Maternal major depression during early pregnancy is associated with impaired child executive functioning at 4.5 years of age.

BACKGROUND: Maternal depression is a serious condition that affects up to 1 in 7 pregnancies. Despite evidence linking maternal depression to pregnancy complications and adverse fetal outcomes, there remain large gaps in its identification and treatment. More work is needed to define the specific timing and severity of depression that most urgently requires intervention, where feasible, to protect maternal health and the developing fetus. OBJECTIVE: This study aimed to examine whether the timing and severity of maternal depression and/or anxiety during pregnancy affect child executive functioning at age 4.5 years. Executive functioning in the preschool years is a strong predictor of both school readiness and long-term quality of life. STUDY DESIGN: This longitudinal observational pregnancy cohort study included a sample of 323 mother-child dyads taking part in the Ontario Birth Study, an open pregnancy cohort in Toronto, Ontario, Canada. Maternal symptoms of depression and anxiety were assessed at 12 to 16 and 28 to 32 weeks of gestation and at the time of child testing at age 4.5 years using the 4-item Patient Health Questionnaire. Child executive functioning was measured during a home visit using standardized computerized administration of the Flanker test (a measure of attention) and the Dimensional Change Card Sort (a measure of cognitive flexibility). Stepwise linear regressions, controlling for possible confounding variables, were used to assess the predictive value of continuous measures of maternal depression and/or anxiety symptoms at each assessment time on the Flanker test and Dimensional Change Card Sort. Posthoc general linear models were used to assess whether maternal depression severity categories (no symptom, mild symptoms, or probable major depressive disorder) were helpful in identifying children at risk. RESULTS: Across all children, after controlling for potential confounds, greater maternal depressive symptoms at weeks 12 to 16 weeks of gestation predicted worse performance on both the Flanker test (ΔR2=0.058; P<.001) and the Dimensional Change Card Sort (ΔR2=0.017; P=.018). Posthoc general linear modeling further demonstrated that the children of mothers meeting the screening criteria for major depression in early pregnancy scored 11.3% lower on the Flanker test and 9.8% lower on the Dimensional Change Card Sort than the children of mothers without maternal depressive symptoms in early pregnancy. Mild depressive symptoms had no significant effect on executive function scores. There was no significant effect of anxiety symptoms or maternal antidepressant use in early pregnancy or pandemic conditions or maternal symptoms in later pregnancy or at the time of child testing on either the Flanker or Dimensional Change Card Sort results. CONCLUSION: This study demonstrated that fetal exposure to maternal major depression, but not milder forms of depression, at 12 to 16 weeks of gestation is associated with impaired executive functioning in the preschool years. Child executive functioning is crucial for school readiness and predicts long-term quality of life. This emphasizes an urgent need to improve the recognition and treatment of maternal major depression, particularly in early pregnancy, to limit its negative effects on the patient and on child cognitive development.

Navigating relationship dynamics, pregnancy and fatherhood in the Bukhali trial: a qualitative study with men in Soweto, South Africa.

BACKGROUND: South Africa has a complex range of historical, social, political, and economic factors that have shaped fatherhood. In the context of the Bukhali randomised controlled trial with young women in Soweto, South Africa, a qualitative study was conducted with the male partners of young women who had become pregnant during the trial. This exploratory study aimed to explore individual perceptions around relationship dynamics, their partner's pregnancy, and fatherhood of partners of young women in Soweto, South Africa. METHODS: Individual, in-depth interviews were conducted with male partners (fathers, n = 19, 25-46 years old) of Bukhali participants. A thematic approach was taken to the descriptive and exploratory process of analysis, and three final themes and subthemes were identified: (1) relationship dynamics (nature of relationship, relationship challenges); (2) pregnancy (feelings about the pregnancy, effect of the pregnancy on their relationship, providing support during pregnancy; and 3) fatherhood (view of fatherhood, roles of fathers, influences on views and motivation, challenges of fatherhood). RESULTS: While most male participants were in a committed ("serious") relationship with their female partner, less than half of them were cohabiting. Most reported that their partner's pregnancy was not planned, and shared mixed feelings about the pregnancy (e.g., happy, excited, shocked, nervous), although their views about fatherhood were overwhelmingly positive. Many were concerned about how they would economically provide for their child and partner, particularly those who were unemployed. Participants identified both general and specific ways in which they provided support for their partner, e.g., being present, co-attending antenatal check-ups, providing material resources. For many, the most challenging aspect of fatherhood was having to provide financially. They seemed to understand the level of responsibility expected of them as a father, and that their involvement and presence related to love for and connection with their child. Participants' responses indicated that there were some changes in the norms around fatherhood, suggesting that there is a possibility for a shift in the fatherhood narrative in their context. CONCLUSIONS: These findings suggest that the complex array of factors influencing fatherhood in South Africa continue to play out in this generation, although promising changes are evident.

Immune-privileged tissues formed from immunologically cloaked mouse embryonic stem cells survive long term in allogeneic hosts.

The immunogenicity of transplanted allogeneic cells and tissues is a major hurdle to the advancement of cell therapies. Here we show that the overexpression of eight immunomodulatory transgenes (Pdl1, Cd200, Cd47, H2-M3, Fasl, Serpinb9, Ccl21 and Mfge8) in mouse embryonic stem cells (mESCs) is sufficient to immunologically 'cloak' the cells as well as tissues derived from them, allowing their survival for months in outbred and allogeneic inbred recipients. Overexpression of the human orthologues of these genes in human ESCs abolished the activation of allogeneic human peripheral blood mononuclear cells and their inflammatory responses. Moreover, by using the previously reported FailSafe transgene system, which transcriptionally links a gene essential for cell division with an inducible and cell-proliferation-dependent kill switch, we generated cloaked tissues from mESCs that served as immune-privileged subcutaneous sites that protected uncloaked allogeneic and xenogeneic cells from rejection in immune-competent hosts. The combination of cloaking and FailSafe technologies may allow for the generation of safe and allogeneically accepted cell lines and off-the-shelf cell products.

Hepcidin across pregnancy and its correlation with maternal markers of iron and inflammation, maternal body weight outcomes, and offspring neurodevelopmental outcomes: a systematic review and meta-analysis.

OBJECTIVE: This study evaluated the correlation between maternal hepcidin and other biomarkers of iron status, markers of inflammation, and maternal body weight during pregnancy, as well as neurodevelopment in the offspring. DATA SOURCES: PubMed, Web of Science, Scopus, and Embase were searched from inception until March 2022. STUDY ELIGIBILITY CRITERIA: Studies conducted among pregnant women without apparent pregnancy complications were included. Eligible studies reported correlation coefficients between maternal hepcidin and any outcomes of maternal biomarkers of iron status or inflammatory load during pregnancy, prenatal maternal body weight, and offspring neurodevelopment. Studies without correlation data were eligible if they quantitatively reported volumes of both maternal hepcidin and any marker of iron status and/or inflammatory load during gestation. METHODS: Pooled correlation coefficients between maternal hepcidin and outcomes of interest were calculated using the Fisher r-to-Z transformation. Both fixed-effects and DerSimonian and Laird random-effects models were used to calculate pooled correlation coefficient. When meta-analysis was not feasible, results were descriptively synthesized. RESULTS: Forty-six studies with 6624 participants were eligible. Hepcidin was significantly correlated with hemoglobin in the third trimester (r=0.21; 95% confidence interval, 0.1-0.32); ferritin in the first (r=0.31; 95% confidence interval, 0.01-0.61) and third trimester (r=0.35; 95% confidence interval, 0.23-0.48); soluble transferrin receptor in the second trimester (r=-0.27; 95% confidence interval, -0.4 to -0.14); total iron-binding capacity in the second trimester (r=0.37; 95% confidence interval, 0.24-0.50); and serum iron in the third trimester (r=0.11; 95% confidence interval, 0.02-0.19). Hepcidin was significantly correlated with the inflammatory marker interleukin-6 in the third trimester (r=0.26; 95% confidence interval, 0.17-0.34) and C-reactive protein in the second (r=0.16; 95% confidence interval, 0.03-0.30) and third trimester (r=0.28; 95% confidence interval, 0.04-0.52). Four out of 5 studies reported weak-to-moderate positive correlation between hepcidin and body mass index. Hepcidin levels varied across body mass index categories. No single study reported the relationship between maternal hepcidin and neurodevelopment in offspring. CONCLUSION: Hepcidin weakly to moderately correlates with biomarkers of iron and inflammation in pregnancy.

Development, Implementation, and Process Evaluation of Bukhali: An Intervention from Preconception to Early Childhood.

The Healthy Life Trajectories Initiative, an international consortium developed in partnership with the World Health Organization, is addressing childhood obesity from a life-course perspective. It hypothesises that an integrated complex intervention from preconception, through pregnancy, infancy and early childhood, will reduce childhood adiposity and non-communicable disease risk, and improve child development. As part of the Healthy Life Trajectories Initiative in South Africa, the Bukhali randomised controlled trial is being conducted with 18-28-year-old women in Soweto, where young women face numerous challenges to their physical and mental health. The aims of this paper were to describe the intervention development process (including adaptations), intervention components, and process evaluation; and to highlight key lessons learned. Intervention materials have been developed according to the life-course stages: preconception (Bukhali), pregnancy (Bukhali Baby), infancy (Bukhali Nana; birth-2 years), and early childhood (Bukhali Mntwana, 2-5 years). The intervention is delivered by community health workers, and includes the provision of health literacy resources, multi-micronutrient supplementation, in-person health screening, services and referral, nutrition risk support, SMS-reminders and telephonic contacts to assist with behaviour change goals. A key adaption is the incorporation of principles of trauma-information care, given the mental health challenges faced by participants. The Bukhali process evaluation is focussing on context, implementation and mechanisms of impact, using a mixed methods approach. Although the completion of the trial is still a number of years away, the documentation of the intervention development process and process evaluation of the trial can provide lessons for the development, implementation, and evaluation of such complex life-course trials. Supplementary Information: The online version contains supplementary material available at 10.1007/s43477-023-00073-8.

Maternal acetaminophen use and cognitive development at 4 years: the Ontario Birth Study.

BACKGROUND: Studies have suggested a link between prenatal maternal acetaminophen use and adverse developmental outcomes in children. However, there exists a knowledge gap regarding overall cognitive development and use of acetaminophen, especially concerning the timing of use in pregnancy. This study aimed to characterize the relationship between maternal acetaminophen use and cognitive development at 4 years. METHODS: This analysis included data collected throughout pregnancy and delivery from women in the Ontario Birth Study prospective cohort from 2013 to 2019 and from the NIH Toolbox Early Childhood Cognition battery administered to 4-year-old children between 2018 and 2021 (n = 436). The exposure was maternal acetaminophen use and the primary outcome was a cognition composite score. The relationship between exposure and outcome was determined using Poisson regression with a robust error variance. RESULTS: We did not observe any association between maternal acetaminophen intake any time before or during pregnancy and low cognition composite score of offspring. The IRR of suboptimal overall cognition was 1.38 (0.78-2.45), 1.22 (0.67-2.22), 0.80 (0.44-1.47), and 1.56 (0.74-3.29) for maternal use of acetaminophen before, in early, late, or overall pregnancy, respectively. CONCLUSION: Current data do not provide evidence to support a relationship of maternal acetaminophen use during pregnancy with adverse cognitive effects at 4 years. IMPACT: Acetaminophen use during pregnancy may influence the risk of child neurocognitive disorders, but there is conflicting evidence of its relationship to sub-clinical measures of cognitive development such as executive function. The study design allowed us to examine the role of timing of acetaminophen use in its relationship with cognitive development, based on a validated and standardized tablet-administered instrument for children, instead of a teacher or parent report. We did not observe a clear relationship between maternal acetaminophen use at different timepoints during pregnancy and child cognitive development.

Adaptation of the gut holobiont to malnutrition during mouse pregnancy depends on the type of nutritional adversity.

Malnutrition can influence maternal physiology and programme offspring development. Yet, in pregnancy, little is known about how dietary challenges that influence maternal phenotype affect gut structure and function. Emerging evidence suggests that interactions between the environment, multidrug resistance (MDR) transporters and microbes may influence maternal adaptation to pregnancy and regulate fetoplacental development. We hypothesized that the gut holobiont (host and microbes) during pregnancy adapts differently to suboptimal maternal diets, evidenced by changes in the gut microenvironment, morphology, and expression of key protective MDR transporters during pregnancy. Mice were fed a control diet (CON) during pregnancy, or undernourished (UN) by 30% of control intake from gestational day (GD) 5.5-18.5, or fed 60% high fat diet (HF) for 8 weeks before and during pregnancy. At GD18.5, maternal small intestinal (SI) architecture (H&E), proliferation (Ki67), P-glycoprotein (P-gp - encoded by Abcb1a/b) and breast cancer resistance protein (BCRP/Abcg2) MDR transporter expression and levels of pro-inflammatory biomarkers were assessed. Circulating inflammatory biomarkers and maternal caecal microbiome composition (G3 PhyloChipTM) were measured. MDR transporter expression was also assessed in fetal gut. HF diet increased maternal SI crypt depth and proinflammatory load, and decreased SI expression of Abcb1a mRNA, whilst UN increased SI villi proliferation and Abcb1a, but decreased Abcg2, mRNA expression. There were significant associations between Abcb1a and Abcg2 mRNA levels with relative abundance of specific microbial taxa. Using a systems physiology approach we report that common nutritional adversities provoke adaptations in the pregnancy holobiont in mice, and reveal new mechanisms that could influence reproductive outcomes and fetal development.

Increasing maternal age predicts placental protein expression critical for fetal serotonin metabolism: Potential implications for neurodevelopmental research.

High fetal exposure to serotonin and increasing maternal age both contribute to the risk for neurodevelopmental disorders. While identifying covariates for a study of placental protein expression, we found a significant negative correlation between maternal age and the expression of monoamine oxidase A (MAOA), and a significant positive correlation between maternal age and the expression of the serotonin transporter SERT. MAOA and SERT play key roles in placental serotonin metabolism relevant to fetal neurodevelopment. These preliminary findings suggest that the effect of increasing maternal age on neurodevelopmental risk may be mediated in part by changes in placental protein expression relevant to fetal serotonin metabolism.

Protocol to derive human trophoblast stem cells directly from primed pluripotent stem cells.

Human trophoblast stem cells (hTSCs) are useful for studying human placenta development and diseases, but primed human pluripotent stem cells (hPSCs) routinely cultured in most laboratories do not support hTSC derivation. Here, we present a protocol to derive hTSCs directly from primed hPSCs. This approach, containing two strategies either with or without bone morphogenetic protein 4 (BMP4), provides a simple and accessible tool for deriving hTSCs to study placenta development and disease modeling without ethical limitations or reprogramming process. For complete details on the use and execution of this protocol, please refer to Wei et al. (2021).

Cross-sectional associations between mental health indicators and social vulnerability, with physical activity, sedentary behaviour and sleep in urban African young women.

BACKGROUND: Relationships between mental health and multiple health behaviours have not been explored in young South African women experiencing social constraints. The aim of this study was to identify associations between mental health indicators and risk factors with physical activity, sedentary behaviour, and sleep, amongst young women living in Soweto, a predominantly low-income, urban South African setting. METHODS: For this cross-sectional study, baseline measurements for participants (n = 1719, 18.0-25.9 years old) recruited for the Healthy Life Trajectories Initiative were used including: physical activity, sedentary behaviour (sitting, screen and television time), sleep (duration and quality), depression and anxiety indicators, emotional health, adverse childhood experiences, alcohol-use risk; social vulnerability, self-efficacy, and social support. RESULTS: Multiple regression analyses showed that depression (ß = 0.161, p < 0.001), anxiety (ß = 0.126, p = 0.001), adverse childhood experiences (ß = 0.076, p = 0.014), and alcohol-use risk (ß = 0.089, p = 0.002) were associated with poor quality sleep. Alcohol-use risk was associated with more screen time (ß = 0.105, p < 0.001) and television time (ß = 0.075, p < 0.016). Social vulnerability was associated with lower sitting time (ß = - 0.187, p < 0001) and screen time (ß = - 0.014, p < 0.001). Higher self-efficacy was associated with more moderate- to vigorous-intensity physical activity (ß = 0.07, p = 0.036), better-quality sleep (ß = - 0.069, p = 0.020) and less television time (ß = - 0.079, p = 0.012). Having no family support was associated with more sitting time (ß = 0.075, p = 0.022). Binomial logistic regression analyses supported these findings regarding sleep quality, with anxiety and depression risk doubling the risk of poor-quality sleep (OR = 2.425, p < 0.001, OR = 2.036, p = 0.003 respectively). CONCLUSIONS: These findings contribute to our understanding of how mental health indicators and risk factors can be barriers to health behaviours of young women in Soweto, and that self-efficacy and social support can be protective for certain of these behaviours for these women. Our results highlight the uniqueness of this setting regarding associations between mental health and behaviours associated with non-communicable diseases risk.

Human leukocyte antigen HLA-C, HLA-G, HLA-F, and HLA-E placental profiles are altered in early severe preeclampsia and preterm birth with chorioamnionitis.

BACKGROUND: The extravillous trophoblast expresses each of the nonclassical major histocompatibility complex class I antigens-human leukocyte antigens E, F, and G-and a single classical class I antigen, human leukocyte antigen C. We recently demonstrated dynamic expression patterns of human leukocyte antigens C, G, and F during early extravillous trophoblast invasion and placentation. OBJECTIVE: This study aimed to investigate the hypothesis that the immune inflammatory mediated complications of pregnancy such as early preeclampsia and preterm labor may show altered expression profiles of nonclassical human leukocyte antigens. STUDY DESIGN: Real-time quantitative polymerase chain reaction, western blot, and immunohistochemistry were performed on placental villous tissues and basal plate sections from term nonlaboring deliveries, preterm deliveries, and severe early-onset preeclampsia, both with and without small-for-gestational-age neonates. RESULTS: Human leukocyte antigen G is strongly and exclusively expressed by the extravillous trophoblast within the placental basal plate, and its levels increase in pregnancies complicated by severe early-onset preeclampsia with small-for-gestational-age neonates relative to those of healthy term controls. Human leukocyte antigen C shows a similar profile in the extravillous trophoblast of preeclamptic pregnancies, but significantly decreases in the villous placenta. Human leukocyte antigen F protein levels are decreased in both extravillous trophoblast and villous placenta of severe early-onset preeclamptic pregnancies, both with and without small-for-gestational-age neonates, compared with those found in term and preterm birth deliveries. Human leukocyte antigen E decreases in blood vessels in placentas from preeclamptic pregnancies relative to its levels in term and preterm birth deliveries. Placental levels of human leukocyte antigens F and C are increased in cases of preterm birth with chorioamnionitis relative to those of cases of idiopathic preterm birth. CONCLUSION: Dysregulation of placental human leukocyte antigen expression at the maternal-fetal interface may contribute to compromised maternal tolerance in preterm birth with chorioamnionitis and excessive maternal systemic inflammation associated with severe early-onset preeclampsia.

Defining the role of the hypothalamic-pituitary-adrenal axis in the relationship between fetal growth and adult cardiometabolic outcomes.

Animal and human data demonstrate independent relationships between fetal growth, hypothalamic-pituitary-adrenal axis function (HPA-A) and adult cardiometabolic outcomes. While the association between fetal growth and adult cardiometabolic outcomes is well-established, the role of the HPA-A in these relationships is unclear. This study aims to determine whether HPA-A function mediates or moderates this relationship. Approximately 2900 pregnant women were recruited between 1989-1991 in the Raine Study. Detailed anthropometric data was collected at birth (per cent optimal birthweight [POBW]). The Trier Social Stress Test was administered to the offspring (Generation 2; Gen2) at 18 years; HPA-A responses were determined (reactive responders [RR], anticipatory responders [AR] and non-responders [NR]). Cardiometabolic parameters (BMI, systolic BP [sBP] and LDL cholesterol) were measured at 20 years. Regression modelling demonstrated linear associations between POBW and BMI and sBP; quadratic associations were observed for LDL cholesterol. For every 10% increase in POBW, there was a 0.54 unit increase in BMI (standard error [SE] 0.15) and a 0.65 unit decrease in sBP (SE 0.34). The interaction between participant's fetal growth and HPA-A phenotype was strongest for sBP in young adulthood. Interactions for BMI and LDL-C were non-significant. Decomposition of the total effect revealed no causal evidence of mediation or moderation.

Maternal prenatal psychological distress and vitamin intake with children's neurocognitive development.

BACKGROUND: Maternal prenatal psychological distress (PPD) is increasingly linked to sub-optimal child neurodevelopment. Daily intake of prenatal vitamin during pre-conception and early pregnancy may ameliorate the effects of PPD on cognition in the offspring. METHODS: PPD was assessed in early (12-16 weeks) and late (28-32 weeks) gestation in the Ontario Birth Study. Prenatal vitamin supplement intake information was collected in early gestation. Child cognition at 4 years was assessed using the NIH Toolbox. Poisson regression was used to investigate associations between PPD and/or prenatal vitamin intake and child cognition. RESULTS: Four hundred and eighteen mother-child dyads were assessed. Moderate-severe PPD experienced during early gestation was associated with reduced cognition (adjusted incidence rate ratio (IRRadj) = 3.71, 95% confidence interval (CI): 1.57-8.77, P = 0.003). Daily intake of prenatal vitamins was not associated with cognition (IRRadj = 1.34, 95% CI: 0.73-2.46, P = 0.34). Upon stratification, the experience of mild-severe PPD with daily intake of prenatal vitamins was associated with higher incident rates of suboptimal cognition compared to children of women with daily prenatal vitamin intake without any episode of PPD (IRRadj = 2.88, 95% CI: 1.1-7.4). CONCLUSIONS: Moderate-severe PPD in early pregnancy is associated with poor cognition in children and daily intake of prenatal vitamin did not ameliorate this association. IMPACT: Our findings expand on existing literature by highlighting that exposure to prenatal psychological distress (PPD), in moderate-to-severe form, in the early stages of pregnancy, can have detrimental effects on the offspring's cognitive development at 4 years. Overall, prenatal vitamin intake did not ameliorate the effects of PPD. Early screening and treatment of prenatal maternal mental illness is crucial.

Evaluating depression and anxiety throughout pregnancy and after birth: impact of the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic presents unique social, economic, and psychological challenges for individuals globally. Thus, women who are pregnant face unprecedented mental health challenges. OBJECTIVE: We sought to determine the impact of the pandemic on perinatal depression and anxiety in a longitudinal pregnancy cohort. We hypothesized increased depression and anxiety scores in women during pregnancy and after birth in the pandemic at all time points. STUDY DESIGN: Participants were enrolled in the Ontario Birth Study, a pregnancy cohort embedded in clinical care at Mount Sinai Hospital, Toronto, Canada. Perinatal depression and anxiety were assessed using the 2-Item Patient Health Questionnaire and 2-Item Generalized Anxiety Disorder Questionnaire in early pregnancy, whereas the Edinburgh Postnatal Depression Scale and 2-Item Generalized Anxiety Disorder Questionnaire were used in late pregnancy and after birth. Logistic regression models were created to examine the association of the pandemic with clinically elevated mental health scores in the prepandemic group vs pandemic group while adjusting for covariates. RESULTS: A total of 1159 survey responses from 649 participants between March 1, 2019, and February 28, 2021, were used to conduct this study. Participants were assessed in early pregnancy (n=416), in late pregnancy (n=373), and after birth (n=370). Responses received on or before February 29, 2020, were considered the "prepandemic" responses, whereas responses after the aforementioned date were considered the "pandemic" responses. Mean rank scores of depression and anxiety were significantly higher in the pandemic group (P=.02 and P=.003, respectively) in the postpartum period. There was no significant association between pandemic time and antenatal scores. However, postnatally, mothers were 2.6 times more likely to score ≥13 on the Edinburgh Postnatal Depression Scale during the pandemic than before the pandemic (95% confidence interval, 1.2-5.7; P=.02). Adjustment for ethnicity and income strengthened this association as the odds ratio increased to 3.3 (95% confidence interval, 1.4-8.0; P=.007). CONCLUSION: Pandemic-associated increases in depression and anxiety scores were confined to the postpartum period, highlighting a need for increased screening and interventions for perinatal mood and anxiety disorders postnatally as this pandemic continues.

Prevalence and socio-structural determinants of tobacco exposure in young women: Data from the Healthy Trajectories Initiative (HeLTI) study in urban Soweto, South Africa.

BACKGROUND: Tobacco use is a major public health risk worldwide, which has increased on the African continent over the past 40 years. Socio-economic factors impact tobacco use and exposure, but little is known about the scope of this problem in young women living in an urban, historically disadvantaged township in contemporary South Africa. This study aimed to identify the prevalence of tobacco use in a cohort of young South African women using serum cotinine, and to assess the association between a number of socio-economic and social factors and tobacco use in this setting. METHODS: Secondary analysis was conducted on cross-sectional data from the Healthy Life Trajectories Initiative (HeLTI) study. Serum cotinine was measured and a cut-off of ≥ 10 ng/mL was classified as tobacco use. Household socio-economic, socio-demographic and health information were collected by an interviewer-administered questionnaire. RESULTS: Cotinine data was available for 1508 participants, of whom 29.2% (n = 441) had cotinine levels indicative of tobacco use. In regression analyses, moderate to severe socio-economic vulnerability (score 2-3 OR 1.66, p = 0.008; score ≥4: OR 1.63, p = 0.026) and multiparity (OR 1.74, p = 0.013) were associated with tobacco use. In addition, alcohol dependence (OR 3.07, p < 0.001) and drug use (OR 4.84, p < 0.001) were associated with tobacco use. CONCLUSION: Young women with multiple children, moderate to severe socio-economic vulnerability, and alcohol and drug use were identified as more likely to use tobacco, indicating the need for targeted anti-tobacco interventions to curb the impact of tobacco on the growing burden of noncommunicable diseases in this setting.

Maternal BMI, breastfeeding and perinatal factors that influence early childhood growth trajectories: a scoping review.

Obesity rates among children are rapidly rising internationally and have been linked to noncommunicable diseases in adulthood. Individual preventive strategies have not effectively reduced global obesity rates, leading to a gap in clinical services regarding the development of early perinatal interventions. The objective of this scoping review is to explore the relationship between maternal BMI and breastfeeding behaviors on child growth trajectories to determine their relevance in developing interventions aimed at preventing childhood obesity.The scoping review was guided and informed by the Arksey and O'Malley (2005) framework. A systematic search was performed in four databases. Studies included in the final review were collated and sorted into relevant themes. A systematic search yielded a total of 5831 records (MEDLINE: 1242, EMBASE: 2629, CINAHL: 820, PubMed: 1140). Results without duplicates (n = 4190) were screened based on relevancy of which 197 relevant-full-text articles were retrieved and assessed for eligibility resulting in 14 studies meeting the inclusion criteria. Data were extracted and charted for the studies and six themes were identified: (1) healthy behaviors, lifestyle, and social economic status; (2) parental anthropometrics and perinatal weight status; (3) genetics, epigenetics, and fetal programming; (4) early infant feeding; (5) infant growth trajectories; and (6) targeted prevention and interventions. Early life risk factors for child obesity are multifactorial and potentially modifiable. Several at-risk groups were identified who would benefit from early preventative interventions targeting the importance of healthy weight gain, exclusive breastfeeding to 6 months, and healthy lifestyle behaviors.

Maternal blood EBF1-based microRNA transcripts as biomarkers for detecting risk of spontaneous preterm birth: a nested case-control study.

OBJECTIVE: Both genetic variants and maternal blood mRNA levels of EBF1 gene have been linked to sPTB. Animal and human studies suggest that specific EBF1-based miRNAs are involved in various physiological and pathophysiological processes. However, to date, we did not find any reports of EBF1-based miRNAs or miRNA transcripts in relation to sPTB. We therefore aimed to examine whether maternal blood early B cell factor 1 (EBF1) gene-based microRNA (miRNA) transcripts can be used for detecting risk of spontaneous preterm birth (sPTB). METHODS: We conducted a nested case-control study within a Canadian cohort consisting of 1878 singleton pregnancies enrolled from May 2008 to December 2010 in Calgary, Alberta, Canada. We used a public gene expression dataset (GSE59491) derived from maternal blood in trimesters 2-3 that included women with sPTB (n = 51) and term births (n = 106) matched for maternal age, race/ethnicity, pre-pregnancy body mass index, smoking during pregnancy, and parity within the Canadian cohort. Two bioinformatics tools, miRWalk and STarMirDB, with different algorithms were applied to retrieve miRNA transcripts that putatively target the EBF1 gene (i.e. EBF1-based). Limma moderated t-tests were used to examine differentially expressed (DE) miRNA transcripts (sPTB vs term) within trimesters. Logistic regression models with miRNA transcript tertiles were applied to assess threshold associations between candidate miRNA transcripts' levels and sPTB. Receiver operating characteristic (ROC) analyses were used to identify the maximum Youden Index and its corresponding optimal sensitivity/specificity cut-point of EBF1-based miRNA transcripts for classifying sPTB, and to compare the classification performance of a linear combination (score) of miRNA transcripts with that of individual miRNA transcripts. A five-fold cross-validation was applied to examine the possible overfitting problem of the final ROC model. RESULTS: Four maternal blood EBF1-based miRNA transcripts (MIR4266, MIR1251, MIR601, MIR3612) in the 3rd trimester were significantly associated with sPTB. The odds ratios (95%CIs) for highest versus lowest tertile of the four miRNA transcripts were 3.01-5.25(1.21-13.14, p ≤ .018). The combined 4-miRNA transcripts' score significantly improved the classification of sPTB compared to individual miRNA transcripts (AUC increased from 0.65-0.69 to 0.82, p ≤ .0034) and showed a sensitivity for sPTB of 0.81 and a specificity of 0.72. The final ROC model of the EBF1-based 4 miRNA transcripts' score in cases and controls had no significant overfitting issue. CONCLUSIONS: Maternal blood EBF1-based miRNA transcripts may, along with other biomarkers, be useful in screening for sPTB risk in 3rd trimester. Our results also provide clues for further study of potential molecular mechanisms underlying the relationship between EBF1 gene and sPTB, e.g. connecting genetic variants, mRNA expression, and miRNA regulation.

The selective progesterone receptor modulator-promegestone-delays term parturition and prevents systemic inflammation-mediated preterm birth in mice.

BACKGROUND: Progesterone, acting via its nuclear receptors called progesterone receptors, promotes myometrial relaxation during pregnancy, and suspension of this activity triggers labor. We previously found that 20α-hydroxysteroid dehydrogenase causes a local withdrawal of progesterone in the term and preterm myometrium by converting the progesterone into an inactive form before it accesses the progesterone receptors. OBJECTIVE: We hypothesized that a selective progesterone receptor modulator called promegestone, which is not metabolized by 20α-hydroxysteroid dehydrogenase, would sustain progesterone receptor signaling and prevent/delay term labor and preterm labor in mice. STUDY DESIGN: In the term labor mouse model, promegestone (0.2 mg/dam) or a vehicle were administered subcutaneously in timed-pregnant CD-1 mice at gestational days 15, 16, and 17 (term gestational days, 19.5). In the inflammation preterm labor model, pregnant mice received promegestone or a vehicle on gestational days 15, 16, and 17, which was 24 hours before, immediately before, and 24 hours after systemic bacterial endotoxin (50 µg intraperitoneal; lipopolysaccharide group) or vehicle (saline) administration. The maternal and fetal tissues were collected on gestational day 16 6 hours after lipopolysaccharide±promegestone injection and at term gestational day 18.75. The protein levels of 10 cytokines were measured by multiplex immunoassay in maternal plasma and amniotic fluid. Myometrial, decidual, and placental messenger RNA levels of multiple cytokines and procontractile proteins were evaluated by real-time polymerase chain reaction and confirmed by immunoblotting. RESULTS: Promegestone prevented term labor and maintained mice pregnancy postterm >24 hours. The litter size and fetal weights were not different from the controls. Promegestone prevented systemic bacterial-endotoxin-induced preterm labor in 100% of the mice, blocked uterine contractions, significantly inhibited all systemic inflammation-induced myometrial cytokines, and partially inhibited decidual and placental inflammation. Promegestone did not prevent bacterial-endotoxin-induced fetal toxicity. CONCLUSION: Promegestone a selective progesterone receptor modulator that binds progesterone receptors with high affinity and is not metabolized by 20α-hydroxysteroid dehydrogenase could completely suppress term parturition and systemic bacterial-endotoxin-induced preterm birth in mice. We suggest that such selective progesterone receptor modulators may represent a potential therapeutic approach to the prevention of preterm labor in women at high risk of preterm birth.

Decidual Inflammation Drives Chemokine-Mediated Immune Infiltration Contributing to Term Labor.

Infiltration of maternal peripheral leukocytes into the uterine tissues is a critical event occurring before, during, and after term labor (TL). In this article, we investigate the contribution of uterine smooth muscle (myometrium) and pregnant endometrium (decidua) to the inflammatory process during human TL. We hypothesize that labor-related physiological inflammation is orchestrated by uterine-secreted cytokines, which dually activate the uterine vascular endothelium and maternal leukocytes to promote their adhesion and infiltration into the uterus. Using Luminex and ELISA assays, we examine a full range of cytokines (45 proteins) in media conditioned by primary decidual and myometrial cells from TL and term not in labor (TNL) women. The effect of conditioned media on the activation of human uterine microvascular endothelial cells was measured by qPCR and on peripheral leukocytes by flow cytometry. Transendothelial migration of calcein-labeled primary leukocytes toward media was assessed by fluorometry. Stromal decidual cells secrete significantly higher levels of multiple cytokines compared with myometrial cells (p < 0.05) and significantly more cytokines during TL than TNL. These cytokines activate uterine microvascular endothelial cells through the upregulation of cell adhesion molecule VCAM-1 and peripheral leukocytes by upregulation of CD11b. Furthermore, multiple cytokines secreted from the TL decidua and myometrium significantly increase migration of granulocytes, monocytes, and lymphocytes compared with TNL (p < 0.05), which was blocked by a broad-spectrum chemokine inhibitor (FX125L). These data reveal the critical role for decidual- and myometrial-secreted cytokines in the activation of inflammatory pathways leading to labor. We suggest that these pathways represent targets for therapeutic intervention during preterm labor.