Jessica Ellen Ringshaw

With the evolution of ultra-low-field MRI and the recognition of antenatal maternal anaemia as an important driver of altered neurodevelopment in toddlers and children, it is critical to determine whether these effects are detectable at ultra-low-field (64 mT) in infancy. The aim of this study was to assess the impact of antenatal maternal anaemia on infant brain structure across the first 2 years of life, using high-field (3 T) and ultra-low-field (64 mT) MRI. This neuroimaging substudy was embedded within Khula, an observational population-based birth cohort in South Africa. Pregnant women were enrolled antenatally and postnatally. Mother-child dyads (n = 394) were followed prospectively with a subsample attending neuroimaging at ∼3, 6, 12, 18 and 24 months of age. Anaemia was classified using World Health Organization thresholds, and neuroimaging data were processed using MiniMORPH. Linear mixed-effects models were used to investigate associations between antenatal maternal anaemia status and absolute regional infant brain volumes using high-field and ultra-low-field MRI. In repeated measures high-field (n = 195) and ultra-low-field (n = 341) infant neuroimaging subsamples, the prevalence of antenatal maternal anaemia was 28.24% (37/131) and 29.76% (61/205), respectively. Maternal anaemia in pregnancy was associated with altered child brain structure across both MRI systems, with group differences becoming detectable at ∼12 months. In the ultra-low-field subsample, infants born to anaemic mothers had 3.77% smaller intracranial volume (β = −0.24, P = 0.004) and 3.32% smaller putamen volumes (β = −0.18, P = 0.040) across the first 2 years of life. The interaction between antenatal maternal anaemia and age was significant for the caudate nucleus (β = −0.13, P = 0.038) and corpus callosum (β = −0.15, P = 0.007). Antenatal maternal anaemia was associated with 3.70% and 4.29% smaller caudate nucleus volumes at 18 and 24 months of age, respectively. Similarly, infants born to anaemic mothers had 4.39% smaller corpus callosum volumes by 12 months and 6.27% smaller corpus callosum volumes by 24 months. Postnatal child anaemia and antenatal maternal iron deficiency status were not associated with total or regional child brain volumes in the ultra-low-field subsample from this cohort. Maternal anaemia remained a robust predictor of volume differences in sensitivity analyses. This study is the first to demonstrate that the impact of maternal anaemia in pregnancy on child brain structure is detectable as early as infancy. The implications of this research are 2-fold: (i) informing the feasibility of ultra-low-field MRI in low- and middle-income countries and (ii) the timing and optimization of targeted recommendations for anaemia management in practice and policy.

Background: Children who are HIV-exposed but uninfected (HEU) are at increased risk of neurodevelopmental delays, yet neuroimmune pathways linking perinatal HIV exposure to school readiness remain unclear. Methods: In the Drakenstein Child Health Study, 268 children (94 HEU, 174 HIV-unexposed [HU]) underwent magnetic resonance spectroscopy in midline parietal grey and left parietal white matter regions at 6–7 years. Peripheral blood serum immune markers were measured in pregnancy and in children at 6 weeks, 2, 3, and 5 years. Linear mixed-effects models characterised child immune trajectories and linear regressions tested associations with creatine-referenced neurometabolite ratios and school readiness scores. Results: Mothers living with HIV had higher sCD14 and lower MMP-9, NGAL, and GM-CSF than mothers without HIV (p<0.05). Perinatal HIV exposure was associated with altered trajectories of child sCD14, GM-CSF, IL-1β, IL-5, IL-10, and YKL-40. At 6–7 years, children who were HEU had lower parietal grey matter glutamate ratios and lower left parietal white matter choline ratios. By school entry, immune–neurometabolite associations were predominantly driven by child serum markers; IL-8 emerged as a consistent correlate across developmental stages. Children who were HEU had lower language scores than HU peers. Left parietal white matter choline ratios were positively associated with language and overall school readiness in HU children, but not HEU. Conclusions: Perinatal HIV exposure was associated with alterations in immune development, neurometabolites reflecting both white matter maturation and neuronal health, and school readiness. Our findings highlight potential neuroimmune pathways contributing to neurodevelopmental risks in children who are HEU.

The availability of ultra‐low‐field (ULF) magnetic resonance imaging (MRI) has the potential to improve neuroimaging accessibility in low‐resource settings. However, the utility of ULF MRI in detecting child brain changes associated with anemia is unknown. The aim of this study was to assess the comparability of 3T high‐field (HF) and 64mT ULF volumes in infants for brain regions associated with antenatal maternal anemia. This neuroimaging substudy is nested within Khula South Africa, a population‐based birth cohort. Pregnant women were enrolled antenatally and postnatally, and mother–child dyads ( n = 394) were followed prospectively at approximately 3, 6, 12, and 18 months. A subgroup of infants was scanned on 3T and 64mT MRI systems across study visits and images were segmented using MiniMORPH. Correlations and concordance coefficients were used to cross‐validate HF and ULF infant brain volumes for the caudate nucleus, putamen, and corpus callosum. Seventy‐eight children (53.85% male) had paired HF (mean [SD] age = 9.64 [5.26] months) and ULF (mean [SD] age = 9.47 [5.32] months) datasets. Results indicated strong agreement between systems for intracranial volume (ICV; r = 0.96, ρ _ccc = 0.95) and brain regions of interest in anemia including the caudate nucleus ( r = 0.89, ρ _ccc = 0.86), putamen ( r = 0.97, ρ _ccc = 0.96) and corpus callosum ( r = 0.87, ρ _ccc = 0.79). This cross‐validation study demonstrates excellent correspondence between 3T and 64mT volumes for infant brain regions implicated in antenatal maternal anemia. Findings validate the use of ULF MRI for pediatric neuroimaging on anemia in Africa.

With the evolution of ultra-low-field MRI and the recognition of antenatal maternal anaemia as an important driver of altered neurodevelopment in toddlers and children, it is critical to determine whether these effects are detectable at 64mT in infancy. The aim of this study was to assess the impact of antenatal maternal anaemia on infant brain structure across the first two years of life, using conventional high-field (3T) and ultra-low-field (64mT) MRI. This neuroimaging sub-study was embedded within Khula, an observational population-based birth cohort in South Africa. Pregnant women were enrolled antenatally and postnatally. Mother-child dyads ( n =394) were followed prospectively with a subsample attending neuroimaging at approximately 3, 6, 12, 18, and 24 months of age. Anaemia was classified using WHO thresholds and neuroimaging data was processed using MiniMORPH. Linear mixed effects models were used to investigate associations between antenatal maternal anaemia status and absolute regional infant brain volumes using high-field and ultra-low-field MRI. In repeated measures high-field ( n =195) and ultra-low-field ( n =341) infant neuroimaging subsamples, the prevalence of antenatal maternal anaemia was 28.24% (37/131) and 29.76% (61/205), respectively. Maternal anaemia in pregnancy was associated with altered child brain structure across both MRI systems, with group differences becoming detectable at approximately 12 months. In the ultra-low-field subsample, infants born to anaemic mothers had 3.77% smaller ICV (β=-0.24, p =0.004) and 3.32% smaller putamen volumes (β=-0.18, p =0.04) across the first 2 years of life. The interaction between antenatal maternal anaemia and age was significant for the caudate nucleus (β=-0.13, p =0.038) and the corpus callosum (β=-0.13, p =0.037). Maternal anaemia in pregnancy was associated with 3.70% and 4.29% smaller caudate nucleus at 18 and 24 months of age, respectively. Similarly, infants born to anaemic mothers had 4.18% smaller corpus callosum volumes by 12 months and 7.10% smaller corpus callosum volumes by 24 months. Postnatal child anaemia and antenatal maternal iron deficiency status were not associated with total or regional child brain volumes in the ultra-low-field subsample from this cohort. Maternal anaemia remained a robust predictor of volume differences in sensitivity analyses. This study is the first to demonstrate that the impact of maternal anaemia in pregnancy on child brain structure is detectable as early as infancy. The implications of this research are two-fold; (1) informing the feasibility of ultra-low-field MRI for use in low- and middle-income countries, as well as (2) the timing and optimisation of targeted recommendations for anaemia management in both practice and policy.

Background The impact of in utero exposure to specific antiretroviral therapy (ART), particularly integrase strand transfer inhibitors, on early brain development remains poorly understood. We used magnetic resonance imaging (MRI) to compare brain structure in children who are HIV-exposed and uninfected (CHEU) with prenatal dolutegravir (DTG) versus efavirenz (EFV) exposure Methods DolPHIN-2 was a randomized trial of pregnant women initiating DTG-versus EFV-based ART in the third trimester. At 3-4 years of age, a subgroup of their children from the South African cohort, along with HIV-unexposed children (CHU), underwent T1-weighted MRI (DolPHIN-2 PLUS). Measurements of brain structure including volume, cortical thickness, and surface area were extracted using Freesurfer. Associations between ART /HIV exposure and child brain structure were examined using multiple linear regression. Results This analysis included 58 children (25 CHEU [13 DTG, 12 EFV] and 33 CHU, mean age 46.35 months, 51.7% male). Demographic characteristics were similar across groups. No significant differences in global or regional brain volumes, cortical thickness, or surface area were observed between DTG- and EFV-exposed children or between CHEU and CHU. Conclusion Among children exposed to ART in the third trimester, brain structural measures at 3–4 years were comparable between DTG and EFV exposure. CHEU also showed similar brain development to CHU. Further longitudinal studies with larger sample sizes are needed to assess the effects of specific ART in the context of new regimens and better maternal HIV disease control, on CHEU brain structure.

The scarcity of epidemiological data on anaemia in low- and middle-income countries, coupled with contrasting approaches to the assessment of iron status with inflammation, represent critical research gaps. This study characterised the prevalence and profile of iron deficiency anaemia, including adjustment for inflammation, in mothers and infants from South Africa. Mother-child dyads (n = 394) were recruited (2021–2022) for the Khula birth cohort in Cape Town. Haematological metrics, iron metrics, and inflammatory biomarkers were obtained from mothers antenatally and 3–6 months postnatally, and infants 3–18 months postnatally. The extent to which inflammation impacted iron deficiency was assessed using two methods; Method A: higher serum ferritin thresholds for classifying iron status in participants with inflammation (World Health Organisation), Method B: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anaemia (BRINDA) regression which corrects serum ferritin based on inflammatory biomarker concentrations. Prevalence of maternal anaemia was 34.74% (107/308) in pregnancy and 22.50% (54/240) in mothers at 3–6 months after childbirth. Of their infants, 46.82% (125/267) and 48.10% (136/283) were anaemic by 6–12 months and 12–18 months, respectively. Using Method A, the prevalence of maternal iron deficiency (regardless of anaemia), increased from 18.35% (20/109) to 55.04% (60/109) in pregnancy, and from 11.97% (28/234) to 46.58% (109/234) postnatally. Similarly, using Method B, maternal iron deficiency prevalence increased to 38.53% (42/109) in pregnancy, and 25.21% (59/234) postnatally. In infants at 12–18 months, the prevalence of iron deficiency increased from 19.79% (19/96) to 31.25% (30/96) and 32.29% (31/96) using Methods A and B, respectively. Approximately half of anaemia cases in mothers antenatally (50%; 20/40) and postnatally (45.10%; 23/51), and infants at 12–18 months (55.56%; 10/18), were attributable to iron deficiency. This is one of the first studies reporting the extent to which iron deficiency anaemia may be underestimated if inflammation is unaccounted for in South African mothers and infants.

Introduction: The availability of ultra- low-field (ULF) magnetic resonance imaging (MRI) has the potential to improve neuroimaging accessibility in low-resource settings. However, the utility of ULF MRI in detecting child brain changes associated with anemia is unknown. Aim: The aim of this study was to assess the comparability of 3T high-field (HF) and 64mT ULF volumes in infants for brain regions associated with antenatal maternal anemia. Method: This neuroimaging sub-study is nested within Khula South Africa, a population-based birth cohort. Pregnant women were enrolled antenatally and postnatally, and mother-child dyads ( n = 394) were followed prospectively at approximately 3, 6, 12 and 18 months. A sub-group of infants was scanned on 3T and 64mT MRI systems across study visits and images were segmented using MiniMORPH. Correlations and concordance coefficients were used to cross-validate HF and ULF infant brain volumes for the caudate nucleus, putamen, and corpus callosum. Results: 78 children (53.85% male) had paired HF ( Mean [ SD ] age = 9.64 [5.26] months) and ULF ( Mean [ SD ] age = 9.47 [5.32] months) datasets. Results indicated strong agreement between systems for intracranial volume (ICV; r = 0.96, ρ _ccc = 0.95), and brain regions of interest in anemia including the caudate ( r = 0.89, ρ _ccc = 0.86), putamen ( r = 0.97, ρ _ccc = 0.96), and corpus callosum ( r = 0.87, ρ _ccc = 0.79). Conclusion: This cross-validation study demonstrates excellent correspondence between 3T and 64mT volumes for infant brain regions implicated in antenatal maternal anemia. Findings validate the use of ULF MRI for paediatric neuroimaging on anemia in Africa. HIGHLIGHTS: This cross-validation study is the first to compare HF and ULF volume estimates for infant brain regions previously found to be associated with antenatal maternal anemia within the first two years of life. Key findings of this research demonstrate linear associations and strong agreement between HF and ULF volume estimates for the caudate nucleus, putamen, and corpus callosum in infants between 3-18 months of age. Improved correspondence between HF and ULF MRI was observed in older infants, particularly for basal ganglia structures. These novel findings validate the use of ULF MRI for paediatric neuroimaging work on antenatal maternal anemia and other prevalent health priorities in low- and middle-income countries. GRAPHICAL This cross-validation study assessed the comparability of high-field (3T) and ultra- low-field (64mT) volumes in infants for brain regions associated with antenatal maternal anemia. Key findings demonstrated strong agreement between HF and ULF volume estimates for the caudate nucleus, putamen, and corpus callosum in infants between 3-18 months of age.

Background: This study aimed to determine whether associations of antenatal maternal anaemia with smaller corpus callosum, caudate nucleus, and putamen volumes previously described in children at age 2–3 years persisted to age 6–7 years in the Drakenstein Child Health Study (DCHS). Methods: This neuroimaging sub-study was nested within the DCHS, a South African population-based birth cohort. Pregnant women were enrolled (2012–2015) and mother–child dyads were followed prospectively. A sub-group of children had magnetic resonance imaging at 6–7 years of age (2018–2022). Mothers had haemoglobin measurements during pregnancy and a proportion of children were tested postnatally. Maternal anaemia (haemoglobin < 11 g/dL) and child anaemia were classified using WHO and local guidelines. Linear modeling was used to investigate associations between antenatal maternal anaemia status, maternal haemoglobin concentrations, and regional child brain volumes. Models included potential confounders and were conducted with and without child anaemia to assess the relative roles of antenatal versus postnatal anaemia. Results: Overall, 157 children (Mean [SD] age of 75.54 [4.77] months; 84 [53.50%] male) were born to mothers with antenatal haemoglobin data. The prevalence of maternal anaemia during pregnancy was 31.85% (50/157). In adjusted models, maternal anaemia status was associated with smaller volumes of the total corpus callosum (adjusted percentage difference, − 6.77%; p = 0.003), left caudate nucleus (adjusted percentage difference, − 5.98%, p = 0.005), and right caudate nucleus (adjusted percentage difference, − 6.12%; p = 0.003). Continuous maternal haemoglobin was positively associated with total corpus callosum (β = 0.239 [CI 0.10 to 0.38]; p < 0.001) and caudate nucleus (β = 0.165 [CI 0.02 to 0.31]; p = 0.027) volumes. In a sub-group (n = 89) with child haemoglobin data (Mean [SD] age of 76.06 [4.84]), the prevalence of antenatal maternal anaemia and postnatal child anaemia was 38.20% (34/89) and 47.19% (42/89), respectively. There was no association between maternal and child anaemia (χ ² = 0.799; p = 0.372), and child anaemia did not contribute to regional brain volume differences associated with maternal anaemia. Conclusions: Associations between maternal anaemia and regional child brain volumes previously reported at 2–3 years of age were consistent and persisted to 6–7 years of age. Findings support the importance of optimising antenatal maternal health and reinforce these brain regions as a future research focus.

Objectives: The scarcity of epidemiological data on anaemia in low- and middle-income countries, coupled with poor characterisation of overlapping risk factors in high-risk settings and contrasting approaches to the assessment of iron status with inflammation, represent critical gaps to address. This study aimed to characterise the prevalence and profile of iron deficiency anaemia, including adjustment for inflammation, in pregnant and postpartum women, as well as infants from South Africa. Methods: Mother-child dyads ( n =394) were recruited (2021-2022) for the Khula birth cohort study in Cape Town, South Africa. Haematological metrics (haemoglobin, mean corpuscular volume [MCV]), iron metrics (serum ferritin and soluble transferrin receptor [sTfR]), and inflammatory biomarkers (highly sensitive C-Reactive Protein [ hs CRP]; Alpha-1 Acid Glycoprotein [AGP]) were obtained from mothers antenatally and postnatally, as well as from infants 3-18 months after birth. World Health Organisation (WHO) guidelines were used to classify anaemia and iron deficiency. The extent to which inflammation impacted iron deficiency was assessed using two methods: Method A: higher serum ferritin thresholds for classifying iron status in participants with inflammation (WHO), Method B: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anaemia (BRINDA) regression which corrects serum ferritin levels based on inflammatory biomarker concentrations. Results: Prevalence of anaemia was 34.74% (107/308) in pregnancy and 22.50% (54/240) in mothers at 3-6 months postpartum. Of their infants, 46.82% (125/267) and 48.10% (136/283) were anaemic at least once by 6-12 months and 12-18 months, respectively. When accounting for inflammation using Method A, the prevalence of maternal iron deficiency (regardless of anaemia), increased from 18.35% (20/109) to 55.04% (60/109) in pregnancy, and from 11.97% (28/234) to 46.58% (109/234) postnatally. Similarly, using Method B, the estimated prevalence of maternal iron deficiency increased to 38.53% (42/109) in pregnancy, and 25.21% (59/234) postnatally. In infants at 12-18 months, the prevalence of iron deficiency increased from 19.79% (19/96) to 31.25% (30/96) and 32.29% (31/96) using Methods A and B, respectively. Approximately half of anaemia cases in mothers antenatally (50%; 20/40) and postnatally (45.10%; 23/51), and infants at 12-18 months (55.56%; 10/18), were attributable to iron deficiency. However, there was little overlap in the estimated prevalence of microcytic anaemia (based on MCV) and iron deficiency anaemia (based on adjusted serum ferritin) in pregnant and postpartum mothers, as well as infants at 3-6 and 6-12 months. At these timepoints, microcytic anaemia underestimated the likely proportion of anaemia cases attributable to iron deficiency. Conclusion: This is one of the first studies to report the true prevalence of iron deficiency anaemia in South African mothers and infants, and the extent to which it may be underestimated if inflammation is not accounted for. Additionally, the results indicate that, while microcytic anaemia classification may be a valid proxy for iron deficiency anaemia in infants over 1 year of age, it seems less useful for pregnant and postpartum mothers and younger infants within the context of inflammation. Overall, the findings contribute to a global effort to understand the complex aetiology of iron deficiency anaemia, informing guidelines for optimised detection, prevention, and intervention in high-risk communities.

Social impairment in Autism Spectrum Disorder (ASD) has been linked to Theory of Mind (ToM) deficits. However, little research has investigated the relationship between ToM and moral decision-making in children with ASD. This study compared moral decision-making and ToM between aggregate-matched ASD and neurotypical boys (n = 38 per group; aged 6–12). In a third-party resource allocation task manipulating recipient merit, wealth, and health, neurotypical children allocated significantly more resources to the morally deserving recipient, suggesting equitable allocation. A comparatively larger portion of the ASD group allocated equally. ToM emerged as a predictor of moral decision-making. We suggest that ToM (cognitive empathy) deficits may underly atypical moral decision-making in ASD by limiting the integration of empathic arousal (affective empathy) with moral information.