Pregnant Women with Multiple Sclerosis: An Overview of Gene Expression and Molecular Interaction Using Bioinformatics Analysis.

Multiple sclerosis (MS) is a common disease in young women of reproductive age, characterized by demyelination of the central nervous system (CNS). Understanding how genes related to MS are expressed during pregnancy can provide insights into the potential mechanisms by which pregnancy affects the course of this disease. This review article presents evidence-based studies on these patients' gene expression patterns. In addition, it constructs interaction networks using bioinformatics tools, such as STRING and KEGG pathways, to understand the molecular role of each of these genes. Bioinformatics research identified 25 genes and 21 signaling pathways, which allows us to understand pregnancy patients' genetic and biological phenomena and formulate new questions about MS during pregnancy.

Gestational hypothyroxinemia induces ASD-like phenotypes in behavior, proinflammatory markers, and glutamatergic protein expression in mouse offspring of both sexes.

Background: The prevalence of autism spectrum disorder (ASD) has significantly risen in the past three decades, prompting researchers to explore the potential contributions of environmental factors during pregnancy to ASD development. One such factor of interest is gestational hypothyroxinemia (HTX), a frequent condition in pregnancy associated with cognitive impairments in the offspring. While retrospective human studies have linked gestational HTX to autistic traits, the cellular and molecular mechanisms underlying the development of ASD-like phenotypes remain poorly understood. This study used a mouse model of gestational HTX to evaluate ASD-like phenotypes in the offspring. Methods: To induce gestational HTX, pregnant mice were treated with 2-mercapto-1-methylimidazole (MMI), a thyroid hormones synthesis inhibitor, in the tap-drinking water from embryonic days (E) 10 to E14. A separate group received MMI along with a daily subcutaneous injection of T4, while the control group received regular tap water during the entire pregnancy. Female and male offspring underwent assessments for repetitive, anxious, and social behaviors from postnatal day (P) 55 to P64. On P65, mice were euthanized for the evaluation of ASD-related inflammatory markers in blood, spleen, and specific brain regions. Additionally, the expression of glutamatergic proteins (NLGN3 and HOMER1) was analyzed in the prefrontal cortex and hippocampus. Results: The HTX-offspring exhibited anxious-like behavior, a subordinate state, and impaired social interactions. Subsequently, both female and male HTX-offspring displayed elevated proinflammatory cytokines in blood, including IL-1ß, IL-6, IL-17A, and TNF-α, while only males showed reduced levels of IL-10. The spleen of HTX-offspring of both sexes showed increased Th17/Treg ratio and M1-like macrophages. In the prefrontal cortex and hippocampus of male HTX-offspring, elevated levels of IL-17A and reduced IL-10 were observed, accompanied by increased expression of hippocampal NLGN3 and HOMER1. All these observations were compared to those observed in the Control-offspring. Notably, the supplementation with T4 during the MMI treatment prevents the development of the observed phenotypes. Correlation analysis revealed an association between maternal T4 levels and specific ASD-like outcomes. Discussion: This study validates human observations, demonstrating for the first time that gestational HTX induces ASD-like phenotypes in the offspring, highlighting the need of monitoring thyroid function during pregnancy.

Eucommia granules activate Wnt/ß-catenin pathway, and improve oxidative stress, inflammation, and endothelial injury in preeclampsia rats.

PURPOSE: Pre-eclampsia (PE) is a pregnancy-related complication. Eucommia is effective in the treatment of hypertensive disorders in pregnancy, but the specific effects and possible mechanisms of Eucommia granules (EG) in PE remain unknown. The aim of this study was to investigate the effects and possible mechanisms of EG in PE rats. METHODS: Pregnant Sprague Dawley rats were divided into five groups (n = 6): the control group, the model group, the low-dose group, the medium-dose group, and the high-dose group of EG. The PE model was established by subcutaneous injection of levonitroarginine methyl ester. Saline was given to the blank and model groups, and the Eucommia granules were given by gavage to the remaining groups. Blood pressure and urinary protein were detected. The body length and weight of the pups and the weight of the placenta were recorded. Superoxide dismutase (SOD) activity and levels of malondialdehyde (MDA), placental growth factor (PIGF), and soluble vascular endothelial growth factor receptor-1 (sFIt-1) were measured in the placenta. Pathological changes were observed by hematoxylin-eosin staining. Wnt/ß-catenin pathway-related protein expression was detected using Western blot. RESULTS: Compared with the model group, the PE rats treated with EG had lower blood pressure and urinary protein. The length and weight of the pups and placental weight were increased. Inflammation and necrosis in the placental tissue was improved. SOD level increased, MDA content and sFIt-1/PIGF ratio decreased, and Wnt/ß-catenin pathway-related protein expression level increased. Moreover, the results of EG on PE rats increased with higher doses of EG. CONCLUSIONS: EG may activate the Wnt/ß-catenin pathway and inhibit oxidative stress, inflammation, and vascular endothelial injury in PE rats, thereby improving the perinatal prognosis of preeclamptic rats. EG may inhibit oxidative stress, inflammation, and vascular endothelial injury through activation of the Wnt/ß-catenin pathway in preeclampsia rats, thereby improving perinatal outcomes in PE rats.

Biochemical profiling study in umbilical cord blood in mothers with metabolic disorders.

BACKGROUND: During pregnancy metabolic disorders that affect differently the fetus, are known. These could be early or late disorders. OBJECTIVES: To analyze different biochemical parameters in umbilical cord blood (UCB) of healthy and pathological newborns from mothers with metabolic disorders. MATERIALS AND METHODS: Samples from UCB (121) were analyzed of newborn from mothers with metabolic disorders who attended at Obstetrics Division. Patients were consecutive, prospective and transversally studied. Newborn were classified as healthy (n = 65) and pathological (n = 56). The maternal metabolic disorders were gestational or non-gestational diabetes, glucose intolerance, insulin resistance and/or obesity).The disorders of the pathological newborns were intrauterine growth restriction (IUGR) and/or fetal distress. Glucose (Glu), urea, creatinine, uric acid (UA), total bilirubin (TB), total proteins (TP), albumin (Alb), transaminases (ALT/AST), alkaline-phosphatase (ALP), gammaglutamyltranspeptidase (GGT), creatinkinasa (CK), lactatedehydrogenase, amylase (amy), pseudocholinesterase, iron, calcium, phosphorus, magnesium (Mg), sodium, potassium, chlorine, cholesterol (Chol), HDL-Chol, LDL-Chol, triglycerides (TG), high sensitivity C reactive protein (hsCRP) were determined by recommended methods. T-Student's and Mann Withney tests were applied, p < .05. RESULTS: Pathological neonates (n: 56) showed a significant decrease in maternal gestation weeks (GW) and in newborn weight (NW) with respect to healthy newborns (n: 65) from mothers with metabolic disorders (p < .0001). Pathological neonates from mothers with metabolic pathologies (n: 56) showed significant increases in Chol, TG, TB (p < .01), LDL-Chol, UA, Mg, hsCRP, ALP levels (p < .05) and significant decreases in TP, Alb (p < .0001) and Glu, ALT, CK, GGT, amy (p < .05) in UCB with respect to healthy newborns. CONCLUSIONS: In pathological newborn, the decrease in GW and NW would be related to IUGR that accompany these metabolic disorders. The increases observed of the analyzed parameters would be related to cellular destruction associated to maternal pathology and decreases of the parameters to IUGR with hepatic immaturity.

Astroglial Hemichannels and Pannexons: The Hidden Link between Maternal Inflammation and Neurological Disorders.

Maternal inflammation during pregnancy causes later-in-life alterations of the offspring's brain structure and function. These abnormalities increase the risk of developing several psychiatric and neurological disorders, including schizophrenia, intellectual disability, bipolar disorder, autism spectrum disorder, microcephaly, and cerebral palsy. Here, we discuss how astrocytes might contribute to postnatal brain dysfunction following maternal inflammation, focusing on the signaling mediated by two families of plasma membrane channels: hemi-channels and pannexons. [Ca2+]i imbalance linked to the opening of astrocytic hemichannels and pannexons could disturb essential functions that sustain astrocytic survival and astrocyte-to-neuron support, including energy and redox homeostasis, uptake of K+ and glutamate, and the delivery of neurotrophic factors and energy-rich metabolites. Both phenomena could make neurons more susceptible to the harmful effect of prenatal inflammation and the experience of a second immune challenge during adulthood. On the other hand, maternal inflammation could cause excitotoxicity by producing the release of high amounts of gliotransmitters via astrocytic hemichannels/pannexons, eliciting further neuronal damage. Understanding how hemichannels and pannexons participate in maternal inflammation-induced brain abnormalities could be critical for developing pharmacological therapies against neurological disorders observed in the offspring.

Effects of lipoproteins on endothelial cells and macrophages function and its possible implications on fetal adverse outcomes associated to maternal hypercholesterolemia during pregnancy.

Hypercholesterolemia is one of the main risk factors associated with atherosclerosis and cardiovascular disease, the leading cause of death worldwide. During pregnancy, maternal hypercholesterolemia develops, and it can occur in a physiological (MPH) or supraphysiological (MSPH) manner, where MSPH is associated with endothelial dysfunction and early atherosclerotic lesions in the fetoplacental vasculature. In the pathogenesis of atherosclerosis, endothelial activation and endothelial dysfunction, characterized by an imbalance in the bioavailability of nitric oxide, contribute to the early stages of this disease. Macrophages conversion to foam cells, cholesterol efflux from these cells and its differentiation into a pro- or anti-inflammatory phenotype are also important processes that contribute to atherosclerosis. In adults it has been reported that native and modified HDL and LDL play an important role in endothelial and macrophage function. In this review it is proposed that fetal lipoproteins could be also relevant factors involved in the detrimental vascular effects described in MSPH. Changes in the composition and function of neonatal lipoproteins compared to adults has been reported and, although in MSPH pregnancies the fetal lipid profile does not differ from MPH, differences in the lipidomic profiles of umbilical venous blood have been reported, which could have implications in the vascular function. In this review we summarize the available information regarding the effects of lipoproteins on endothelial and macrophage function, emphasizing its possible implications on fetal adverse outcomes associated to maternal hypercholesterolemia during pregnancy.

Quality or Quantity of Proteins in the Diet for CKD Patients: Does "Junk Food" Make a Difference? Lessons from a High-Risk Pregnancy.

BACKGROUND: How to manage patients with severe kidney disease in pregnancy is still a matter of discussion, and deciding if and when to start dialysis is based on the specialist's experience and dialysis availability. The effect of toxic substances usually cleared by the kidney may be more severe and readily evident. The review, and related case, underlines the importance of considering the presence of additives in food in delicate conditions, such as CKD pregnancy. The Case: A 39-year-old indigenous woman from a low-resourced area in Mexico was referred to the obstetric nephrology at 25 gestational weeks because of serum creatinine at 3.6 mg/dL, hypertension on low-dose alpha-methyl-dopa, and nephrotic-range proteinuria. Kidney ultrasounds showed small poorly differentiated kidneys; foetal ultrasounds detected a female foetus, normal for gestational age. The patient's baseline protein intake, which was estimated at 1.2-1.3 g/kg/day, was mostly of animal-origin (>70%) poor-quality food ("junk food"). In the proposed diet, protein intake was only slightly reduced (1.0-1.2 g/kg/day), but the source of proteins was changed (only 30% of animal origin) with attention to food quality. A remarkable decrease in BUN was observed, in concomitance with adequate dietary follow-up, with rapid rise of BUN when the patient switched temporarily back to previous habits. A healthy female baby weighing 2,460 g (11th centile for gestational age) was delivered at 37 gestational weeks. Discussion and Literature Review: While data on patients with chronic kidney disease are scant, the long list of contaminants present in food, especially if of low quality, should lead us to reflect on their potential negative effect on kidney function and make us realize that eating healthy, unprocessed "organic" food should be encouraged, in delicate conditions such as pregnancy and breastfeeding and for young children, in particular when kidney function is failing. The case herein described gave us the opportunity to reflect on the importance of diet quality and on the potential risks linked to food additives, many of which, including phosphates and potassium, are not declared on food labels, while others, including dyes, antioxidants, thickeners, emulsifiers, and preservatives, are qualitatively, but not quantitatively, reported.

Protein and genetic expression of CDKN1C and IGF2 and clinical features related to human umbilical cord length.

BACKGROUND: Umbilical cord (UC) abnormalities are related to neurological outcome and death; specific molecular factors that might be involved are, as yet, unknown; however, protein-coding genes insulin-like growth factor 2 (IGF2) and cyclin-dependent kinase inhibitor 1C (CDKN1C) have been identified as potential candidates. METHODS: An analytical observational study was carried out. Newborn UCs were collected, along with their clinical and morphological features. Immunohistochemical analysis was made on paraffin-embedded sections and quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed in fresh UC tissue for the assessment of gene expression. RESULTS: A total of 100 newborns were included. A significant association was found between long UC and prematurity [odds ratio (OR) 9] and long UC and respiratory distress (OR 4.04). Gestational diabetes (OR 8.55) and hypertensive disorders of pregnancy (HDP) (OR 4.71) were found to be related to short UCs. The frequency for abnormal UC length was higher than expected. UC length was positively correlated with maternal, newborn and placental weight. No statistical association was found between IGF2 and CDKN1C (p57) expression and UC length; however, there was a tendency for higher CDKN1C expression in short UCs, while, on the contrary, higher IGF2 expression for long UCs. CONCLUSION: UC length was observed to be associated with maternal and newborn complications. Protein expression, messenger RNA (mRNA) activity and the activity of said genes seem to be related to UC length.

Coenzyme Q 10 supplementation: A potential therapeutic option for the treatment of intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy specific liver disease characterized by pruritus, elevated serum bile acids and abnormal liver function that may be associated with severe adverse pregnancy outcomes. We previously reported that plasma coenzyme Q10 (CoQ10) is decreased in women with ICP as it is its analogue coenzyme Q9 (CoQ9) in rats with ethinyl estradiol (EE)-induced cholestasis. The aim of the present study was to evaluate the possible therapeutic role of CoQ10 in experimental hepatocellular cholestasis and to compare it with ursodeoxycholic acid (UDCA) supplementation. Bile acids, CoQ9, CoQ10, transaminases, alkaline phosphatase, retinol, α-tocopherol, ascorbic acid, thiobarbituric acid reactive substances, carbonyls, glutathione, superoxide dismutase and catalase were assessed in plasma, liver and/or hepatic mitochondria in control and cholestatic rats supplemented with CoQ10 (250 mg/kg) administered alone or combined with UDCA (25 mg/kg). CoQ10 supplementation prevented bile flow decline (P < 0.05) and the increase in serum alkaline phosphatase and bile acids, particularly lithocholic acid (P < 0.05) in cholestatic rats. Furthermore, it also improved oxidative stress parameters in the liver, increased both CoQ10 and CoQ9 plasma levels and partially prevented the fall in α-tocopherol (P < 0.05). UDCA also prevented cholestasis, but it was less efficient than CoQ10 to improve the liver redox environment. Combined administration of CoQ10 and UDCA resulted in additive effects. In conclusion, present findings show that CoQ10 supplementation attenuated EE-induced cholestasis by promoting a favorable redox environment in the liver, and further suggest that it may represent an alternative therapeutic option for ICP.

Pregnant Smokers Receiving Opioid Agonist Therapy Have an Elevated Nicotine Metabolite Ratio: A Replication Study.

INTRODUCTION: Pregnant women exposed chronically to opioids smoked more cigarettes per day (CPD) and had a higher nicotine metabolite ratio (NMR), 3-hydroxycotinine/cotinine, a biomarker of nicotine metabolism and clearance, than those not receiving opioids. We examined CPD and NMR in a group of pregnant smokers, a quarter of whom were receiving opioid agonist therapy (OAT). AIMS AND METHODS: Pregnant smokers recruited to participate in a placebo-controlled trial of bupropion for smoking cessation provided a blood sample for measurement of NMR. RESULTS: Half (52.4%) of the 124 women with NMR data were African American. OAT-treated women (n = 34, 27.4%; 27 receiving methadone and 7 buprenorphine) were more likely to be white (79% vs. 30%, p < .001) and to have a lower mean PHQ-9 total score (2.91 [SD = 2.83] vs. 4.83 [SD = 3.82], p = .007). OAT-treated women reported smoking more CPD (9.50 [SD = 5.26] vs. 7.20 [SD = 3.65], p = .005) and had higher NMR (0.78 [SD = 0.36] vs. 0.56 [SD = 0.25], p = .001) than the non-OAT-treated group. In a linear regression analysis adjusting for race, depression severity, and CPD, NMR was greater in the OAT group (p = .025), among whom the daily methadone-equivalent dosage correlated with NMR (Spearman's ρ = 0.49, p = .003). CONCLUSIONS: Consistent with the findings of Oncken et al. (2019), we found that OAT smokers smoked more and had higher NMR than non-OAT smokers. As higher NMR is associated with a reduced likelihood of smoking cessation, the effects on NMR of both pregnancy and OAT could contribute to a lower smoking cessation rate in pregnant smokers receiving chronic opioid therapy. IMPLICATIONS: We replicated the finding that the NMR is significantly greater among pregnant smokers receiving OAT than those not receiving this treatment for opioid use disorder. Furthermore, we found that the dosage of the OAT was significantly associated with the NMR level. These findings may contribute to a poorer response to smoking cessation treatment in pregnant women treated with OAT, particularly those receiving high-dose therapy, and raise the question of whether novel approaches are needed to treat smoking in this subgroup of pregnant smokers.

Branding of subjects affected with genetic syndromes of severe short stature in developing countries.

In Ecuador, a developing South American country, subjects affected with genetic syndromes of severe short stature are commonly referred to as dwarfs or midgets. Furthermore, and because in earlier studies some patients had evidenced mental retardation, such abnormality is assumed to exist in all affected subjects. Herein, we present two discrete instances in which this type of branding occurs. The first is that of individuals with Laron syndrome who are still called 'dwarfs' and considered as having a degree of mental retardation despite evidence showing otherwise. A similar problem, that of a girl affected with a genetic syndrome of short stature, which might include mental retardation, is also discussed. Considering that stigmatising is a form of discrimination, it concerns us all. Hence, the use of derogatory terms such as midget, dwarf or cretin, that might unintentionally occur even when delivering the best and most devoted medical care, must be eliminated.

Fructose consumption during pregnancy and lactation causes DNA damage and biochemical changes in female mice.

The consumption of fructose during pregnancy can cause hyperglycaemia and may stimulate production of reactive oxygen species; however, there are only a few studies reporting whether fructose consumption during pregnancy causes DNA damage. Therefore, the aim of this study was to evaluate the effects of fructose consumption on genetic and biochemical parameters in Swiss mice treated during pregnancy and lactation. For this, 15 couples of 60-day-old Swiss mice were divided into three groups of five couples: negative control (water) and two fructose groups (fructose dose of 10%/l and 20%/l). During this period, we evaluated food consumption, energy efficiency and body weight. Samples of blood were collected from the females before copulation, after the 15th day of conception and on the 21st day after the lactation period, for the glycaemic and lipid profiles as well as comet assay and micronucleus (MN) test. Comet assay and MN test evaluate DNA damage and clastogenicity, respectively. In the gestation and lactation period, the two fructose doses tested showed DNA damage as observed in the comet assay, which is associated with an increase in dietary intake, body weight, lipid profile and fasting glycaemia in females. Thus, it can be suggested that the high consumption of fructose during these periods is harmful for pregnancy and lactation.

Malnutrition during late pregnancy exacerbates high-fat-diet-induced metabolic dysfunction associated with lower sympathetic nerve tonus in adult rat offspring.

Objectives: We aimed to assess the effects of a maternal protein-caloric restriction diet during late pregnancy on the metabolism of rat offspring fed a high-fat diet (HFD) during adulthood.Methods: During late pregnancy, rat dams received either a low-protein (4%; LP group) or normoprotein (23%; NP group) diet. After weaning, the offspring were fed a standard diet (Control; C). Male offspring (60 days old) from both groups were then fed either the C diet or HFD until they were 90 days old. The adult offspring and maternal metabolic parameters and autonomic nervous system (ANS) were then evaluated.Results: Dams exhibited low body weight gain and food intake during the LP diet consumption. At lactation, these dams showed high body weight gain, hypoinsulinemia and hyperglycemia. The maternal LP diet resulted in low body weights for the pups. There were also no differences in the metabolic parameters between the adult LP offspring that were fed the C diet and the NP group. Adults of both groups that were fed the HFD developed obesity associated with altered insulin/ glucose homeostasis and altered ANS activity; however, the magnitudes of these parameters were higher in the LP group than in the NP group.Conclusions: Maternal protein malnutrition during the last third of pregnancy malprograms the metabolism of rat offspring, resulting in increased vulnerability to HFD-induced obesity, and the correlated metabolic impairment might be associated with lower sympathetic nerve activity in adulthood.

Endothelial dysfunction in pregnancy metabolic disorders.

In recent years, the vascular endothelium has gained attention as a key player in the initiation and development of pregnancy disorders. Endothelium acts as an endocrine organ that preserves the homeostatic balance by responding to changes in metabolic status. However, in metabolic disorders, endothelial cells adopt a dysfunctional function, losing their normal responsiveness. During pregnancy, several metabolic changes occur, in which endothelial function decisively participates. Similarly, when pregnancy metabolic disorders occur, endothelial dysfunction plays a key role in pathogenesis. This review outlines the main findings regarding endothelial dysfunction in three main metabolic pathological conditions observed during pregnancy: gestational diabetes, hypertensive disorders, and obesity and hyperlipidemia. Organ, histological and cellular characteristics were thoroughly described. Also, we focused in discussing the underlying molecular mechanisms involved in the cellular signaling pathways that mediate responses in these pathological conditions.

Adipokines underlie the early origins of obesity and associated metabolic comorbidities in the offspring of women with pregestational obesity.

Maternal pregestational obesity is a well-known risk factor for offspring obesity, metabolic syndrome, cardiovascular disease and type 2 diabetes. The mechanisms by which maternal obesity can induce alterations in fetal and later neonatal metabolism are not fully elucidated due to its complexity and multifactorial causes. Two adipokines, leptin and adiponectin, are involved in fetal and postnatal growth trajectories, and both are altered in women with pregestational obesity. The placenta synthesizes leptin, which goes mainly to the maternal circulation and in lesser amount to the developing fetus. Maternal pregestational obesity and hyperleptinemia are associated with placental dysfunction and changes in nutrient transporters which directly affect fetal growth and development. By the other side, the embryo can produce its own leptin from early in development, which is associated to fetal weight and adiposity. Adiponectin, an insulin-sensitizing adipokine, is downregulated in maternal obesity. High molecular weight (HMW) adiponectin is the most abundant form and with most biological actions. In maternal obesity lower total and HMW adiponectin levels have been described in the mother, paralleled with high levels in the umbilical cord. Several studies have found that cord blood adiponectin levels are related with postnatal growth trajectories, and it has been suggested that low adiponectin levels in women with pregestational obesity enhance placental insulin sensitivity and activation of placental amino acid transport systems, supporting fetal overgrowth. The possible mechanisms by which maternal pregestational obesity, focusing in the actions of leptin and adiponectin, affects the fetal development and postnatal growth trajectories in their offspring are discussed.

Metabolomics for predicting hyperglycemia in pregnancy: a protocol for a systematic review and potential meta-analysis.

BACKGROUND: Hyperglycemia in pregnancy (HIP) has been recently differentiated between diabetes in pregnancy (DIP) and gestational diabetes mellitus (GDM). The proposed protocol is relevant, and clinical concern is due to the higher risk of adverse pregnancy outcomes (APO) and long-term effects on both the mother and the fetus. Fasting plasma glucose level (FPG) and oral glucose tolerance test (OGTT) are current diagnostic tools. However, controversy persists concerning diagnostic criteria, cut-off points, and even selective or universal screening. The objective of this systematic review is to assess the performance of metabolomic markers in the prediction of HIP. METHODS: This is a protocol for a systematic review with potential meta-analysis. The primary outcome is GDM, defined as glucose intolerance identified in the second and third trimesters of pregnancy (any FPG ≥ 92 mg/dL and < 126 mg/dL OR when 75-g OGTT shows one altered value among these: FPG ≥ 92 mg/dL or 1-h post glucose load ≥ 180 mg/dL or 2-h post glucose load ≥ 153 mg/dL); the secondary outcome is HIP, defined as hyperglycemia detected in the first trimester of pregnancy (any FPG ≥ 126 mg/dL). A detailed systematic literature search will be carried out in electronic databases and conference abstracts, using the keywords "gestational diabetes mellitus," "metabolomics," "pregnancy," and "screening" (and their variations). We will include original peer-reviewed articles published from Jan 1, 1999, to Dec 31, 2018. Original studies including diabetes diagnosed before pregnancy (T2DM and T1DM), multiple pregnancies, and congenital malformations will be excluded. All results regarding samples, participant characteristics, metabolomic techniques, and diagnostic accuracy measures will be retrieved and analyzed. Since this is a systematic review, no ethical approval is necessary. DISCUSSION: This systematic review may have the potential to provide significant evidence-based findings on the prediction performance of metabolomics. There are short and long-term repercussions for the mother and the newborn. Therefore, both may benefit from an accurate prediction technique for HIP. SYSTEMATIC REVIEW REGISTRATION: This protocol was registered in the PROSPERO platform under number CRD42018100175 .

Prospective Relations Between Prenatal Maternal Cortisol and Child Health Outcomes.

OBJECTIVE: The aim of the study was to investigate prospective, longitudinal associations between maternal prenatal cortisol response to an interpersonal stressor and child health for the subsequent 3 years. METHODS: One hundred twenty-three women expecting their first child provided salivary cortisol samples between 12 and 32 weeks of gestation (M (SD) = 22.4 (4.9) weeks) before and after a videotaped couple conflict discussion with their partner. Mothers reported on overall child health and several indicators of child illness (sick doctor visits, fevers, ear, and respiratory infections) when children were 6 months (n = 114), 1 (n = 116), and 3 (n = 105) years old. Associations between maternal prenatal cortisol reactivity and recovery and later child health at each of the three time points were analyzed using longitudinal regression models. RESULTS: Greater cortisol reactivity in response to the couple conflict discussion was associated with maternal self-report of better overall child health (p = .016, 95% CI = 0.06-1.30, Cohen's f = 0.045) across the study period. Greater cortisol reactivity was also associated with lower incidence rate ratios for maternal reports of sick doctor visits (incidence rate ratio 95% CI = 0.25-0.83, p = .006), fevers (95% CI = 0.25-0.73, p = .002), ear infections (95% CI = 0.25-0.58, p < .001), and respiratory infections (95% CI = 0.08-1.11, p = .073). Cortisol recovery was unrelated to study outcomes (all p's > 0.05). Maternal prenatal depressive symptoms moderated the association between cortisol reactivity and overall child health (p = .034, 95% CI = 0.07-1.87 for interaction term) but no other health outcomes (p's > 0.05). Among women with lower depressive symptoms, cortisol reactivity was not associated with overall child health; among women with higher levels of depressive symptoms, greater cortisol reactivity was associated with better overall child health. CONCLUSIONS: This study provides longitudinal evidence that greater maternal cortisol reactivity to a salient interpersonal stressor during pregnancy is associated with fewer child health problems and better maternal report of overall child health during infancy and into early childhood. TRIAL REGISTRATION: Clinicaltrials.gov ID NCT01901536.

Relations of neuropeptide Y and heme oxygenase-1 expressions with fetal brain injury in rats with intrahepatic cholestasis of pregnancy.

PURPOSE: To investigate the relations of neuropeptide Y (NPY) and heme oxygenase-1 (HO-1) expressions with fetal brain injury in rats with intrahepatic cholestasis of pregnancy (ICP). METHODS: Sixty rats pregnant for 15 days were randomly divided into experimental and control groups. The ICP model was established in experimental group. On the 21st day, the blood biochemical test, histopathological examination of pregnant rat liver and fetal brain tissues and immunohistochemical analysis of fetal rat brain tissues were performed. RESULTS: On the 21st day, the alanineaminotransferase, aspartate aminotransferase and total bile acid levels in experimental group were significantly higher than control group (P<0.01). Compared with control group, there was obvious vacuolar degeneration in pregnant rat liver tissue and fetal brain tissue in experimental group. NPY expression in fetal brain tissue was negative in control group and positive in experimental group. HO-1 expression in fetal brain tissue was strongly positive in control group and positive in experimental group. There was significant difference of immunohistochemical staining optical density between two groups (P<0.01). CONCLUSION: In fetal brain of ICP rats, the NPY expression is increased, and the HO-1 expression is decreased, which may be related to the fetal brain injury.

Metabolic Culprits in Obese Pregnancies and Gestational Diabetes Mellitus: Big Babies, Big Twists, Big Picture : The 2018 Norbert Freinkel Award Lecture.

Pregnancy has been equated to a "stress test" in which placental hormones and growth factors expose a mother's predisposition toward metabolic disease, unleashing her previously occult insulin resistance (IR), mild ß-cell dysfunction, and glucose and lipid surplus due to the formidable forces of pregnancy-induced IR. Although pregnancy-induced IR is intended to assure adequate nutrition to the fetus and placenta, in mothers with obesity, metabolic syndrome, or those who develop gestational diabetes mellitus, this overnutrition to the fetus carries a lifetime risk for increased metabolic disease. Norbert Freinkel, nearly 40 years ago, coined this excess intrauterine nutrient exposure and subsequent offspring developmental risk "fuel-mediated teratogenesis," not limited to only excess maternal glucose. Our attempts to better elucidate the causes and mechanisms behind this double-edged IR of pregnancy, to metabolically characterize the intrauterine environment that results in changes in newborn body composition and later childhood obesity risk, and to examine potential therapeutic approaches that might target maternal metabolism are the focus of this article. Rapidly advancing technologies in genomics, proteomics, and metabolomics offer us innovative approaches to interrogate these metabolic processes in the mother, her microbiome, the placenta, and her offspring that contribute to a phenotype at risk for future metabolic disease. If we are successful in our efforts, the researcher, endocrinologist, obstetrician, and health care provider fortunate enough to care for pregnant women have the unique opportunity to positively impact health outcomes not only in the short term but in the long run, not just in one life but in two-and possibly, for the next generation.