A machine-learning exploration of the exposome from preconception in early childhood atopic eczema, rhinitis and wheeze development.

BACKGROUND: Most previous research on the environmental epidemiology of childhood atopic eczema, rhinitis and wheeze is limited in the scope of risk factors studied. Our study adopted a machine learning approach to explore the role of the exposome starting already in the preconception phase. METHODS: We performed a combined analysis of two multi-ethnic Asian birth cohorts, the Growing Up in Singapore Towards healthy Outcomes (GUSTO) and the Singapore PREconception Study of long Term maternal and child Outcomes (S-PRESTO) cohorts. Interviewer-administered questionnaires were used to collect information on demography, lifestyle and childhood atopic eczema, rhinitis and wheeze development. Data training was performed using XGBoost, genetic algorithm and logistic regression models, and the top variables with the highest importance were identified. Additive explanation values were identified and inputted into a final multiple logistic regression model. Generalised structural equation modelling with maternal and child blood micronutrients, metabolites and cytokines was performed to explain possible mechanisms. RESULTS: The final study population included 1151 mother-child pairs. Our findings suggest that these childhood diseases are likely programmed in utero by the preconception and pregnancy exposomes through inflammatory pathways. We identified preconception alcohol consumption and maternal depressive symptoms during pregnancy as key modifiable maternal environmental exposures that increased eczema and rhinitis risk. Our mechanistic model suggested that higher maternal blood neopterin and child blood dimethylglycine protected against early childhood wheeze. After birth, early infection was a key driver of atopic eczema and rhinitis development. CONCLUSION: Preconception and antenatal exposomes can programme atopic eczema, rhinitis and wheeze development in utero. Reducing maternal alcohol consumption during preconception and supporting maternal mental health during pregnancy may prevent atopic eczema and rhinitis by promoting an optimal antenatal environment. Our findings suggest a need to include preconception environmental exposures in future research to counter the earliest precursors of disease development in children.

Association of pain, analgesic, psychological, and socioeconomic factors with sub-acute pain after childbirth: A prospective cohort study.

STUDY OBJECTIVE: To determine if acute postpartum pain, psychological distress, socioeconomic factors, and labor analgesia were associated with sub-acute pain after childbirth (SAPC; pain starting after childbirth and lasting between four weeks to three months). DESIGN: Prospective cohort study, from pre-conception to post-partum three months. SETTING: Singapore's major public maternity institution. PATIENTS: We included women planning to conceive within a year. We excluded women who were pregnant, taking chemotherapy or psychotropic medications, had diabetes mellitus, received assisted fertility interventions or contraception, did not conceive after 12 months, with multiple pregnancies, or who developed obstetric complications. INTERVENTIONS: None. MEASUREMENTS: We investigated the relationship between average pain score during the three days after childbirth (primary exposure) and incidence of SAPC at postpartum three months (primary outcome). Secondarily, psychological distress at pre-conception (Beck Depression Inventory (BDI), Edinburgh Postnatal Depression Scale (EPDS), State-Trait Anxiety Inventory (STAI), Perceived Stress Scale (PSS), General Health Questionnaire-12 (GHQ-12), Life Experiences Survey (LES)) and second trimester of pregnancy (BDI, EPDS, STAI, PSS, Pregnancy Experience Scale (PES)) were assessed. Baseline maternal and socioeconomic characteristics, labor analgesia, maternal and neonatal outcomes were also collected accordingly. MAIN RESULTS: Of 317 women who met the study criteria, 30 (9.5%) developed SAPC. Higher average pain score during the three days after childbirth (adjusted odds ratio (aOR) 1.46, 95% CI 1.17 to 1.82, p = 0.001), use of meperidine for labor analgesia (aOR 4.23, 95% CI 1.03 to 17.43, p = 0.046), higher pre-conception GHQ-12 score (aOR 1.14, 95% CI 1.03 to 1.27, p = 0.013), and lack of employment with income during pregnancy (aOR 9.62, 95% CI 3.07 to 30.30, p < 0.001) were independently associated with SAPC, with area under the curve (AUC) of 0.837. CONCLUSIONS: Higher acute postpartum pain scores, use of meperidine for labor analgesia, poorer pre-conception general psychological health, and lack of employment with income during pregnancy are associated with SAPC.

Associations Between Maternal Distress During Early Life Periods and Offspring Respiratory Infections and Allergic Outcomes.

Background: Increasing evidence suggests that maternal distress is a risk factor for development of respiratory infections and allergic diseases in the offspring. We aim to evaluate the link between maternal distress during critical periods in early life, namely the preconception, pregnancy and postnatal periods, and development of respiratory infections and allergic diseases in the offspring from the Singapore PREconception Study of long Term maternal and child Outcomes (S-PRESTO) cohort. Methods: Maternal perceived distress was evaluated using validated questionnaires including Beck Depression Inventory-II (BDI-II) administered during three time periods: preconception (three months apart at four timepoints), pregnancy (during each trimester) and postnatal (3 and 6 months post-delivery). Child eczema, rhinitis and wheeze outcomes were evaluated using a modified ISAAC questionnaire at ages 3, 6, 12, and 18 months. Child allergic sensitization was determined by skin prick testing at 18 months. Results: Among 332 mother-child pairs studied, higher maternal distress during preconception and pregnancy increased the risks of wheeze development in the first 18 months; for example, preconception and pregnancy BDI-II scores ≥20 were associated with increased risks of wheeze by 18 months [adjusted risk ratios 3.2 (95%CI 1.1-9.4) and 2.5 (1.0-5.9), respectively]. Emotional and practical support from family during preconception decreased the risks of offspring wheeze. No associations were observed between maternal distress and offspring eczema, rhinitis and allergic sensitization. Conclusion: Maternal distress during critical early life periods was associated with offspring wheeze in the first 18 months of life. Supporting maternal mental health even before pregnancy could reduce the risk of offspring wheeze.

Disruption of Esrom and Ryk identifies the roof plate boundary as an intermediate target for commissure formation.

Growth cones are guided to their final destination by intermediate targets. Here, we identify intermediate targets and signaling components acting on zebrafish habenula commissural axons. Live imaging establishes that axons pause at the medial habenula before and after crossing the roof plate. esrom mutants axons fail to advance beyond the ipsilateral medial habenula. Tsc2 function is reduced in mutant axons, indicating cell autonomous defects in signaling. Consistent with signaling properties changing outside the roof plate, EphB is surface localized on axon segments within a zone demarcated by the medial habenula. wnt4a is expressed in the medial habenula and morpholino knockdown causes loss of the commissure. Electroporation of truncated Ryk causes axons to reenter the midline after reaching the contralateral habenula. These data identify Esrom as a mediator of growth cone navigation at an intermediate target and underscore the importance of midline boundaries as signaling centers for commissure formation.