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Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from −90% to +30%, were reported in many countries following early COVID-19 pandemic response measures (‘lockdowns’). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95–0.98, P value

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.

Context Preterm birth (PTB) and suboptimal prepregnancy body mass index (BMI) operate through inflammatory pathways to impair fetoplacental development. Placental efflux transporters mediate fetal protection and nutrition; however, few studies consider the effect of both PTB and BMI on fetal protection. We hypothesized that PTB would alter the expression of placental multidrug resistance (MDR) transporters and selected proinflammatory cytokines, and that maternal underweight and obesity would further impair placental phenotype. Objective To determine whether placental MDR transporters P-glycoprotein (P-gp, encoded by ABCB1) and breast cancer resistance protein (BCRP/ABCG2), and proinflammatory cytokine levels are altered by PTB and maternal BMI. Methods A cross-sectional study was conducted to assess the effect of PTB (with/without chorioamnionitis), or the effect of maternal prepregnancy BMI on placental MDR transporter and interleukin (IL)-6 and -8 expression in 60 preterm and 36 term pregnancies. Results ABCB1 expression was increased in preterm compared to term placentae (P = .04). P-gp (P = .008) and BCRP (P = .01) immunolabeling was increased among all preterm compared to term placentae, with P-gp expression further increased in preterm pregnancies with chorioamnionitis (PTC, P = .007). Placental IL-6 mRNA expression was decreased in PTC compared to term placentae (P = .0005) and PTC associated with the greatest proportion of anti-inflammatory medications administered during pregnancy. Maternal BMI group did not influence placental outcomes. Conclusion PTB and infection, but not prepregnancy BMI, alter placental expression of MDR transporters and IL-6. This may have implications for fetal exposure to xenobiotics that may be present in the maternal circulation in pregnancies complicated by PTB.

Introduction Neural tube defects (NTDs) are amongst the most common congenital anomalies and are associated with significant postnatal morbidity, but also with a higher incidence of low birthweight and fetal growth restriction. Despite the placenta being a critical determinant of fetal growth, placental development has not been extensively studied in fetuses with NTDs. Methods We performed a matched case-cohort study using data from the Collaborative Perinatal Project to assess the risk of placental pathology in pregnancies with an isolated fetal NTD (cases; n = 74) compared to those without any congenital anomalies (controls; n = 148). We hypothesised that cases would be at an increased risk of placental pathology compared to controls. Data were analysed using adjusted generalized linear and nominal logistic regression models. Results are presented as adjusted β or adjusted odds ratio (aOR; 95% confidence interval). Results Cases had lower placental weight (β = −22.2 g [-37.8 to −6.6]), surface area (β = −9.6 cm2 [-18.3 to −1.0]) and birth length z-scores (β = −0.4 [-0.7 to −0.001]) compared to controls. Cases were more likely to have a single umbilical artery (vs. two; 6 [8.1%] vs. 1 [0.7%]; aOR = 301 [52.6–1726]), placental hypermaturity (9 [12.2%] vs. 5 [3.4%]; aOR = 6.8 [3.1–14.7]), many (vs. few) Hofbauer cells (9 [12.2%] vs. 7 [4.7%]; aOR = 3.02 [1.2–7.3]), and stromal fibrosis (9 [12.2%] vs. 10 [6.8%]; aOR = 3.0 [1.4–6.3]) in placental terminal villi compared to controls. Conclusions Fetuses with isolated NTDs may be at increased risk of placental pathology, which could be contributing to poor fetal growth in these pregnancies and subsequent postnatal morbidities.

Iron deficiency (ID) and iron deficiency with anaemia (IDA) are serious global health problems that disproportionately affect women aged 15-49 years. Although food fortification is one of the most effective and sustainable ways to combat nutritional deficiencies, iron remains one of the most difficult micronutrients to fortify, given its tendency to react strongly with food constituents. Therefore, it is important to assess the sensory properties of foods fortified with iron to determine the acceptability and palatability in target populations. We aimed to determine the palatability and acceptability of a novel iron and zinc enriched powder fortified in tap water by women of reproductive age. A 9-point hedonic scale was used to evaluate the colour, odour, and taste properties of samples containing different amounts of the mineral-enriched powder compared to placebo. We found significant differences between samples reconstituted at 1g/L, 2g/L, and 3g/L for sensory properties, including overall taste. Participants were more willing to drink the mineral-enriched powder when prepared at the lowest concentration (1g/L) compared to higher concentrations. Our results provide important insight on sensory qualities of a novel mineral-enriched powder for at-home fortification, and indicate consumer acceptability in women of reproductive age, a key group at risk for ID/IDA. If found to improve iron status, novel treatments like this product will contribute to global efforts to develop safe, acceptable, and sustainable interventions for ID and IDA.

Marina White,1 Ute D Feucht,2– 4 Louise de Villiers du Toit,5 Theresa Rossouw,3– 5 Kristin L Connor1 1Health Sciences, Carleton University, Ottawa, Ontario, Canada; 2Paediatrics, University of Pretoria, Pretoria, Gauteng, South Africa; 3Research Centre for Maternal, Fetal, Newborn & Child Health Care Strategies, University of Pretoria, Pretoria, Gauteng, South Africa; 4Maternal and Infant Health Care Strategies Unit, South African Medical Council, Pretoria, Gauteng, South Africa; 5Department of Immunology, University of Pretoria, Pretoria, Gauteng, South AfricaCorrespondence: Kristin L ConnorDepartment of Health Sciences, Carleton University, Ottawa, Ontario, K1S5B6, CanadaEmail kristin.connor@carleton.caUte D FeuchtResearch Centre for Maternal, Fetal, Newborn & Child Health Care Strategies, University of Pretoria, Pretoria, Gauteng Province, 0002, South AfricaEmail ute.feucht@up.ac.zaAbstract: 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.Keywords: HIV, PMTCT, breastfeeding, growth, neurodevelopment, immune

Neural tube defects (NTDs) remain among the most common congenital anomalies. Contributing risk factors include genetics and nutrient deficiencies, however, a comprehensive assessment of nutrient-gene interactions in NTDs is lacking. We applied a nutrient-focused gene expression analysis pipeline to identify nutrient-sensitive gene regulatory networks in amniocyte gene expression data (GSE4182) from fetuses with NTDs (cases; n=3) and fetuses with no congenital anomalies (controls; n=5). Differentially expressed genes (DEGs) were screened for having nutrient cofactors. Nutrient-dependent transcriptional regulators (TRs) that regulated DEGs, and nutrient-sensitive miRNAs with a previous link to NTDs, were identified. Of the 880 DEGs in cases, 10% had at least one nutrient cofactor. DEG regulatory network analysis revealed that 39% and 52% of DEGs in cases were regulated by 22 nutrient-sensitive miRNAs and 10 nutrient-dependent TRs, respectively. Zinc- and B vitamin-dependent gene regulatory networks (Zinc: 10 TRs targeting 50.6% of DEGs; B vitamins: 4 TRs targeting 37.7% of DEGs, 9 miRNAs targeting 17.6% of DEGs) were dysregulated in cases. We identified novel, nutrient-sensitive gene regulatory networks not previously linked to NTDs, which may indicate new targets to explore for NTD prevention or to optimise fetal development.

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.

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 (HE), 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 PhyloChip

Maternal underweight and obesity are prevalent conditions, associated with chronic, low-grade inflammation, poor fetal development, and long-term adverse outcomes for the child. The placenta senses and adapts to the pregnancy environment in an effort to support optimal fetal development. However, the mechanisms driving these adaptations, and the resulting placental phenotypes, are poorly understood. We hypothesised that maternal underweight and obesity would be associated with increased prevalence of placental pathologies in term and preterm pregnancies. Data from 12,154 pregnancies were obtained from the Collaborative Perinatal Project, a prospective cohort study conducted from 1959 to 1974. Macro- and microscopic placental pathologies were analysed across maternal prepregnancy body mass index (BMI) to assess differences in the presence of pathologies among underweight, overweight, and obese BMI groups compared to normal weight reference BMI at term and preterm. Placental pathologies were also assessed across fetal sex. Pregnancies complicated by maternal obesity had placentae with increased fetal inflammation at preterm, and increased inflammation of maternal gestational tissues at term. In term pregnancies, increasing maternal BMI associated with increased maternal vascular malperfusion (MVM), odds of an appropriately mature placenta for gestational age, and placental weight, and decreased placental efficiency. Male placentae, independent of maternal BMI, had increased inflammation, MVM, and placental efficiency than female placentae, particularly at term. Maternal underweight and obesity are not inert conditions for the placenta, and the histomorphological changes driven by suboptimal maternal BMI may serve as indicators of adversities experienced in utero and potential predictors of future health trajectories.

The placenta undergoes morphological and functional adaptions to adverse exposures during pregnancy. The effects of suboptimal maternal body mass index (BMI), preterm birth, and infection on placental histopathological phenotypes remain unclear, despite the association between these conditions and poor offspring outcomes. We hypothesized that suboptimal maternal prepregnancy BMI and preterm birth (with and without infection) would associate with altered placental maturity and morphometry, and that altered placental maturity would associate with poor birth outcomes. Clinical data and human placentae were collected from 96 pregnancies where mothers were underweight, normal weight, overweight, or obese, without other major complications. Placental histopathological characteristics were scored with an anatomical pathologist. Associations between maternal BMI, placental pathology (immaturity and hypermaturity), placental morphometry, and infant outcomes were investigated at term and preterm, with and without infection. Fetal vascular endothelium volumetric proportion was decreased, whereas syncytial knot volumetric proportion was increased, in placentae from preterm pregnancies with chorioamnionitis compared to term placentae. At term and preterm, pregnancies with overweight and obesity had a high percentage increase in proportion of immature placentae compared to normal weight. Placental maturity did not associate with infant birth outcomes. We observed placental hypermaturity and altered placental morphometry among preterm pregnancies with chorioamnionitis, suggestive of altered placental development, which may inform about pregnancies susceptible to preterm birth and infection. Our data increase our understanding of how common metabolic exposures and preterm birth, in the absence of other comorbidities or perinatal events, potentially contribute to poor pregnancy outcomes and the programming of offspring development.

The yolk sac (YS) is the oldest of the extraembryonic membranes in vertebrates. Considered a transitory structure in the human species, the importance of the YS for a successful pregnancy is often overlooked. Due to the general inaccessibility of healthy human YS tissue for research, the use of experimental animal models is of great value. In order to better understand whether the mouse could be used as a translational model for the study of the human YS under normal and pathological conditions, this review comprehensively describes key developmental aspects of the human and mouse YS, detailing their development and function. YS major similarities in both species comprise the following: (1) histological composition (both being composed of endoderm, mesoderm, and mesothelium layers); (2) endoderm endocytosis, synthesis, secretion, and transport capabilities; and (3) mesoderm onset of haematopoiesis and angiogenesis. Examples of main dissimilarities include (1) persistence across pregnancy (i.e. early pregnancy in humans vs term pregnancy in mice); (2) the existence of a secondary YS in humans; (3) the presence of proliferative primordial germ cells (PGCs) in the human versus their absence in mice; and (4) eversion of histological layers in the mouse. Although these differences should be considered when interpreting data from mouse-based studies, the overall morphofunctional similarities in the YS between these species indicate that the mouse can be potentially used as a translational model for the study of the human YS.

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 hypothesised 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 eight 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.

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.

ContextPreterm birth (PTB) and suboptimal prepregnancy body mass index (BMI) operate through inflammatory pathways to impair fetoplacental development. Placental efflux transporters mediate fetal protection and nutrition, however few studies consider the effect of both PTB and BMI on fetal protection. We hypothesized that PTB would alter the expression of placental multidrug resistance (MDR) transporters and selected pro-inflammatory cytokines, and that maternal underweight and obesity would further impair placental phenotype.ObjectiveTo determine whether placental MDR transporters P-glycoprotein (P-gp, encoded by ABCB1) and breast cancer resistance protein (BCRP/ABCG2), and pro-inflammatory cytokine levels are altered by PTB and maternal BMI.Design and OutcomesA cross-sectional study was conducted to assess the effect of PTB (+/- chorioamnionitis), or the effect of maternal prepregnancy BMI on placental MDR transporter and interleukin [IL]-6 and 8 expression in 60 preterm and 36 term pregnancies.ResultsABCB1 expression was increased in preterm compared to term placentae (p=0.04). P-gp (p=0.008) and BCRP (p=0.01) immunolabeling was increased among all preterm compared to term placentae, with P-gp expression further increased in preterm pregnancies with chorioamnionitis (PTC, p=0.007). Placental IL-6 mRNA expression was decreased in PTC compared to term placentae (p=0.0005), and PTC was associated with the greatest proportion of anti-inflammatory medications administered during pregnancy. Maternal BMI group did not influence placental outcomes.ConclusionsPTB and infection, but not prepregnancy BMI, alter placental expression of MDR transporters and IL-6. This may have implications for fetal exposure to xenobiotics that may be present in the maternal circulation in pregnancies complicated by PTB.

Assisted reproductive technologies (ART) may increase risk for abnormal placental development, preterm delivery and low birthweight. We investigated placental morphology, transporter expression and paired maternal/umbilical fasting blood nutrient levels in human term pregnancies conceived naturally (n = 10) or by intracytoplasmic sperm injection (ICSI, n = 11). Maternal and umbilical vein blood from singleton term (&gt, 37 weeks) C-section pregnancies were assessed for levels of free amino acids, glucose, free fatty acids (FFA), cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), very low-density lipoprotein (VLDL) and triglycerides. We quantified placental expression of GLUT1 (glucose), SNAT2 (amino acids), P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) (drug) transporters, and placental morphology and pathology. Following ICSI, placental SNAT2 protein expression was downregulated and umbilical cord blood levels of citrulline were increased, while FFA levels were decreased at term (p &lt, 0.05). Placental proliferation and apoptotic rates were increased in ICSI placentae (p &lt, 0.05). No changes in maternal blood nutrient levels, placental GLUT1, P-gp and BCRP expression, or placental histopathology were observed. In term pregnancies, ICSI impairs placental SNAT2 transporter expression and cell turnover, and alters umbilical vein levels of specific nutrients without changing placental morphology. These may represent mechanisms through which ICSI impacts pregnancy outcomes and programs disease risk trajectories in offspring across the life course.

IntroductionMaternal underweight and obesity are prevalent conditions, associated with chronic, low-grade inflammation, poor fetal development, and long-term adverse outcomes for the child. The placenta senses and adapts to the pregnancy environment in an effort to support optimal fetal development. However, the mechanisms driving these adaptations, and the resulting placental phenotypes, are poorly understood. We hypothesised that maternal underweight and obesity would be associated with increased prevalence of placental pathologies in term and preterm pregnancies.MethodsData from 12,154 pregnancies were obtained from the Collaborative Perinatal Project, a prospective cohort study conducted from 1959 to 1974. Macro and microscopic placental pathologies were analysed across maternal prepregnancy body mass index (BMI) to assess differences in the presence of pathologies among underweight, overweight, and obese BMI groups compared to normal weight reference BMI at term and preterm. Placental pathologies were also assessed across fetal sex.ResultsPregnancies complicated by obesity had placentae with increased fetal inflammation at preterm, and increased inflammation of maternal gestational tissues at term. In term pregnancies, increasing maternal BMI associated with increased maternal vascular malperfusion (MVM), odds of an appropriately mature placenta for gestational age, and placental weight, and decreased placental efficiency. Male placentae, independent of maternal BMI, had increased inflammation, MVM, and placental efficiency than female placentae, particularly at term.DiscussionMaternal underweight and obesity are not inert conditions for the placenta, and the histomorphological changes driven by suboptimal maternal BMI may serve as indicators of adversities experienced in utero and potential predictors of future health trajectories.

ObjectiveTo compare placental pathology and fetal growth in pregnancies with an isolated fetal neural tube defect (NTD; cases) to those without congenital anomalies (controls). We hypothesised that cases would be at an increased risk of placental pathology and poorer anthropometric outcomes at birth compared to controlsMethodsWe performed a matched case-cohort study using data from the Collaborative Perinatal Project. Cases (n=74) and controls (n=148) were matched (1:2 ratio) for maternal pre-pregnancy BMI, maternal race, infant sex, gestational age at birth and study site. Primary outcomes were placental characteristics (weight and size measurements, pathology). Secondary outcomes were infant birth outcomes. Subgroup analysis was done by type of NTD (spina bifida, anencephaly or encephalocele), infant sex, and preterm/term delivery. Data were analysed using adjusted generalized linear and nominal logistic regression models. Results are presented as adjusted β or adjusted odds ratio (aOR; 95% confidence interval).ResultsCases had lower placental weight (β=-22.2 g [-37.8 – −6.6]), surface area (β=-9.6 cm2 [-18.3 – −1.0]) and birth length z-scores (β=-0.4 [-0.7 – −0.001]) compared to controls. Cases were more likely to have a single umbilical artery (vs. two; 6 [8.1%] vs. 1 [0.7%]; aOR=301 [52.6 – 1726]), overall placental hypermaturity (9 [12.2%] vs. 5 [3.4%]; aOR=6.8 [3.1 – 14.7]), and many (vs. few) Hofbauer cells (9 [12.2%] vs. 7 [4.7%]; aOR=3.02 [1.2 – 7.3]), stromal fibrosis (9 [12.2%] vs. 10 [6.8%]; aOR=3.0 [1.4 – 6.3]) and pathological edema (11 [14.9%] vs. 12 [8.1%]; aOR=3.04 [1.4 – 6.7]) in placental terminal villi compared to controls. Placental pathology varied across NTD subtypes, infant sex, and preterms vs. term pregnancies.ConclusionsFetuses with isolated NTDs may be at increased risk of placental pathology, which could be contributing to poor fetal growth in these pregnancies and subsequent postnatal morbidities.

Exposome research aims to comprehensively understand the multiple environmental exposures that influence human health. To date, much of exposome science has focused on environmental chemical exposures and does not take a lifecourse approach. The rising prevalence of obesity, and the limited success in its prevention points to the need for a better understanding of the diverse exposures that associate with, or protect against, this condition, and the mechanisms driving its pathogenesis. The objectives of this review were to 1. evaluate the evidence on the maternal metabolic exposome in the programming of offspring growth/obesity and 2. identify and discuss the mechanisms underlying the programming of obesity. A systematic review was conducted following PRISMA guidelines to capture articles that investigated early life metabolic exposures and offspring weight and/or obesity outcomes. Scientific databases were searched using pre-determined indexed search terms, and risk of bias assessments were conducted to determine study quality. A final total of 76 articles were obtained and extracted data from human and animal studies were visualised using GOfER diagrams. Multiple early life exposures, including maternal obesity, diabetes and adverse nutrition, increase the risk of high weight at birth and postnatally, and excess adipose accumulation in human and animal offspring. The main mechanisms through which the metabolic exposome programmes offspring growth and obesity risk include epigenetic modifications, altered placental function, altered composition of the gut microbiome and breast milk, and metabolic inflammation, with downstream effects on development of the central appetite system, adipose tissues and liver. Understanding early life risks and protectors, and the mechanisms through which the exposome modifies health trajectories, is critical for developing and applying early interventions to prevent offspring obesity later in life.

Probiotic and prebiotic products are increasingly popular due to their potential health benefits, including in pregnancy where probiotic supplementation has been associated with prevention of gestational diabetes and mastitis. The incidence of adverse effects in pregnant people and their infants associated with probiotic, prebiotic and/or synbiotic product intake, however, remains unclear. The objectives of this study were to evaluate the evidence on adverse effects of maternal probiotic, prebiotic and/or synbiotic supplementation before and during pregnancy and lactation and interpret the findings to help inform clinical decision-making and care of pre-pregnant, pregnant and lactating people. A systematic review was conducted following PRISMA guidelines. Scientific databases were searched using pre-determined terms, and risk of bias assessments were conducted to determine study quality. Inclusion criteria were English language studies, human studies, access to full-text, and probiotic/prebiotic/synbiotic supplementation to the mother and not the infant. 11/70 eligible studies reported adverse effects and were eligible for inclusion in quantitative analysis, and data were visualised in a GOfER diagram. Probiotic and prebiotic products are safe for use during pregnancy and lactation. Only one study reported increased risk of vaginal discharge and changes in stool consistence (Relative Risk [95% CI]: 3.67 [1.04, 12.2]) when administering Lactobacillus rhamnosus and L. reuteri. Adverse effects associated with probiotic and prebiotic use do not pose any serious health concerns to mother or infant. Our findings and knowledge translation visualisations provide healthcare professionals and consumers with information to make evidence-informed decisions about the use of pre- and probiotics.

Preterm birth is the leading cause of infant death worldwide, but the causes of preterm birth are largely unknown. During the early COVID-19 lockdowns, dramatic reductions in preterm birth were reported; however, these trends may be offset by increases in stillbirth rates. It is important to study these trends globally as the pandemic continues, and to understand the underlying cause(s). Lockdowns have dramatically impacted maternal workload, access to healthcare, hygiene practices, and air pollution - all of which could impact perinatal outcomes and might affect pregnant women differently in different regions of the world. In the international Perinatal Outcomes in the Pandemic (iPOP) Study, we will seize the unique opportunity offered by the COVID-19 pandemic to answer urgent questions about perinatal health. In the first two study phases, we will use population-based aggregate data and standardized outcome definitions to: 1) Determine rates of preterm birth, low birth weight, and stillbirth and describe changes during lockdowns; and assess if these changes are consistent globally, or differ by region and income setting, 2) Determine if the magnitude of changes in adverse perinatal outcomes during lockdown are modified by regional differences in COVID-19 infection rates, lockdown stringency, adherence to lockdown measures, air quality, or other social and economic markers, obtained from publicly available datasets. We will undertake an interrupted time series analysis covering births from January 2015 through July 2020. The iPOP Study will involve at least 121 researchers in 37 countries, including obstetricians, neonatologists, epidemiologists, public health researchers, environmental scientists, and policymakers. We will leverage the most disruptive and widespread “natural experiment” of our lifetime to make rapid discoveries about preterm birth. Whether the COVID-19 pandemic is worsening or unexpectedly improving perinatal outcomes, our research will provide critical new information to shape prenatal care strategies throughout (and well beyond) the pandemic.

The developing brain is especially vulnerable to infection and suboptimal nutrition during the pre- and early postnatal periods. Exposure to maternal 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/ART-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/ART 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/ART 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 outcome later in life, and should be a priority of future research.

The Developmental Origins of Health and Disease (DOHaD) framework aims to understand how environmental exposures in early life shape lifecycle health. Our understanding and the ability to prevent poor health outcomes and enrich for resiliency remain limited, in part, because exposure–outcome relationships are complex and poorly defined. We, therefore, aimed to determine the major DOHaD risk and resilience factors. A systematic approach with a 3-level screening process was used to conduct our Rapid Evidence Review following the established guidelines. Scientific databases using DOHaD-related keywords were searched to capture articles between January 1, 2009 and April 19, 2019. A final total of 56 systematic reviews/meta-analyses were obtained. Studies were categorized into domains based on primary exposures and outcomes investigated. Primary summary statistics and extracted data from the studies are presented in Graphical Overview for Evidence Reviews diagrams. There was substantial heterogeneity within and between studies. While global trends showed an increase in DOHaD publications over the last decade, the majority of data reported were from high-income countries. Articles were categorized under six exposure domains: Early Life Nutrition, Maternal/Paternal Health, Maternal/Paternal Psychological Exposure, Toxicants/Environment, Social Determinants, and Others. Studies examining social determinants of health and paternal influences were underrepresented. Only 23% of the articles explored resiliency factors. We synthesized major evidence on relationships between early life exposures and developmental and health outcomes, identifying risk and resiliency factors that influence later life health. Our findings provide insight into important trends and gaps in knowledge within many exposures and outcome domains.

Pre-eclampsia is associated with an increased risk of future cardiovascular disease. Maladaptive placentation or malperfusion, as well as predisposing cardiovascular or metabolic risk for endothelial dysfunction, contribute to the systemic inflammatory response that establishes the origins of the disease. The purpose of this study was to investigate the relationship between placental size and cardiovascular risk when assessed at six months postpartum in women who experienced pre-eclampsia.Maternal clinical and biochemical cardiovascular risk factors were used to categorize preeclamptic women into high vs. low lifetime cardiovascular disease risk profiles at six months postpartum. A multivariable logistic regression model was then used to identify the association between placental weight to birth weight ratio and high lifetime cardiovascular disease risk, adjusting for maternal age, pre-pregnancy BMI, and severity of pre-eclampsia. A p-value of 0.05 was deemed statistically significant.186/216 women with pre-eclampsia who attended the Maternal Health Clinic met inclusion criteria. No significant differences were observed for placental morphometric measurements between women who screened as having a high vs. low lifetime risk profile for cardiovascular disease at six months postpartum. However, using multivariable modelling that controlled for maternal age, pre-pregnancy body mass index, gestational age at delivery, and severity of pre-eclampsia, a low placenta to birth weight ratio (15%) was associated with an increased odds of high lifetime cardiovascular disease risk (p 0.009).The findings of the current study identify clinical measurements that can be collected at the time of delivery which may help identify specific women who may benefit most from postpartum cardiovascular risk screening and intervention.

Maternal malnutrition and micronutrient deficiencies can alter fetal development. However, the mechanisms underlying these relationships are poorly understood. We used a systems-physiology approach to investigate diet-induced effects on maternal gut microbes and folate/inositol transport in the maternal/fetal gut and placenta. Female mice were fed a control diet (CON) diet, undernourished (UN, restricted by 30% of CON intake) or a high fat diet (HF, 60% kcals fat) during pregnancy to model normal pregnancy, fetal growth restriction, or maternal metabolic dysfunction, respectively. At gestational day 18.5 we assessed circulating folate levels by microbiological assay, relative abundance of gut lactobacilli by G3PhyloChip™, and folate/inositol transporters in placenta and maternal/fetal gut by qPCR/immunohistochemistry. UN and HF-fed mothers had lower plasma folate concentrations vs. CON. Relative abundance of three lactobacilli taxa were higher in HF vs. UN and CON. HF-fed mothers had higher gut proton coupled folate transporter (Pcft) and reduced folate carrier 1 (Rfc1), and lower sodium myo-inositol co-transporter 2 (Smit2), mRNA expression vs. UN and CON. HF placentae had increased folate receptor beta (Frβ) expression vs. UN. mRNA expression of Pcft, folate receptor alpha (Frα) and Smit2 was higher in gut of HF fetuses vs. UN and CON. Transporter protein expression was not different between groups. Maternal malnutrition alters abundance of select gut microbes and folate/inositol transporters, which may influence maternal micronutrient status and delivery to the fetus, impacting pregnancy/fetal outcomes.

Malnutrition and infectious disease often coexist in socially inequitable contexts. Malnutrition in the perinatal period adversely affects offspring development and lifelong non-communicable disease risk. Less is known about the effects ofinfectiousdisease exposure during critical windows of development and health, and links betweenin uteroHIV-exposure in the absence of neonatal infection, perinatal nutritional environments, and infant development are poorly defined. In a pilot feasibility study at Kalafong Hospital, Pretoria, South Africa, we aimed to better understand relationships between maternal HIV infection and the early nutritional environment ofin uteroHIV exposed uninfected (HEU) infants. We also undertook exploratory analyses to investigate relationships between food insecurity and infant development. Mother-infant dyads were recruited after delivery and followed until 12 weeks postpartum. Household food insecurity, nutrient intakes and dietary diversity scores did not differ between mothers living with or without HIV. Maternal reports of food insecurity were associated with lower maternal nutrient intakes 12 weeks postpartum, and in infants, higher brain-to-body weight ratio at birth and 12 weeks of age, and attainment of fewer large movement and play activities milestones at 12 weeks of age, irrespective of maternal HIV status. Reports of worry about food runout were associated with increased risk of stunting for HEU, but not unexposed, uninfected infants. Our findings suggest that food insecurity, in a vulnerable population, adversely affects maternal nutritional status and infant development.In uteroexposure to HIV may further perpetuate these effects, which has implications for early child development and lifelong human capital.

The placenta promotes fetal growth through nutrient transfer and selective barrier systems. An optimally developed placenta can adapt to changes in the pregnancy environment, buffering the fetus from adverse exposures. We hypothesized that the placenta adapts differently to suboptimal maternal diets, evidenced by changes in placental morphology, developmental markers and key transport systems. Mice were fed a control diet (CON) during pregnancy, undernourished (UN) by 30% of control intake from gestational day (GD) 5.5-18.5 or fed 60% high-fat diet (HF) 8 weeks before and during pregnancy. At GD18.5, placental morphometry, development and transport were assessed. Junctional and labyrinthine areas of UN and HF placentae were smaller than CON by >10%. Fetal blood space area and fetal blood space:fetal weight ratios were reduced in HF vs. CON and UN. Trophoblast giant cell marker Ctsq mRNA expression was lower in UN vs. HF, and expression of glycogen cell markers Cx31.1 and Pcdh12 was lower in HF vs. UN. Efflux transporter Abcb1a mRNA expression was lower in HF vs. UN, and Abcg2 expression was lower in UN vs. HF. mRNA expression of fatty acid binding protein Fabppm was higher in UN vs. CON and HF. mRNA and protein levels of the lipid transporter FAT/CD36 were lower in UN, and FATP4 protein levels were lower in HF vs. UN. UN placentae appear less mature with aberrant transport, whereas HF placentae adapt to excessive nutrient supply. Understanding placental adaptations to common nutritional adversities may reveal mechanisms underlying the developmental origins of later disease.

The placenta promotes fetal growth through nutrient transfer and selective barrier systems. An optimally developed placenta can adapt to changes in the pregnancy environment, buffering the fetus from adverse exposures. We hypothesised that the placenta adapts differently to suboptimal maternal diets, evidenced by changes in placental morphology, developmental markers, and key transport systems. 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) eight weeks before and during pregnancy. At GD18.5, placental morphometry, development, and transport were assessed. Junctional and labyrinthine areas of UN and HF placentae were smaller than CON by >10%. Fetal blood space area and fetal blood space:fetal weight ratios were reduced in HF vs. CON and UN. Trophoblast giant cell marker Ctsq mRNA expression was lower in UN vs. HF, and expression of glycogen cell markers Cx31.1 and Pcdh12 was lower in HF vs. UN. Efflux transporter Abcb1a mRNA expression was lower in HF vs. UN, and Abcg2 expression was lower in UN vs. HF. mRNA expression of fatty acid binding protein Fabppm was higher in UN vs. CON and HF. mRNA and protein levels of the lipid transporter FAT/CD36 were lower in UN, and FATP4 protein levels were lower in HF vs. UN. UN placentae appear less mature with aberrant transport. HF placentae adapt to excessive nutrient supply. Understanding placental adaptations to common nutritional adversities may reveal mechanisms underlying the developmental origins of later disease.

Small intestinal Paneth cells, enteric glial cells (EGC), and goblet cells maintain gut mucosal integrity, homeostasis, and influence host physiology locally and through the gut-brain axis. Little is known about their roles during pregnancy, or how maternal malnutrition impacts these cells and their development. Pregnant mice were fed a control diet (CON), undernourished by 30% vs. control (UN), or fed a high fat diet (HF). At day 18.5 (term = 19), gut integrity and function were assessed by immunohistochemistry and qPCR. UN mothers displayed reduced mRNA expression of Paneth cell antimicrobial peptides (AMP, Lyz2, Reg3g) and an accumulation of villi goblet cells, while HF had reduced Reg3g and mucin (Muc2) mRNA and increased lysozyme protein. UN fetuses had increased mRNA expression of gut transcription factor Sox9, associated with reduced expression of maturation markers (Cdx2, Muc2), and increased expression of tight junctions (TJ, Cldn-7). HF fetuses had increased mRNA expression of EGC markers (S100b, Bfabp, Plp1), AMP (Lyz1, Defa1, Reg3g), and TJ (Cldn-3, Cldn-7), and reduced expression of an AMP-activator (Tlr4). Maternal malnutrition altered expression of genes that maintain maternal gut homeostasis, and altered fetal gut permeability, function, and development. This may have long-term implications for host-microbe interactions, immunity, and offspring gut-brain axis function.

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.

OBJECTIVE Fetal myelomeningocele (fMMC) surgery improves infant outcomes when compared with postnatal surgery. Surgical selection criteria and the option of pregnancy termination, however, limit the number of cases that are eligible for prenatal surgery. We aimed to quantify what proportion of cases could ultimately benefit from fetal therapy. METHODS We retrospectively reviewed all cases of fMMC referred to a large tertiary care center over a 10-year period and assessed their eligibility for fetal surgery, pregnancy termination rates, and actual uptake of the surgery. RESULTS Of 158 cases, 67 (42%) were ineligible for fetal surgery based on surgical exclusion criteria. Eleven fetuses (7%) had chromosomal anomalies, 10 of which (91%) had other anomalies on ultrasound. Thirty-four patients had a combination of maternal and fetal contraindications. Of the remaining 91 eligible cases (58%), 45 (49%) pregnancies were terminated, leaving only 46 (29% of initial 158 cases) as potential candidates for fetal repair. Actual uptake of fetal surgery was 15% (n = 14 of 91), but this increased after a national program was started. CONCLUSION Only a minority of fMMC cases will ultimately undergo fetal surgery. These numbers support the centralization of care in expert centers.

Malnutrition is a global threat to pregnancy health and impacts offspring development. Establishing an optimal pregnancy environment requires the coordination of maternal metabolic and immune pathways, which converge at the gut. Diet, metabolic, and immune dysfunctions have been associated with gut dysbiosis in the nonpregnant individual. In pregnancy, these states are associated with poor pregnancy outcomes and offspring development. However, the impact of malnutrition on maternal gut microbes, and their relationships with maternal metabolic and immune status, has been largely underexplored. To determine the impact of undernutrition and overnutrition on maternal metabolic status, inflammation, and the microbiome, and whether relationships exist between these systems, pregnant mice were fed either a normal, calorically restricted (CR), or a high fat (HF) diet. In late pregnancy, maternal inflammatory and metabolic biomarkers were measured and the cecal microbiome was characterized. Microbial richness was reduced in HF mothers although they did not gain more weight than controls. First trimester weight gain was associated with differences in the microbiome. Microbial abundance was associated with altered plasma and gut inflammatory phenotypes and peripheral leptin levels. Taxa potentially protective against elevated maternal leptin, without the requirement of a CR diet, were identified. Suboptimal dietary conditions common during pregnancy adversely impact maternal metabolic and immune status and the microbiome. HF nutrition exerts the greatest pressures on maternal microbial dynamics and inflammation. Key gut bacteria may mediate local and peripheral inflammatory events in response to maternal nutrient and metabolic status, with implications for maternal and offspring health.Summary SentenceMalnutrition alters immune and metabolic systems in pregnancy, and gut microbes may mediate the maternal response to these suboptimal dietary exposures.

Pyridoxine 5′-phosphate oxidase (PNPO) is an enzyme that converts pyridoxine 5′-phosphate into pyridoxal 5′-phosphate (PLP), an active form of vitamin B6 implicated in several types of cancer. However, the role of PNPO and its regulatory mechanism in epithelial ovarian cancer (EOC) are unknown. In the present study, PNPO expression in human ovarian tumour tissue and its association with the clinicopathological features of patients with EOC were examined. Further, the biological function of PNPO in EOC cells and in xenograft was evaluated. We demonstrated for the first time that PNPO was overexpressed in human EOC. Knockdown of PNPO induced EOC cell apoptosis, arrested cell cycle at G2/M phase, decreased cell proliferation, migration and invasion. Xenografts of PNPO-shRNA-expressing cells into the nude mouse attenuated tumour growth. PNPO at mRNA and protein levels in EOC cells was decreased after transforming growth factor-β1 (TGF-β1) treatment. The inhibitory effect of TGF-β1 on PNPO expression was abolished in the presence of SB-431542, a TGF-β type I receptor kinase inhibitor. Moreover, we found that TGF-β1-mediated PNPO expression was at least in part through the upregulation of miR-143-3p. These data indicate a mechanism underlying PNPO regulation by the TGF-β signalling pathway. Furthermore, PLP administration reduced PNPO expression and decreased EOC cell proliferation, suggesting a feedback loop between PLP and PNPO. Thus, our findings reveal that PNPO can serve as a novel tissue biomarker of EOC and may be a potential target for therapeutic intervention.

Maternal obesity predisposes offspring to metabolic and reproductive dysfunction. We have shown previously that female rat offspring born to mothers fed a high-fat (HF) diet throughout pregnancy and lactation enter puberty early and display aberrant reproductive cyclicity. The mechanisms driving this reproductive phenotype are currently unknown thus we investigated whether changes in ovarian function were involved. Wistar rats were mated and randomized to: dams fed a control diet (CON) or dams fed a HF diet from conception until the end of lactation (HF). Ovaries were collected from fetuses at Embryonic Day (E) 20, and neonatal ovaries at Day 4 (P4), prepubertal ovaries at P27 and adult ovaries at P120. In a subset of offspring, the effects of a HF diet fed postweaning were evaluated. The present study shows that fetuses of mothers fed a HF diet had significantly fewer oocytes at E20, and in neonates, have reduced AMH signaling that may facilitate an increased number of assembled primordial follicles. Both prepubertally and in adulthood, ovaries show increased follicular atresia. As adults, offspring have reduced FSH responsiveness, low expression levels of estrogen receptor alpha (Eralpha), the oocyte-secreted factor, Gdf9, oocyte-specific RNA binding protein, Dazl, and high expression levels of the granulosa-cell derived factor, AMH, in antral follicles. Together, these data suggest that ovarian compromise in offspring born to HF-fed mothers may arise from changes already observable in the fetus and neonate and in the long term, associated with increased follicular atresia through adulthood.