Genevieve Eastabrook

Background/Objectives: Individuals with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) in pregnancy are two distinct cardiometabolic populations, each potentially necessitating alternative clinical management. However, our understanding of the unique physiological effects of uncomplicated MHO on fetoplacental growth and metabolism remains limited. In this study, we aimed to identify changes in placental morphology and metabolites associated with maternal obesity, independent of pregnancy-related cardiometabolic complications. Methods: Placentae from women with a prepregnancy body mass index (BMI) < 25 kg/m² (control; n = 15) and women with MHO (prepregnancy BMI > 30 kg/m² with no cardiometabolic diseases; n = 15) were analyzed for indices of placental growth and untargeted metabolomics. Complementary assessments were conducted on proinflammatory genes and antioxidant defense system genes, proteins, and enzymes, along with lipid peroxidation markers. Results: Clear placentomegaly without histopathological changes was observed in uncomplicated MHO pregnancies. The metabolite 3-aminoisobutanoic acid emerged as the top-ranked feature distinguishing placentae from MHO individuals from control placentae, and changes in the cysteine, methionine, and vitamin B6 metabolism pathways were among the most distinct differences identified. Conclusions: These findings illustrate an altered placental morphology and metabolomic profile specific to uncomplicated MHO, offering new insights into how obesity, without cardiometabolic complications, may influence fetoplacental growth and metabolism. They may also represent a crucial first step towards marker identification for MHO pregnancy and underscore the importance of alternative care pathways when obesity is present but metabolic comorbidities are absent.

Metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) in pregnancy represent two distinct cardiometabolic populations, each potentially necessitating alternative clinical management. However, the understanding of the unique physiological effects of uncomplicated MHO or MUO on fetoplacental growth and metabolism remains limited. This study aimed to identify changes in placental morphology and metabolites concerning maternal obesity, independent of pregnancy-related cardiometabolic complications. Placentae from women with a pre-pregnancy body mass index (BMI) 30 kg/m ² with no cardiometabolic diseases; n = 15) were analysed for indices of placental growth and untargeted metabolomics. Complementary measures of pro-inflammatory and antioxidant genes, as well as antioxidant proteins, enzymes, and lipid peroxidation markers were conducted. A clear placentomegaly without histopathological changes was observed in uncomplicated MHO pregnancies. The metabolite 3-aminoisobutanoic acid emerged as the top-ranked feature distinguishing MHO from control placentae, and cysteine, methionine, and vitamin B6 metabolism pathways were among the most distinct signatures identified. These findings illustrate an altered placental morphology and metabolomic profile specific to uncomplicated MHO, offering new insights into how obesity without cardiometabolic complications influences fetoplacental growth and metabolism. They also represent a crucial first step towards marker identification for MHO pregnancies and underscore the importance of alternative care pathways when obesity is present but metabolic comorbidities are absent.

Metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) in pregnancy represent two distinct cardiometabolic populations, each potentially necessitating alternative clin-ical management. However, the understanding of the unique physiological effects of uncomplicated MHO or MUO on fetoplacental growth and metabolism remains limited. This study aimed to identify changes in placental morphology and metabolites concerning maternal obesity, inde-pendent of pregnancy-related cardiometabolic complications. Placentae from women with a pre-pregnancy body mass index (BMI) 30 kg/m² with no cardiometabolic diseases; n = 15) were analysed for indices of placental growth and untargeted metabolomics. Complementary measures of pro-inflammatory and antioxidant genes, as well as antioxidant proteins, enzymes, and lipid peroxidation markers were conducted. A clear placentomegaly without histopathological changes was observed in un-complicated MHO pregnancies. The metabolite 3-aminoisobutanoic acid emerged as the top-ranked feature distinguishing MHO from control placentae, and cysteine, methionine, and vitamin B6 metabolism pathways were among the most distinct signatures identified. These findings illustrate an altered placental morphology and metabolomic profile specific to uncomplicated MHO, offering new insights into how obesity without cardiometabolic complications influences fetoplacental growth and metabolism. They also represent a crucial first step towards marker identification for MHO pregnancies and underscore the importance of alternative care pathways when obesity is present but metabolic comorbidities are absent.

Background: We determined the effect of fetal sex on birth/placental weight and umbilical vein and artery oxygen values with implications for placental efficiency and regulatory mechanisms underlying fetal–placental growth differences. Methods: A hospital database was used to obtain birth/placental weight, cord PO₂ and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA > 34 weeks (N = 69,836). Oxygen saturation was calculated from the cord PO₂ and pH data, while fractional O₂ extraction was calculated from the oxygen saturation data. The effect of fetal sex on birth/placental weight, cord PO₂, O₂ saturation, and fractional O₂ extraction was examined in all patients adjusting for pregnancy and labor/delivery covariates, and in a subset of low-risk patients. Results: Birth/placental weights were lower in females indicating decreased placental efficiency. Umbilical vein oxygen values were higher in females attributed to increased uterine blood flow, while artery oxygen values were lower in females attributed to decreased hemoglobin and umbilical blood flow, and increased oxygen consumption. Fetal O₂ extraction was increased in females confirming increased O₂ consumption relative to delivery. Conclusions: Sex-related differences in uterine/umbilical blood flows, placental development, and fetal O₂ consumption can be linked to the differences observed in cord oxygen. The lower umbilical artery oxygen in females as a measure of systemic oxygenation signaling growth could account for their decreased birth weights, while slower development in female placentae could account for their lower placental weights, which could be differentially effected contributing to their lower birth/placental weights.

Adrenal Cushing syndrome during pregnancy is rare, and there is limited information on the effect and safety of metyrapone treatment both for mother and fetus. We present a 24-year-old woman diagnosed with adrenal Cushing syndrome at the end of the second trimester. We elected treatment with metyrapone titrated to 250 mg 3 times daily, resulting in good clinical response and maternal serum and saliva cortisol levels in the upper half of the normal pregnancy range. A healthy male infant was born at 35 weeks’ gestation, with no clinical signs of adrenal insufficiency, this despite a low cortisol of 5 nmol/L on the first day of life. We measured metyrapone in maternal and umbilical cord blood samples, demonstrating fetal venous metyrapone levels similar to maternal venous concentration, and a fetal arterial cord concentration at about 60% of the fetal venous cord concentration. This case demonstrates that salivary cortisol levels may be used to monitor the effect of metyrapone on adrenal Cushing syndrome during pregnancy. We show, for the first time in humans, that metyrapone does cross the placenta and may suppress fetal cortisol production without necessarily causing clinical signs of adrenal insufficiency.

Aim: Obesity has been associated with changes in autophagy and its increasing prevalence among pregnant women is implicated in higher rates of placental‐mediated complications of pregnancy such as pre‐eclampsia and intrauterine growth restriction. Autophagy is involved in normal placentation, thus changes in autophagy may lead to impaired placental function and development. The aim of this study was to investigate the connection between obesity and autophagy in the placenta in otherwise uncomplicated pregnancies.Methods: Immunohistochemistry and western blot analysis were done on placental and omental samples from obese (body mass index [BMI] ≥30 kg/m²) and normal weight (BMI 2) pregnant women with singleton pregnancies undergoing planned Caesarean delivery without labor at term. Samples were analyzed for autophagic markers LC3B and p62 in the peripheral, middle and central regions of the placenta and in omental adipocytes, milky spots and vasculature.Results: As pre‐pregnancy BMI increased, there was an increase in both placental and fetal weight as well as decreased levels of LC3B in the central region of the placenta (P = 0.0046). Within the obese patient group, LC3B levels were significantly decreased in the placentas of male fetuses compared to females (P < 0.0001). Adipocytes, compared to milky spots and vasculature, had lower levels of p62 (P = 0.0127) and LC3B (P = 0.003) in obese omenta and lower levels of LC3B in control omenta (P = 0.0071).Conclusion: Obesity leads to reduced placental autophagy in uncomplicated pregnancies; thus, changes in autophagy may be involved in the underlying mechanisms of obesity‐related placental diseases of pregnancy.

Many viruses are detrimental to pregnancy and negatively affect fetal growth and development. What is not well understood is how virus-induced inflammation impacts fetal–placental growth and developmental trajectories, particularly when inflammation occurs in early pregnancy during nascent placental and embryo development. To address this issue, we simulated a systemic virus exposure in early pregnant rats (gestational day 8.5) by administering the viral dsRNA mimic polyinosinic:polycytidylic acid (PolyI:C). Maternal exposure to PolyI:C induced a potent antiviral response and hypoxia in the early pregnant uterus, containing the primordial placenta and embryo. Maternal PolyI:C exposure was associated with decreased expression of the maternally imprinted genes Mest, Sfrp2, and Dlk1, which encode proteins critical for placental growth. Exposure of pregnant dams to PolyI:C during early pregnancy reduced fetal growth trajectories throughout gestation, concomitant with smaller placentas, and altered placental structure at midgestation. No detectable changes in placental hemodynamics were observed, as determined by ultrasound biomicroscopy. An antiviral response was not evident in rat trophoblast stem (TS) cells following exposure to PolyI:C, or to certain PolyI:C-induced cytokines including IL-6. However, TS cells expressed high levels of type I IFNR subunits (Ifnar1 and Ifnar2) and responded to IFN-⍺ by increasing expression of IFN-stimulated genes and decreasing expression of genes associated with the TS stem state, including Mest. IFN-⍺ also impaired the differentiation capacity of TS cells. These results suggest that an antiviral inflammatory response in the conceptus during early pregnancy impacts TS cell developmental potential and causes latent placental development and reduced fetal growth. Key Points dsRNA induces an intrauterine antiviral response in early pregnancy. The antiviral response reduces imprinted gene expression and fetal–placental size. Type I IFNs inhibit trophoblast stem cell developmental potential.