Long-term Consequences For Offspring Research Articles

Metformin use in pregnancy: What about long-term effects in offspring?

Metformin use in pregnancy is increasing worldwide. Unlike insulin, metformin crosses the placenta. Consequently, maternal and fetal concentrations are comparable. Teratogenic effects are not reported, nor are adverse pregnancy outcomes. Reduced risk of hypertensive disorders, hypoglycemia, and macrosomia are potential benefits, together with lower gestational weight gain. Although metformin has been prescribed for pregnant women during the last 40 years, long-term data regarding offspring outcomes are still lacking. Independent of maternal glycemic control, recent meta-analyses report lower birthweight but accelerated postnatal growth and higher body mass index in metformin-exposed children. The longest follow-up study of placebo-controlled metformin exposure in utero found an increased prevalence of central adiposity and obesity among children 5-10 years old. Recently, a Danish study reported a threefold increased risk of genital anomalies in boys, whose fathers used metformin around the time of conception. This commentary addresses the current controversies on metformin use in pregnancy.

Stressors interact across generations to influence offspring telomeres and survival.

Parental stress often has long-term consequences for offspring. However, the mechanisms underlying these effects and how they are shaped by conditions offspring subsequently experience are poorly understood. Telomeres, which often shorten in response to stress and predict longevity, may contribute to, and/or reflect these cross-generational effects. Traditionally, parental stress is expected to have negative effects on offspring telomeres, but experimental studies in captive animals suggest that these effects may depend on the subsequent conditions that offspring experience. Yet, the degree to which parental stress influences and interacts with stress experienced by offspring to affect offspring telomeres and survival in free-living organisms is unknown. To assess this, we experimentally manipulated the stress exposure of free-living parent and offspring house sparrows (Passer domesticus). We found a weak, initial, negative effect of parental stress on offspring telomeres, but this effect was no longer evident at the end of post-natal development. Instead, the effects of parental stress depended on the natural sources of stress that offspring experienced during post-natal development whereby some outcomes were improved under more stressful rearing conditions. Thus, the effects of parental stress on offspring telomeres and survival are context-dependent and may involve compensatory mechanisms of potential benefit under some circumstances.

Metabolomic signatures of low- and high-adiposity neonates differ based on maternal BMI.

Maternal obesity [body mass index (BMI) > 30 kg/m2] is associated with greater neonatal adiposity, cord blood (CB) insulin levels, and a proinflammatory phenotype at birth, contributing to risk of future cardiometabolic disease in the offspring. Variation in neonatal adiposity within maternal BMI groups is underappreciated, and it remains unclear whether the metabolic impairments at birth are an outcome of maternal obesity or excess fetal fat accrual. We examined the hypothesis that CB metabolites associated with fetal fat accrual differ between offspring of normal-weight and obese women. Umbilical venous blood was collected at the time of scheduled cesarean delivery from 50 normal-weight women (LE; pregravid BMI = 22.3 ± 1.7 kg/m2) and 50 obese women (OB; BMI = 34.5 ± 3.0 kg/m2). Neonatal adiposity was estimated from flank skinfold thickness. The first (low adiposity, LA) and third (high adiposity, HA) tertiles of neonatal %body fat were used to create four groups: OBLA, OBHA, LELA, and LEHA. CB metabolites were measured via untargeted metabolomics. Broadly, the LA offspring of OB women (OBLA) metabolite signature differed from other groups. Lauric acid (C12:0) was 82-118% higher in OBLA vs. all other groups [false discovery rate (FDR) < 0.01]. Several other fatty acids, including palmitate, stearate, and linoleate, were higher in OBLA vs. OBHA groups. CB metabolites, such as lauric acid, a medium-chain fatty acid that may improve insulin sensitivity, were associated with neonatal adiposity differently between offspring of women with and without obesity. Changes in metabolically active lipids at birth may have long-term consequences for offspring metabolism.NEW & NOTEWORTHY Using untargeted metabolomics in 100 newborns, we found that cord blood metabolite signatures associated with neonatal adiposity differed between offspring of women with and without obesity.

Consequences of Viral Infection and Cytokine Production During Pregnancy on Brain Development in Offspring.

Infections during pregnancy can seriously damage fetal neurodevelopment by aberrantly activating the maternal immune system, directly impacting fetal neural cells. Increasing evidence suggests that these adverse impacts involve alterations in neural stem cell biology with long-term consequences for offspring, including neurodevelopmental disorders such as autism spectrum disorder, schizophrenia, and cognitive impairment. Here we review how maternal infection with viruses such as Influenza A, Cytomegalovirus, and Zika during pregnancy can affect the brain development of offspring by promoting the release of maternal pro-inflammatory cytokines, triggering neuroinflammation of the fetal brain, and/or directly infecting fetal neural cells. In addition, we review insights into how these infections impact human brain development from studies with animal models and brain organoids. Finally, we discuss how maternal infection with SARS-CoV-2 may have consequences for neurodevelopment of the offspring.

Prenatal exposure to neurotoxic metals and micronutrients and neurodevelopmental outcomes in early school age children from Poland.

Exposure to environmental factors, such as neurotoxic metals and micronutrients, during critical periods of development can contribute to long-term consequences in offspring's health, including neurodevelopmental outcomes. The aim of this study was to evaluate the association between simultaneous prenatal exposure to metals [lead (Pb), cadmium (Cd), mercury (Hg)] and micronutrients [selenium (Se), zinc (Zn), copper (Cu)] and neurodevelopmental outcomes in school-age children from the Polish Mother and Child Cohort (REPRO_PL). Metals and micronutrients concentrations were measured in cord blood (Pb, Cd, Se, Zn, Cu) and in maternal hair (Hg) collected during the 3rd trimester of pregnancy. Behavioral and emotional problems, as well as children's cognitive and psychomotor development, were assessed in 436 school-age children using the Strengths and Difficulties Questionnaire (SDQ, filled in by the mothers) and the Polish adaptation of the Intelligence and Development Scales (IDS, administered by trained psychologists). Multivariate regression models were applied after imputation of missing values, using two approaches: (i) a joint analysis taking into account all metals and micronutrients simultaneously, and (ii) an ExWAS study (single-exposure model). In the SDQ, Hyperactivity/Inattention problems and Total difficulties were associated with higher Hg concentrations in maternal hair (0.18, 95% CI: 0.05; 0.3; and 0.14, 95% CI: 0.01; 0.3, respectively), whereas Emotional symptoms were inversely associated with Se and Zn levels in cord blood (-0.13, 95% CI: -0.3; 0.004; and -0.10, 95% CI: -0.2; 0.02, respectively). In the IDS, cord blood Pb levels were found to be negatively associated with Fluid and Crystallized IQ (-0.12, 95% CI: -0.3; 0.02; and -0.14, 95% CI: -0.3; 0.007, respectively) as well as Mathematical skills (-0.15, 95% CI: -0.3; 0.01). The current research has been able to simultaneously assess the exposure to various interacting chemicals during the prenatal period. We demonstrate that prenatal co-exposures to Pb, Hg, Zn and Se have long-term influences on the neuropsychological outcome of school-age children.

Cardiovascular and Cerebrovascular Implications of Growth Restriction: Mechanisms and Potential Treatments.

Fetal growth restriction (FGR) is a common complication of pregnancy, resulting in a fetus that fails to reach its genetically determined growth potential. Whilst the fetal cardiovascular response to acute hypoxia is well established, the fetal defence to chronic hypoxia is not well understood due to experiment constraints. Growth restriction results primarily from reduced oxygen and nutrient supply to the developing fetus, resulting in chronic hypoxia. The fetus adapts to chronic hypoxia by redistributing cardiac output via brain sparing in an attempt to preserve function in the developing brain. This review highlights the impact of brain sparing on the developing fetal cardiovascular and cerebrovascular systems, as well as emerging long-term effects in offspring that were growth restricted at birth. Here, we explore the pathogenesis associated with brain sparing within the cerebrovascular system. An increased understanding of the mechanistic pathways will be critical to preventing neuropathological outcomes, including motor dysfunction such as cerebral palsy, or behaviour dysfunctions including autism and attention-deficit/hyperactivity disorder (ADHD).

Exposure to maternal high-fat diet induces extensive changes in the brain of adult offspring

Maternal environmental exposures, such as high-fat diets, diabetes and obesity, can induce long-term effects in offspring. These effects include increased risk of neurodevelopmental disorders (NDDs) including autism spectrum disorder (ASD), depression and anxiety. The mechanisms underlying these late-life neurologic effects are unknown. In this article, we measured changes in the offspring brain and determined which brain regions are sensitive to maternal metabolic milieu and therefore may mediate NDD risk. We showed that mice exposed to a maternal high-fat diet display extensive brain changes in adulthood despite being switched to a low-fat diet at weaning. Brain regions impacted by early-life diet include the extended amygdalar system, which plays an important role in reward-seeking behaviour. Genes preferentially expressed in these regions have functions related to feeding behaviour, while also being implicated in human NDDs, such as autism. Our data demonstrated that exposure to maternal high-fat diet in early-life leads to brain alterations that persist into adulthood, even after dietary modifications.

Acetaminophen Attenuates invasion and alters the expression of extracellular matrix enzymes and vascular factors in human first trimester trophoblast cells

Acetaminophen is one of the most common medications taken during pregnancy, considered safe for maternal health and fetal development. However, recent epidemiological studies have associated prenatal acetaminophen use with several developmental disorders in offspring. As acetaminophen can freely cross into and through the placenta, epidemiological associations with prenatal acetaminophen use may reflect direct actions on the fetus and/or the impact of altered placental functions. In the absence of rigorous mechanistic studies, our understanding of how prenatal acetaminophen exposure can cause long-term effects in offspring is limited. The objective of this study was to determine whether acetaminophen can alter key functions of a major placental cell type by utilizing immortalized human first trimester trophoblast cells. This study employed a comparative analysis with the nonsteroidal, anti-inflammatory drug aspirin, which has established effects in first trimester trophoblast cells. We report that immortalized trophoblast cells express the target proteins of acetaminophen and aspirin: cyclooxygenase (COX) −1 and −2. Unlike aspirin, acetaminophen significantly repressed the expression of angiogenesis and vascular remodeling genes in HTR-8/SVneo cells. Moreover, acetaminophen impaired trophoblast invasion by over 80%, while aspirin had no effect on invasion. Acetaminophen exposure reduced the expression of matrix metalloproteinase (MMP)-2 and −9 and increased the expression of tissue inhibitors of matrix metalloproteinases 2, leading to an imbalance in the ratio of proteolytic enzymes. Finally, a bioinformatic approach identified novel acetaminophen-responsive gene networks associated with key trophoblast functions and disease. Together these results suggest that prenatal acetaminophen use may interfere with critical trophoblast functions early in gestation, which may subsequently impact fetal development.

The Effect of Embryo Culture on Ontogenesis of Mammalian Offspring

A review of data about the impact of assisted reproductive technologies, mainly in vitro culture of preimplantation embryos, on pre- and postnatal development is presented. Specificities of the influence of nutrient media on the development of the embryo and the formation of fetuses are considered. Special attention is paid to the long-term effects in offspring that is born after the application of these procedures.

Gestational Diabetes Mellitus Affects Offspring's Epigenome. Is There a Way to Reduce the Negative Consequences?

Gestational diabetes mellitus (GDM) is the most common pregnancy complication worldwide and may result in short-term and long-term consequences for offspring. The present review highlights evidence of epigenetic programming, mostly from human studies, which occurs in offspring exposed to maternal GDM during different stages of development, paying special attention to the differences in sensitivity of offspring to maternal hyperglycemia as a result of sex-related factors. We also aim to answer the following question: If these epigenetic changes are constant throughout the lifetime of the offspring, how do they present phenotypically?

The impact of maternal obesity and diabetes on fetal brain development (mechanisms and prevention)

The review presents the results of clinical and experimental studies that indicate a high frequency of neuropsychiatric diseases and mechanisms of adverse effects during intrauterine development, determining long-term effects in offspring of obese and / or diabetic mothers. Approaches to prevention in the planning stage and during pregnancy are also discussed in the review.

Perinatal exposure to the SSRI paroxetine alters the methylome landscape of the developing dentate gyrus.

Evidence in humans and rodents suggests that perinatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants can have serious long-term consequences in offspring exposed in utero or infancy via breast milk. In spite of this, there is limited knowledge of how perinatal SSRI exposure impacts brain development and adult behaviour. Children exposed to SSRIs in utero exhibit increased internalizing behaviour and abnormal social behaviour between the ages of 3 and 6, and increased risk of depression in adolescence; however, the neurobiological changes underlying this behaviour are poorly understood. In rodents, perinatal SSRI exposure perturbs hippocampal gene expression and alters adult emotional behaviour (including increased depression-like behaviour). The present study demonstrates that perinatal exposure to the SSRI paroxetine leads to DNA hypomethylation and reduces DNA methyltransferase 3a (Dnmt3a) mRNA expression in the hippocampus during the second and third weeks of life. Next-generation sequencing identified numerous differentially methylated genomic regions, including altered methylation and transcription of several dendritogenesis-related genes. We then tested the hypothesis that transiently decreasing Dnmt3a expression in the early postnatal hippocampus would mimic the behavioural effects of perinatal SSRI exposure. We found that siRNA-mediated knockdown of Dnmt3a in the dentate gyrus during the second to third week of life produced greater depression-like behaviour in adult female (but not male) offspring, akin to the behavioural consequences of perinatal SSRI exposure. Overall, these data suggest that perinatal SSRI exposure may increase depression-like behaviours, at least in part, through reduced Dnmt3a expression in the developing hippocampus.

Prenatal metformin exposure or organic cation transporter 3 knock-out curbs social interaction preference in male mice

Poorly managed gestational diabetes can lead to severe complications for mother and child including fetal overgrowth, neonatal hypoglycemia and increased autism risk. Use of metformin to control it is relatively new and promising. Yet safety concerns regarding gestational metformin use remain, as its long-term effects in offspring are unclear. In light of beneficial findings with metformin for adult mouse social behavior, we hypothesized gestational metformin treatment might also promote offspring sociability. To test this, metformin was administered to non-diabetic, lean C57BL/6 J female mice at mating, with treatment discontinued at birth or wean. Male offspring exposed to metformin through birth lost social interaction preference relative to controls by time in chambers, but not by sniffing measures. Further, prenatal metformin exposure appeared to enhance social novelty preference only in females. However due to unbalanced litters and lack of statistical power, firm establishment of any sex-dependency of metformin’s effects on sociability was not possible. Since organic cation transporter 3 (OCT3) transports metformin and is dense in placenta, social preferences of OCT3 knock-out males were measured. Relative to wild-type, OCT3 knock-outs had reduced interaction preference. Our data indicate gestational metformin exposure under non-diabetic conditions, or lack of OCT3, can impair social behavior in male C57BL6/J mice. Since OCT3 transports serotonin and tryptophan, impaired placental OCT3 function is one common mechanism that could persistently impact central serotonin systems and social behavior. Yet no gross alterations in serotonergic function were evident by measure of serotonin transporter density in OCT3, or serotonin turnover in metformin-exposed offspring brains. Mechanisms underlying the behavioral outcomes, and if with gestational diabetes the same would occur, remain unclear. Metformin’s impacts on placental transporters and serotonin metabolism or AMPK activity in fetal brain need further investigation to clarify benefits and risks to offspring sociability from use of metformin to treat gestational diabetes.

Metformin in the management of diabetes during pregnancy and lactation.

This review explores the current place of metformin in the management of gestational diabetes (GDM) and type 2 diabetes during pregnancy and lactation. The rationale and basic pharmacology of metformin usage in pregnancy is discussed along with the evidence from observational and randomized controlled trials in women with GDM or overt diabetes. There seems to be adequate evidence of efficacy and short-term safety of metformin in relation to maternal and neonatal outcomes in GDM, with possible benefits related to lower maternal weight gain and lower risk of neonatal hypoglycemia and macrosomia. Additionally, metformin offers the advantages of oral administration, convenience, less cost and greater acceptability. Metformin may, therefore, be considered in milder forms of GDM where glycemic goals are not attained by lifestyle modification. However, failure rate is likely to be higher in those with an earlier diagnosis of GDM, higher blood glucose, higher body mass index (BMI) or previous history of GDM, and insulin remains the cornerstone of pharmacological treatment in such cases. The use of metformin in type 2 diabetes has been assessed in observational and small randomized trials. Metformin monotherapy in women with overt diabetes is highly unlikely to achieve glycemic targets. Hence, the use should be restricted as adjunct to insulin and may be considered in women with high insulin dose requirements or rapid weight gain. There is clearly a need for more clinical trials to assess the effect of combined insulin plus metformin therapy in pregnancy with type 2 diabetes. Additionally, there is a paucity of data on long-term effects in offspring exposed to metformin in utero. It is imperative to further explore its impact on offspring as metformin has significant transplacental transfer and has the potential to impact the programming of the epigenome. Therefore, caution must be exercised when prescribing metformin in pregnant women. More research is clearly needed before metformin can be considered as standard of care in the management of diabetes during pregnancy.

Obesity in mares promotes uterine inflammation and alters embryo lipid fingerprints and homeostasis.

Maternal body composition can be an important determinant for development of obesity and metabolic syndrome in adult offspring. Obesity-related outcomes in offspring may include epigenetic alterations; however, mechanisms of fetal programming remain to be fully elucidated. This study was conducted to determine the impact of maternal obesity in the absence of a high fat diet on equine endometrium and preimplantation embryos. Embryos were collected from normal and obese mares at 8 and 16 days and a uterine biopsy at 16 days (0 day=ovulation). With the exception of 8 day embryos, each sample was divided into two pieces. One piece was analyzed for gene expression markers related to carbohydrate metabolism, lipid homeostasis, inflammation, endoplasmic reticulum stress, oxidative stress, mitochondrial stress, and components of the insulin-like growth factor (IGF) system. The second piece was analyzed for lipid content using matrix-assisted laser desorption/ionization mass spectrometry. Obese mares had elevated concentrations of insulin, leptin, and total cholesterol, and they tended to have increased triglycerides and decreased insulin sensitivity. Embryos from obese mares had altered transcript abundance in genes for inflammation and lipid homeostasis, as well as endoplasmic reticulum, oxidative and mitochondrial stress and altered lipid fingerprints. Endometrium from obese mares had increased expression of inflammatory cytokines, lipid homeostasis regulation, mitochondrial stress, and the IGF2 system. This study demonstrates that increased adiposity in mares alters the uterine environment, transcript abundance of genes for cellular functions, and lipid profiles of embryos. These alterations could affect prenatal programming, with potential long-term effects in offspring.

The influence of LPS and zinc on interaction between mother and offspring

IntroductionThe maternal behavior consists of a set of behavioral and physiological changes in adults, performed around the reproductively immature individuals, ensuring their survival and propagation of the species. Offsprings give signal to be collected when separated from their mother through olfactory, visual and sound signals. Infection and its influence in the context of the interaction between mother and offspring is poorly investigated. The classic disease model, which is widely used, involves the treatment with lipopolysaccharide (LPS), the major component of the cell wall of Gram‐negative bacteria. The infections can activate a chain of nonspecific host responses, including the immune response and levels of zinc.ObjectiveTo investigate the behavioral and neuroimmunological adaptations of rats and their offspring resulting from experimental inflammation produced by LPS and the possible influence of zinc treatment on these adaptations.MethodsIn this study, virgin, pregnant and lactating female rats received LPS (100 μg/kg, ip) and then were treated with zinc (2 mg/kg, sc). Temperature, body weight, water and food consumption were measured for ninety‐six hours, starting two hours after LPS administration. On the fifth day of lactation, maternal behavior, the overall activity in the open field and ultrasonic vocalization in offsprings were observed. On the day of weaning, pups of these females received a challenge with LPS (50 μg/kg, ip) and two hours after administration were observed for general activity in the open field. The burst and phagocytosis of leukocytes in the blood of pups was also studied.Results1) in virgin, pregnant and lactating rats, the exposure to LPS and the treatment with zinc modified the temperature, body weight, water and food consumption, and the general activity observed in the open field. Virgin, pregnant or lactating rats responded differently to this treatment. 2) In the lactation period the latency to search the first pup was reduced. 3) In the offspring, a change in the pattern of vocalization of the offspring, changes in general activity observed in the open field and changes in the burst and phagocytosis of leukocytes on the twenty‐first day of lactation after challenge with endotoxin were detected.Conclusionthe results indicate that administration of LPS and treatment with zinc have effects modulated according to the physiological stage of the female. These effects interfere with the interaction between a mother and her offspring, resulting in short and long term effects in offspring's behavior. Exposure of mothers to bacterial endotoxin modulates the effects caused by zinc and programs the inflammatory responses in the offspring.Support or Funding InformationCoordination for the Improvement of Higher Education Personnel (CAPES)Natural Sciences and Engineering Research Council (NSERC)Canadian Centre for Health and Safety in Agriculture (CCHSA)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Early sex-dependent differences in response to environmental stress

Developmental plasticity enables the appearance of long-term effects in offspring caused by exposure to environmental stressors during embryonic and foetal life. These long-term effects can be traced to pre- and post-implantation development, and in both cases, the effects are usually sex specific. During preimplantation development, male and female embryos exhibit an extensive transcriptional dimorphism mainly driven by incomplete X chromosome inactivation. These early developmental stages are crucial for the establishment of epigenetic marks that will be conserved throughout development, making it a particularly susceptible period for the appearance of long-term epigenetic-based phenotypes. Later in development, gonadal formation generates hormonal differences between the sexes, and male and female placentae exhibit different responses to environmental stressors. The maternal environment, including hormones and environmental insults during pregnancy, contributes to sex-specific placental development that controls genetic and epigenetic programming during foetal development, regulating sex-specific differences, including sex-specific epigenetic responses to environmental hazards, leading to long-term effects. This review summarizes several human and animal studies examining sex-specific responses to environmental stressors during both the periconception period (caused by differences in sex chromosome dosage) and placental development (caused by both sex chromosomes and hormones). The identification of relevant sex-dependent trajectories caused by sex chromosomes and/or sex hormones is essential to define diagnostic markers and prevention/intervention protocols.

Maternal hypoxia increases hippocampal cell susceptibility to ischemia after middle cerebral artery occlusion in rat offspring.

<i><B>Introduction</B>: Maternal hypoxia induces an adverse uterine environment and may induce long-term effects in offspring. This study investigated whether maternal hypoxia increases hippocampal cell vulnerability and exacerbates neurological impairments in adult rat offspring following ischemia. <B>Material and methods</B>: Pregnant Sprague-Dawley rats were randomly assigned to no maternal hypoxia or maternal hypoxia treatment groups. Adult male rat offspring were subjected to middle cerebral artery occlusion (MCAO). There were four groups: maternal + sham (MH + Sham), sham (Sham), maternal hypoxia + MCAO (MH + MCAO), and MCAO only (MCAO). Neurological deficits were evaluated. Hippocampal cell damage was observed by hematoxylin and eosin (HE) staining. Cell apoptosis in the hippocampus was detected by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining. Caspase-3, cytochrome c, Bax, and bcl-2 expression in the hippocampus was detected by Western blot. <B>Results</B>: More severe hippocampal cell damage was found in the MH + MCAO group than in the MCAO group. Additionally, neurological deficits, percentage of TUNEL positive cells, and expression of caspase-3, cytochrome c, and Bax in the hippocampus were significantly higher (p < 0.05), whereas bcl-2 expression was significantly lower (p < 0.05) in the MH + MCAO group compared to the MCAO group. <B>Conclusions</B>: These findings suggest that maternal hypoxia may exacerbate hippocampal cell apoptosis in rat offspring after MCAO via alterations in the expression of cytochrome c, caspase-3, Bax, and bcl-2, which ultimately affects ischemic stroke prognosis. To our knowledge, this is the first study demonstrating that maternal hypoxia increases hippocampal cell susceptibility to ischemia in adult rat offspring. </i>.

Obesity and Antiphospholipid Syndrome: A Particular Challenge in Pregnancy

Obesity is associated with a broad spectrum of chronic diseases, as well as cardiovas- cular diseases, such as diabetes, dyslipidemia, insulin resistance and hyperglycemia. Obesity during pregnancy is of major concern due to the well-known risk factors for both the mother and the child. Complications in pregnancy include recurrent miscarriages, gestational diabe- tes, hypertensive disorders, thromboembolism, and stillbirth. Additionally, maternal obesity seems to have long-term consequences for offspring, predisposing or programming them to the development of metabolic disease in adulthood. Antiphospholipid syndrome (APS) is an autoimmune disease and is characterized by the presence of antiphospholipid antibodies (an- ticardiolipin antibodies/ACLA, lupus antikoagulans/LA and s2-glycoprotein) in the maternal circulation. These antibodies are associated with arterial and/or venous thromboses and with adverse obstetric outcomes such as recurrent fetal loss, Preeclampsia (PE), Intrauterine growth restriction (IUGR) and Intrauterine fetal death (IUFD). Obesity and APS are both chronic diseases with similar, even long-term consequences for mother and child; a co-occurrence of obesity and APS in pregnancy worsens the situation; the use of novel therapeutical tools should be therefore encouraged. A better understanding of the complex interactions between endothelial dysfunction and obesity and APS should be further investigated. Obese women with known APS should be counselled before conception not only about potential obstetrical complications as well as the long-term consequences for the off-spring, but also about these important life-style modifications. This review will provide an overview of obesity and APS in pregnancy and will discuss endothelial dysfunction as mecha- nism for adverse obstetric outcome in these chronic diseases.

Hepatic steatosis is prevalent in stillborns delivered to women with diabetes mellitus.

Maternal diabetes is a risk factor for pregnancy complications, including stillbirth and macrosomia. Evolving data suggest that diabetes during pregnancy also has long-term consequences for offspring, putting them at risk for obesity and the metabolic syndrome in childhood. Because nonalcoholic fatty liver disease is known to occur in adults and children with insulin resistance, we hypothesized that altered lipid metabolism in fetuses of diabetic mothers may manifest with hepatic steatosis. We undertook a retrospective autopsy study to compare the presence and degree of hepatic steatosis between stillborns delivered to women with pregestational or gestational diabetes mellitus (gestational age 20-40 weeks; n = 33) and age-matched nondiabetic control stillbirth cases (n = 48), the latter enriched for maternal obesity, macrosomia, and similar cause of demise. Histopathologic hepatic steatosis was significantly more prevalent and severe in the diabetic subjects (26/33, 78.8%) than in the controls (8/48, 16.6%) (P < 0.001). Within the diabetic cohort, the severity of steatosis was related directly to gestational age, birth weight, and liver weight, with no correlation of presence or severity of steatosis in the control group to maternal or fetal factors, including maternal body mass index or fetal macrosomia. Although macrosomic stillborns were more common in diabetic women with %hemoglobin A1c >6 and body mass index >30 kg/m, fetal steatosis was independent of glycemic control, maternal obesity, type of diabetes, ethnicity, or fetal sex in our cohort. This study is the first to our knowledge to demonstrate a specific association between fetal hepatic steatosis and maternal diabetes.