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To improve outcomes of fetuses with spina bifida (SB), better knowledge is needed on the molecular drivers of SB and its comorbidities. We have recently shown in historical data that SB often associates with reduced fetal growth. We here use placental transcriptome sequencing and a novel nutrient-focused analysis pipeline to determine whether this association is due to placental dysfunction. We show that fetuses with SB have dysregulation in placental gene networks that play a role in nutrient transport, branching angiogenesis, and immune/inflammatory processes. Several of these networks are sensitive to multiple micronutrients, other than the well-known folic acid, and this deserves further investigation. An improved understanding of placental phenotype in fetuses with SB may help identify novel mechanisms associated with SB and its comorbidities, and reveal new targets to improve fetal outcomes in this population.

Background As mother-to-child transmission of HIV decreases, and the population of infants who are born HIV-exposed, but uninfected (HEU) continues to rise, there is a growing need to understand the development and health outcomes of infants who are HEU to ensure that they have the healthiest start to life. Methods In a prospective cohort pilot study at Kalafong Hospital, Pretoria, South Africa, we aimed to determine if we could recruit new mothers living with HIV on antiretrovirals (ART; n = 20) and not on ART (n = 20) and new mothers without HIV (n = 20) through our clinics to study the effects of HEU on growth and immune- and neurodevelopment in infants in early life, and test the hypothesis that infants who were HEU would have poorer health outcomes compared to infants who were HIV-unexposed, uninfected (HUU). We also undertook exploratory analyses to investigate relationships between the early nutritional environment, food insecurity and infant development. Infant growth, neurodevelopment (Guide for Monitoring Child Development [GMCD]) and levels of monocyte subsets (CD14, CD16 and CCR2 expression [flow cytometry]) were measured in infants at birth and 12 weeks (range 8–16 weeks). Results We recruited 33 women living with HIV on ART and 22 women living without HIV within 4 days of delivery from June to December 2016. Twenty-one women living with HIV and 10 without HIV returned for a follow-up appointment at 12 weeks postpartum. The high mobility of this population presented major challenges to participant retention. Preliminary analyses revealed lower head circumference and elevated CCR2+ (% and median fluorescence intensity) on monocytes at birth among infants who were HEU compared to HUU. Maternal reports of food insecurity were associated with lower maternal nutrient intakes at 12 weeks postpartum and increased risk of stunting at birth for infants who were HEU, but not infants who were HUU. Conclusions Our small feasibility pilot study suggests that HEU may adversely affect infant development, and further, infants who are HEU may be even more vulnerable to the programming effects of suboptimal nutrition in utero and postnatally. This pilot and preliminary analyses have been used to inform our research questions and protocol in our ongoing, full-scale study.

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The developing brain is especially vulnerable to infection and suboptimal nutrition during the pre- and early postnatal periods. Exposure to maternal human immunodeficiency virus (HIV) infection and antiretroviral therapies (ART) in utero and during breastfeeding can adversely influence infant (neuro) developmental trajectories. How early life nutrition may be optimised to improve neurodevelopmental outcomes for infants who are HIV-exposed has not been well characterised. We conducted an up-to-date evidence review and meta-analysis on the influence of HIV exposure in utero and during breastfeeding, and early life nutrition, on infant neurodevelopmental outcomes before age three. We report that exposure to maternal HIV infection may adversely influence expressive language development, in particular, and these effects may be detectable within the first three years of life. Further, while male infants may be especially vulnerable to HIV exposure, few studies overall reported sex-comparisons, and whether there are sex-dependent effects of HIV exposure on neurodevelopment remains a critical knowledge gap to fill. Lastly, early life nutrition interventions, including daily maternal multivitamin supplementation during the perinatal period, may improve neurodevelopmental outcomes for infants who are HIV-exposed. Our findings suggest that the early nutritional environment may be leveraged to improve early neurodevelopmental trajectories in infants who have been exposed to HIV in utero. A clear understanding of how this environment should be optimised is key for developing targeted nutrition interventions during critical developmental periods in order to mitigate adverse outcomes later in life and should be a priority of future research.

The Siyakhula study is an ongoing, observational cohort study in Pretoria, South Africa, that aims to understand how maternal HIV infection and perinatal environmental factors shape development and health in infants who are HIV-exposed (in utero and during breastfeeding) but remain uninfected themselves (HEU). The Siyakhula Collaborative Workshop, which took place at the Research Centre for Maternal, Fetal, Newborn & Child Health Care Strategies at Kalafong Hospital in Pretoria, South Africa on November 15-16, 2018, brought together a group of international health scientists, clinicians, and stakeholders, including women with lived experience, to build capacity for research and training on the impact of HIV infection on women's and infants' health across geographical and disciplinary boundaries. The workshop sought to summarise the state of knowledge on the effects of being HEU on infant development and health in the first two years of life, identify gaps in existing research on modifiable exposures that may be associated with poor infant development, and develop ideas for novel research and interventions to lessen or prevent adverse health outcomes in pregnant or breastfeeding people living with HIV. These proceedings summarise the pre-workshop consensus process that was used to identify priority areas to discuss during small-group breakout sessions, as well as the themes and key challenges that emerged from these discussions during the workshop.

Fetal and child development are shaped by early life exposures, including maternal health states, nutrition and educational and home environments. We aimed to determine if suboptimal pre-pregnancy maternal body mass index (BMI; underweight, overweight, obese) would associate with poorer cognitive outcomes in children, and whether early life nutritional, educational and home environments modify these relationships. Self-reported data were obtained from mother-infant dyads from the pan-Canadian prospective Maternal-Infant Research on Environmental Chemicals cohort. Relationships between potential risk factors (pre-pregnancy maternal BMI, breastfeeding practices and Home Observation Measurement of the Environment [HOME] score) and child cognitive development at age three (Weschler’s Preschool and Primary Scale of Intelligence, Third Edition scale and its subcategories) were each evaluated using analysis of variance, multivariable regression models and moderating analyses. Amongst the 528 mother−child dyads, increasing maternal pre-pregnancy BMI was negatively associated with scores for child full-scale IQ (β [95% CI]; −2.01 [−3.43, −0.59], p = 0.006), verbal composite (−1.93 [−3.33, −0.53], p = 0.007), and information scale (−0.41 [−0.70, −0.14], p = 0.003) scores. Higher maternal education level or HOME score attenuated the negative association between maternal pre-pregnancy BMI and child cognitive outcome by 30%–41% and 7%–22%, respectively, and accounted for approximately 5%–10% greater variation in male children’s cognitive scores compared to females. Maternal education and higher quality home environment buffer the negative effect of elevated maternal pre-pregnancy BMI on child cognitive outcomes. Findings suggest that relationships between maternal, social and environmental factors must be considered to reveal pathways that shape risk for, and resiliency against, suboptimal cognitive outcomes in early life.

The Developmental Origins of Health and Disease (DOHaD) framework aims to understand how early life exposures shape lifecycle health. To date, no comprehensive list of these exposures and their interactions has been developed, which limits our ability to predict trajectories of risk and resiliency in humans. To address this gap, we developed a model that uses text-mining, machine learning, and natural language processing approaches to automate search, data extraction, and content analysis from DOHaD-related research articles available in PubMed. Our first model captured 2469 articles, which were subsequently categorised into topics based on word frequencies within the titles and abstracts. A manual screening validated 848 of these as relevant, which were used to develop a revised model that finally captured 2098 articles that largely fell under the most prominently researched domains related to our specific DOHaD focus. The articles were clustered according to latent topic extraction, and 23 experts in the field independently labelled the perceived topics. Consensus analysis on this labelling yielded mostly from fair to substantial agreement, which demonstrates that automated models can be developed to successfully retrieve and classify research literature, as a first step to gather evidence related to DOHaD risk and resilience factors that influence later life human health.