fetal growth impairment and preterm birth causally related to child attention problems and ADHD? Evidence from a comparison between high-income and middle-income cohorts.
BACKGROUND: 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.
Differential effect of intrauterine growth restriction on childhood neurodevelopment: a systematic review.
BACKGROUND: 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 ≥35 weeks gestation. MAIN RESULTS: Of 28 876 titles identified, 38 were suitable for inclusion. IUGR children born ≥35 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.
Maternal depression and foetal responses to novel stimuli: insights from a socio-economically disadvantaged Indian cohort.
Maternal stress during pregnancy has pervasive effects on stress responsivity in children. This study is the first to test the hypothesis that maternal prenatal depression, as observed in South India, may be associated with how foetuses respond to a potentially stressful stimulus. We employed measures of foetal heart rate at baseline, during exposure to a vibroacoustic stimulus, and post-stimulation, to study patterns of response and recovery in 133 third trimester foetuses of depressed and non-depressed mothers. We show that the association between maternal depression and foetal stress responsivity is U-shaped with foetuses of mothers with high and low depression scores demonstrating elevated responses, and poorer recovery, than foetuses of mothers with moderate levels. The right amount of intra-uterine stimulation is important in conditioning foetuses towards optimal regulation of their stress response. Our results imply that, in certain environmental contexts, exposure to moderate amounts of intra-uterine stress may facilitate this process.
Assessing prenatal depression in the rural developing world: a comparison of two screening measures.
Significant levels of prenatal depression are reported from the Indian subcontinent (25–45%). A wide variety of measures have been used to screen for prenatal depression in western research. However, little evidence exists on the use of such measures in the context of the developing world. The objective of this study was to assess the validity of the Edinburgh Postnatal Depression Scale (EPDS) and the Kessler 10 Scale of Psychological Distress (K10) as screening measures for prenatal depression in rural South India. One hundred ninety-four women in their third trimester of pregnancy were assessed at a rural prenatal clinic in Karnataka, South India, using the EPDS, the K10 (scored 0–40) and a structured diagnostic psychiatric interview to establish a DSM-IV diagnosis of depression. Depressed women scored significantly higher on the EPDS and K-10 than controls. A receiver-operating characteristic analyses showed both scales to be good screening instruments for prenatal depression in rural South India at a cut-off of ≥13 on the EPDS (sensitivity = 100%, specificity = 84.90%, and area under the curve = 0.95) and ≥6 on the K10 (sensitivity = 100%, specificity = 81.30%, and area under the curve = 0.95). The EPDS and K10 have thus been shown to have equally good sensitivity and specificity in rural settings in the developing world at a cut-off score of ≥13 and ≥6, respectively. This study demonstrates the validity of the EPDS and K10 in screening pregnant women for depression during their prenatal check-ups.
Smoking during pregnancy and vision difficulties in children: a systematic review.
Cigarette smoking during pregnancy is a major public health concern. Intra-uterine exposure to maternal cigarette smoking is associated with increased risks of growth and neurodevelopmental problems during childhood and later life. Few studies have focussed on visual difficulties in children in the context of maternal smoking during pregnancy. A systematic search of online databases was carried out between February and May 2013 to examine the trend in visual outcomes in children exposed to maternal cigarette smoking during intra-uterine life. Twenty-four non-randomized studies were identified. Each study was rated for quality using the Newcastle-Ottawa Scale. Most studies (n = 18) reported fetal exposure to active or passive maternal cigarette smoking to be associated with an increased risk of adverse visual outcomes in children. In particular, there were higher rates of strabismus, refractive errors and retinopathy among children of women who smoked during pregnancy. These findings suggest that fetal exposure to cigarette smoke is a significant risk factor for visual problems during later life and that certain visual faculties, such as the intraocular muscles and retinal neurons, are more affected than others. The findings provide evidence in support of public health policies aimed at reducing fetal exposure to smoking by advising both women and their partners to quit smoking during pregnancy.
Fetal cranial growth trajectories are associated with growth and neurodevelopment at 2 years of age: INTERBIO-21st Fetal Study.
Many observational studies and some randomized trials demonstrate how fetal growth can be influenced by environmental insults (for example, maternal infections)1 and preventive interventions (for example, multiple-micronutrient supplementation)2 that can have a long-lasting effect on health, growth, neurodevelopment and even educational attainment and income in adulthood3. In a cohort of pregnant women (n = 3,598), followed-up between 2012 and 2019 at six sites worldwide4, we studied the associations between ultrasound-derived fetal cranial growth trajectories, measured longitudinally from <14 weeks' gestation, against international standards5,6, and growth and neurodevelopment up to 2 years of age7,8. We identified five trajectories associated with specific neurodevelopmental, behavioral, visual and growth outcomes, independent of fetal abdominal growth, postnatal morbidity and anthropometric measures at birth and age 2. The trajectories, which changed within a 20-25-week gestational age window, were associated with brain development at 2 years of age according to a mirror (positive/negative) pattern, mostly focused on maturation of cognitive, language and visual skills. Further research should explore the potential for preventive interventions in pregnancy to improve infant neurodevelopmental outcomes before the critical window of opportunity that precedes the divergence of growth at 20-25 weeks' gestation.
International estimated fetal weight standards of the INTERGROWTH-21st Project.
OBJECTIVE: Estimated fetal weight (EFW) and fetal biometry are complementary measures used to screen for fetal growth disturbances. Our aim was to provide international EFW standards to complement the INTERGROWTH-21st Fetal Growth Standards that are available for use worldwide. METHODS: Women with an accurate gestational-age assessment, who were enrolled in the prospective, international, multicenter, population-based Fetal Growth Longitudinal Study (FGLS) and INTERBIO-21st Fetal Study (FS), two components of the INTERGROWTH-21st Project, had ultrasound scans every 5 weeks from 9-14 weeks' until 40 weeks' gestation. At each visit, measurements of fetal head circumference (HC), biparietal diameter, occipitofrontal diameter, abdominal circumference (AC) and femur length (FL) were obtained blindly by dedicated research sonographers using standardized methods and identical ultrasound machines. Birth weight was measured within 12 h of delivery by dedicated research anthropometrists using standardized methods and identical electronic scales. Live babies without any congenital abnormality, who were born within 14 days of the last ultrasound scan, were selected for inclusion. As most births occurred at around 40 weeks' gestation, we constructed a bootstrap model selection and estimation procedure based on resampling of the complete dataset under an approximately uniform distribution of birth weight, thus enriching the sample size at extremes of fetal sizes, to achieve consistent estimates across the full range of fetal weight. We constructed reference centiles using second-degree fractional polynomial models. RESULTS: Of the overall population, 2404 babies were born within 14 days of the last ultrasound scan. Mean time between the last scan and birth was 7.7 (range, 0-14) days and was uniformly distributed. Birth weight was best estimated as a function of AC and HC (without FL) as log(EFW) = 5.084820 - 54.06633 × (AC/100)3 - 95.80076 × (AC/100)3 × log(AC/100) + 3.136370 × (HC/100), where EFW is in g and AC and HC are in cm. All other measures, gestational age, symphysis-fundus height, amniotic fluid indices and interactions between biometric measures and gestational age, were not retained in the selection process because they did not improve the prediction of EFW. Applying the formula to FGLS biometric data (n = 4231) enabled gestational age-specific EFW tables to be constructed. At term, the EFW centiles matched those of the INTERGROWTH-21st Newborn Size Standards but, at