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The heart switches its energy substrate from glucose to fatty acids at birth, and maternal hyperglycemia is associated with congenital heart disease. However, little is known about how blood glucose impacts heart formation. Using a chemically defined human pluripotent stem-cell-derived cardiomyocyte differentiation system, we found that high glucose inhibits the maturation of cardiomyocytes at genetic, structural, metabolic, electrophysiological, and biomechanical levels by promoting nucleotide biosynthesis through the pentose phosphate pathway. Blood glucose level in embryos is stable in utero during normal pregnancy, but glucose uptake by fetal cardiac tissue is drastically reduced in late gestational stages. In a murine model of diabetic pregnancy, fetal hearts showed cardiomyopathy with increased mitotic activity and decreased maturity. These data suggest that high glucose suppresses cardiac maturation, providing a possible mechanistic basis for congenital heart disease in diabetic pregnancy. Congenital heart disease is the most common type of birth defect, affecting nearly 1 in 100 children born. It can involve a weak heart, narrowed arteries, narrowed heart valves, or the main arteries of the heart switching places. These conditions can be fatal if untreated and often need surgery to correct. The mother’s blood sugar levels during pregnancy can have a large effect on how likely the baby is to have congenital heart disease. If a pregnant woman has poorly controlled diabetes with rapidly fluctuating sugar levels, she may be at a higher risk of having a child with the condition. High sugar levels in the mother’s blood make the baby up to five times more likely to have congenital heart disease. It has been difficult to find out exactly how sugar levels interfere with heart development because diabetes can affect the fetus in many ways. Nakano et al. used stem cells and experiments in pregnant mice with diabetes to hone in on how high sugar levels affect the fetus’s heart development. First, heart cells were grown from human stem cells, and exposed to high levels of glucose in a dish. This revealed a new mechanism for how high sugar levels affect heart formation: the cells created too many nucleotides, the building blocks of molecules such as DNA. It turns out that high glucose levels boosted a chemical process in the cell known as the pentose phosphate pathway. Some of the products of this pathway are nucleotides. This made the cells divide rapidly, but did not allow them to mature well compared with cells exposed to normal levels of sugar. In another experiment, Nakano et al. found similar results in pregnant diabetic mice. The heart cells in mouse fetuses also divided quickly but matured slowly when exposed to high sugar levels. An estimated 60 million women at an age to have children have diabetes. These new findings help us to understand why and how these women are more likely to have children with congenital heart disease, and further study will hopefully lead to a better way to prevent this condition.

The pregnancy complication preeclampsia (PE), which occurs in approximately 3% to 8% of human pregnancies, is characterized by placental pathologies that can lead to significant fetal and maternal morbidity and mortality. Currently, the only known cure is delivery of the placenta. As the etiology of PE remains unknown, it is vital to find models to study this common syndrome. Here we show that matrix metalloproteinase-9 (MMP9) deficiency causes physiological and placental abnormalities in mice, which mimic features of PE. As with the severe cases of this syndrome, which commence early in gestation, MMP9-null mouse embryos exhibit deficiencies in trophoblast differentiation and invasion shortly after implantation, along with intrauterine growth restriction or embryonic death. Reciprocal embryo transfer experiments demonstrated that embryonic MMP9 is a major contributor to normal implantation, but maternal MMP9 also plays a role in embryonic trophoblast development. Pregnant MMP9-null mice bearing null embryos exhibited clinical features of PE as VEGF dysregulation and proteinuria accompanied by preexisting elevated blood pressure and kidney pathology. Thus, our data show that fetal and maternal MMP9 play a role in the development of PE and establish the MMP9-null mice as a much-needed model to study the clinical course of this syndrome.

Background. Human cytomegalovirus (HCMV) is the major viral etiology of congenital infection and birth defects. Fetal transmission is high (30%-40%) in primary maternal infection, and symptomatic babies have permanent neurological, hearing, and vision defects. Recurrent infection is infrequently transmitted (2%) and largely asymptomatic. Congenital infection is also associated with intrauterine growth restriction (IUGR). Methods. To investigate possible underlying HCMV infection in cases of idiopathic IUGR, we studied maternal and cord sera and placentas from 19 pregnancies. Anti-HCMV antibodies, hypoxia-related factors, and cmvIL-10 were measured in sera. Placental biopsy specimens were examined for viral DNA, expression of infected cell proteins, and pathology. Results. Among 7 IUGR cases, we identified 2 primary and 3 recurrent HCMV infections. Virus replicated in glandular epithelium and lymphatic endothelium in the decidua, cytotrophoblasts, and smooth muscle cells in bloodvessels of floating villi and the chorion. Large fibrinoids with avascular villi, edema, and inflammation were significantly increased. Detection of viral proteins in the amniotic epithelium indicated transmission in 2 cases of IUGR with primary infection and 3 asymptomatic recurrent infections. Conclusions. Congenital HCMV infection impairs placental development and functions and should be considered as an underlying cause of IUGR, regardless of virus transmission to the fetus.

Obtaining a nutrient-rich diet during pregnancy is a challenge for pregnant women living in low-income countries. This randomized, controlled trial was designed to determine if a freshly prepared food supplement from local animal-source foods and dark-green leafy vegetables given prior to and/or during pregnancy improved birth outcomes in rural Vietnamese women. Primiparous women, 18 to 30 years of age, who participated in the study were assigned to one of three groups: PC-T women received the supplement from pre-conception to term, MG-T women received the supplement from mid-gestation to term, and the RPC women received routine prenatal care. Supplement intake was observed and quantified. Infant anthropometry was measured at birth and/or within seven days of delivery. The effect of the intervention on maternal and birth outcomes was determined using linear regression modeling. Of the 460 women enrolled in the study, 317 women completed the study. Those not completing the study had either moved from the area, did not conceive within 12 months of study enrollment, or miscarried. The food-based supplement increased protein, iron, zinc, folate, vitamin A and B12 intakes in the PC-T and the MG-T groups. However, it failed to alter infant anthropometric measurements at birth. In the entire cohort, maternal gestational weight gain was greater in women with a low pre-pregnancy BMI (<18.5) and in women with a higher educational attainment. Working as a farmer reduced gestational weight gain but it did not affect birth weight or length. In summary, a nutrient-rich, food-based supplement given to rural Vietnamese women from pre-conception to term or mid-gestation to term did not affect maternal or infant outcomes. The low weight gains, possibly due to demanding farm work done throughout the reproductive cycle, may have obviated any effects of the low energy, nutrient-rich food supplement on birth outcomes. Trial registration : Registered Clinical Trials.gov: NCT01235767.

Growth faltering among children during the first five years of life is a common problem among low and middle-income countries. The purpose of this study was to determine the effect of a nutrient-rich, food-based supplement given to Vietnamese rural women prior to and/or during pregnancy on the growth of their infants during first 24 months of life and to identify maternal and newborn factors associated with the infant's growth. This prospective cohort study included 236 infants born to mothers who had received nutritional advice or a food supplement from pre-conception to term or from mid-gestation to term as part of a prior randomized controlled trial. Infant anthropometry and feeding information were monitored monthly and the infant weight for age Z-score (WAZ), length for age Z-score (LAZ), and weight for length Z-score (WLZ) were assessed at 6, 12, 18, and 24 months of age using mixed-effects regression modeling. Compared to the non-supplemented mothers, infants born to mothers receiving food supplementation from mid-gestation to term had significantly higher WLZ only at 18 months (p = 0.03) and did not differ in other outcomes. Supplementation from pre-conception to term did not affect infant growth at any time point during the first 24 months. In the entire study cohort, maternal height and gestational weight gain were positively associated with the infant's WAZ and LAZ from 6 to 24 months of age. Programs designed to improve gestational weight gain among women performing demanding physical work throughout a reproductive cycle may improve postnatal infant growth.

People are exposed to phthalates through their wide use as plasticizers and in personal care products. Many phthalates are endocrine disruptors and have been associated with adverse health outcomes. However, knowledge gaps exist in understanding the molecular mechanisms associated with the effects of exposure in early and late pregnancy. In this study, we examined the relationship of eleven urinary phthalate metabolites with isoprostane, an established marker of oxidative stress, among pregnant Mexican-American women from an agricultural cohort. Isoprostane levels were on average 20% higher at 26 weeks than at 13 weeks of pregnancy. Urinary phthalate metabolite concentrations suggested relatively consistent phthalate exposures over pregnancy. The relationship between phthalate metabolite concentrations and isoprostane levels was significant for the sum of di-2-ethylhexyl phthalate and the sum of high molecular weight metabolites with the exception of monobenzyl phthalate, which was not associated with oxidative stress at either time point. In contrast, low molecular weight metabolite concentrations were not associated with isoprostane at 13 weeks, but this relationship became stronger later in pregnancy (p-value = 0.009 for the sum of low molecular weight metabolites). Our findings suggest that prenatal exposure to phthalates may influence oxidative stress, which is consistent with their relationship with obesity and other adverse health outcomes.