Complication Of Human Pregnancy Research Articles

PS-1 An evaluation of sodium salicylate in the periparturient management of the sow

Abstract Mortality continues to trend higher in highly prolific sows in the U.S., with the periparturient period being the time of greatest loss (Eckberg, 2021). Sodium salicylate (NaSal) is a nonsteroidal anti-inflammatory drug (NSAID) similar to aspirin, which is used to manage pre-eclampsia-related pregnancy complications in humans (Roberge et al. 2017). The objectives of this experiment were: 1) Collect farrowing data for scoring periparturient health; and 2) Evaluate the impact of NaSal on periparturient health and inflammation. A total of 47 parity 1 and 2 females (PIC 1050) were utilized with a starting body weight (BW) of 214.3kg ± 14.7 SD. Sows were blocked by BW on d 105 gestation and parity and randomly assigned to one of two treatment groups. The treatments were: control (CON) n = 23; or treatment (TRT) n = 24. TRT consisted of NaSal (Oral-Pro, Aurora Pharmaceutical, Northfield, MN) administered via water 3 d pre-farrow to 5 d post-farrow, with a target dose of 50 mg NaSal/kg BW. At d 106 of gestation and weaning, BW, back fat (BF), and body condition by caliper (BCS) were measured. Sows were assigned a farrowing ease score of 1-4 (1 - easy to 4 - extremely difficult) based on duration, restless activity, savaging, and assistance required. Data were analyzed using the GLM procedure in SAS, with sow serving as the experimental unit and LSMeans testing for differences among means. Average farrowing duration for both groups was 335.5 min ± 144.2 SD. Farrowing ease score for all sows was assessed as a mean of 2.28 with 47% scored as difficult (Score 3 to 4). Treatment improved farrowing ease score (TRT avg: 1.9; CON avg 2.7; P < 0.01) and reduced savaging severity and frequency (TRT: 5 sows, 1 severe; CON: 8 sows, 7 severe; P < 0.05). TRT sows (24/24) successfully weaned litters compared with CON sows (20/23). All sows assigned a 1 or 2 score (25/25) weaned litters compared with sows assigned 3 or 4 (19/22). In conclusion, farrowing difficulty contributes to the need for greater care of highly prolific sows. Supplementation of NaSal during the periparturient period may improve farrowing ease and health outcomes.

Perinatal compromise affects development, form, and function of the hippocampus part one; clinical studies.

The hippocampus is a neuron-rich specialised brain structure that plays a central role in the regulation of emotions, learning and memory, cognition, spatial navigation, and motivational processes. In human fetal development, hippocampal neurogenesis is principally complete by mid-gestation, with subsequent maturation comprising dendritogenesis and synaptogenesis in the third trimester of pregnancy and infancy. Dendritogenesis and synaptogenesis underpin connectivity. Hippocampal development is exquisitely sensitive to perturbations during pregnancy and at birth. Clinical investigations demonstrate that preterm birth, fetal growth restriction (FGR), and acute hypoxic-ischaemic encephalopathy (HIE) are common perinatal complications that alter hippocampal development. In turn, deficits in hippocampal development and structure mediate a range of neurodevelopmental disorders, including cognitive and learning problems, autism, and Attention-Deficit/Hyperactivity Disorder (ADHD). In this review, we summarise the developmental profile of the hippocampus during fetal and neonatal life and examine the hippocampal deficits observed following common human pregnancy complications. IMPACT: The review provides a comprehensive summary of the developmental profile of the hippocampus in normal fetal and neonatal life. We address a significant knowledge gap in paediatric research by providing a comprehensive summary of the relationship between pregnancy complications and subsequent hippocampal damage, shedding new light on this critical aspect of early neurodevelopment.

Twist1-IRF9 Interaction Is Necessary for IFN-Stimulated Gene Anti-Zika Viral Infection.

An efficient immune defense against pathogens requires sufficient basal sensing mechanisms that can deliver prompt responses. Type I IFNs are protective against acute viral infections and respond to viral and bacterial infections, but their efficacy depends on constitutive basal activity that promotes the expression of downstream genes known as IFN-stimulated genes (ISGs). Type I IFNs and ISGs are constitutively produced at low quantities and yet exert profound effects essential for numerous physiological processes beyond antiviral and antimicrobial defense, including immunomodulation, cell cycle regulation, cell survival, and cell differentiation. Although the canonical response pathway for type I IFNs has been extensively characterized, less is known regarding the transcriptional regulation of constitutive ISG expression. Zika virus (ZIKV) infection is a major risk for human pregnancy complications and fetal development and depends on an appropriate IFN-β response. However, it is poorly understood how ZIKV, despite an IFN-β response, causes miscarriages. We have uncovered a mechanism for this function specifically in the context of the early antiviral response. Our results demonstrate that IFN regulatory factor (IRF9) is critical in the early response to ZIKV infection in human trophoblast. This function is contingent on IRF9 binding to Twist1. In this signaling cascade, Twist1 was not only a required partner that promotes IRF9 binding to the IFN-stimulated response element but also an upstream regulator that controls basal levels of IRF9. The absence of Twist1 renders human trophoblast cells susceptible to ZIKV infection.

SAMD1 attenuates antiphospholipid syndrome-induced vascular injury and pregnancy complications.

ObjectiveThis study was intended to investigate the effect of SAMD1 on antiphospholipid syndrome (APS)‐induced vascular injury in human umbilical vein endothelial cells (HUVECs) and pregnancy complications in mice.MethodsThe expression of SAMD1 in APS patients and healthy controls was detected by quantitative real‐time polymerase chain reaction (qRT‐PCR). Anti‐B2GPI and anticardiolipin antibody (ACA) levels were tested by enzyme‐linked immunosorbent assay, MMP‐9, iNOS, ICAM‐1, and MCP‐1 mRNA and protein levels determined by qRT‐PCR and Western blot, cellular senescence detected by β‐galactosidase staining, cell proliferation ability detected by CCK‐8 assay, cell viability detected by trypan blue staining, cell mobility detected by Transwell, and cell angiogenesis ability detected by matrigel tube formation assay. An APS pregnant mouse model was constructed, and the embryo absorption rate was calculated.ResultsSAMD1 expression was low in serum of APS patients, which was correlated with the history of thrombosis and the number of adverse pregnancies. Anti‐B2GPI and ACA levels were increased in APS. The expressions of MMP‐9, iNOS, ICAM‐1, and MCP‐1 were also significantly upregulated in HUVECs treated with APS serum. APS promoted HUVEC senescence and inhibited cell proliferation, migration, and angiogenesis. Overexpression of SAMD1 reversed the above results. Experiments on the APS pregnant mouse model confirmed that overexpression of SAMD1 reduced the rate of fetal loss.ConclusionSAMD1 may reduce APS‐induced vascular injury and embryo loss by regulating cellular senescence, proliferation, migration, and angiogenesis.

Fat augments leptin-induced uterine contractions by decreasing JAK2 and BKCa channel expressions in late pregnant rats

Altered lipid metabolism in obesity causes pregnancy complications in humans and animals. Leptin levels increase in pregnancy, as well as obesity. However, the effect of obesity on uterine leptin receptors and its distal signaling is not clear. The present study aimed to understand the effect of increased fat on leptin signaling in rat uterus. Wistar female rats were fed with an HF diet (40% Fat, 17% Sucrose, 1.25% Cholesterol, 0.75% Cholic acid) for 6 weeks before the mating and during pregnancy. HF diet significantly increased the fat depots, liver weight, serum, and tissue cholesterol levels. It produced fatty degeneration in the liver and caused infiltration of inflammatory cells, cystic endometrial glands, and sub endometrial fibrosis of the uterus. In isometric tension experiments, leptin caused a significant increase in uterine contractions in high fat-fed animals compared to control animals. Analysis of receptor expressions revealed no significant difference between the groups. However, a significant decrease in the JAK2 and BKCaα mRNA expression was observed in the uterus of high fat-fed rats. No change in the BKCaβ, eNOS, iNOS, MLCP, and MLCK mRNA expressions was noticed in the HF group compared to the control. The findings of the present study suggest that the contractile response to leptin in the uterus of high fat-fed rats may be attributed to reduced signaling through JAK2 and, lowered expressions of BKCa channel α subunits.

Immunological microenvironment at the maternal-fetal interface

The immune cells, especially innate immune cells (Natural Killer cells and Macrophages) residing at the maternal-fetal interface are playing critical roles during pregnancy. Here we discuss the immunological characteristic at the maternal-fetal interface during normal pregnancy. These key decidual immune cells are reshaped of their uterus-specific homeostatic functions within this uterus microenvironment. Through emphasizing the similarities and differences between decidua immune microenvironments with tumor or transplantation immune microenvironments, distinctive immune cell niche with activated, tolerant, proangiogenic and nurturing characteristic at the maternal interface is exhibited. Deeper understanding of the immunological microenvironment during pregnancy yield important insight not only into the pathogenesis of various human pregnancy complications, but also suggest ways to better manipulate these immune cells in cancer and transplant organs.

Evaluating the Effects of BPA and TBBPA Exposure on Pregnancy Loss and Maternal-Fetal Immune Cells in Mice.

Background:Bisphenol A (BPA) exposure has been linked to miscarriages and pregnancy complications in humans. In contrast, the potential reproductive toxicity of BPA analogs, including tetrabromobisphenol A (TBBPA), is understudied. Furthermore, although environmental exposure has been linked to altered immune mediators, the effects of BPA and TBBPA on maternal–fetal immune tolerance during pregnancy have not been studied. The present study investigated whether exposure resulted in higher rates of pregnancy loss in mice, lower number of regulatory T cells (Tregs), and lower indoleamine 2,3 deoxygenase 1 (Ido1) expression, which provided evidence for mechanisms related to immune tolerance in pregnancy.Objectives:The purpose of this investigation was to characterize the effects of BPA and TBBPA exposure on pregnancy loss in mice and to study the percentage and number of Tregs and Ido1 expression and DNA methylation.Methods:Analysis of fetal resorption and quantification of maternal and fetal immune cells by flow cytometry were performed in allogeneic and syngeneic pregnancies. Ido1 mRNA and protein expression, and DNA methylation in placentas from control and BPA- and TBBPA-exposed mice were analyzed using real-time quantitative polymerase chain reaction, immunofluorescence, and bisulfite sequencing analyses.Results:BPA and TBBPA exposure resulted in higher rates of hemorrhaging in early allogeneic, but not syngeneic, conceptuses. In allogeneic pregnancies, BPA and TBBPA exposure was associated with higher fetal resorption rates and lower maternal Treg number. Importantly, these differences were associated with lower IDO1 protein expression in trophoblast giant cells and higher mean percentage Ido1 DNA methylation in embryonic day 9.5 placentas from BPA- and TBBPA-exposed mice.Discussion:BPA- and TBBPA-induced pregnancy loss in mice was associated with perturbed IDO1-dependent maternal immune tolerance. https://doi.org/10.1289/EHP10640

Vascular alterations impede fragile tolerance to pregnancy in type 1 diabetes

To determine the impact of autoimmunity in the absence of glycemic alterations on pregnancy in type 1 diabetes (T1D). Because nonobese diabetic (NOD) mice experience autoimmunity before the onset of hyperglycemia, we studied pregnancy outcomes in prediabetic NOD mice using flow cytometry and enzyme-linked immunosorbent assays. Once we determined that adverse events in pregnancy occurred in euglycemic mice, we performed an exploratory study using electronic health records to better understand pregnancy complications in humans with T1D and normal hemoglobin A1c levels. University Medical Center. Nonobese diabetic mice and electronic health records from Vanderbilt University Medical Center. Nonobese diabetic mice were administered 200 μg of an anti-interleukin 6 (IL-6) antibody every other day starting on day 5 of gestation. Changes in the number of abnormal and reabsorbed pups in NOD mice and odds of vascular complications in pregnancy in T1D in relation to A1c. Prediabetic NOD mice had increased adverse pregnancy outcomes compared with nonautoimmune mice; blockade of IL-6, which was secreted by endothelial cells, decreased the number of reabsorbed and abnormal fetuses. Similarly, vascular complications were increased in pregnant patients with T1D across all A1c values. The vascular secretion of IL-6 drives adverse pregnancy outcomes in prediabetic NOD mice. Pregnant patients with T1D have increased vascular complications even with normal hemoglobin A1cs, indicating a potential effect of autoimmunity on the placental vasculature.

Disruption of Folate Metabolism Causes Poor Alignment and Spacing of Mouse Conceptuses for Multiple Generations.

Abnormal uptake or metabolism of folate increases risk of human pregnancy complications, though the mechanism is unclear. Here, we explore how defective folate metabolism influences early development by analysing mice with the hypomorphic Mtrr gt mutation. MTRR is necessary for methyl group utilisation from folate metabolism, and the Mtrr gt allele disrupts this process. We show that the spectrum of phenotypes previously observed in Mtrr gt/gt conceptuses at embryonic day (E) 10.5 is apparent from E8.5 including developmental delay, congenital malformations, and placental phenotypes. Notably, we report misalignment of some Mtrr gt conceptuses within their implantation sites from E6.5. The degree of misorientation occurs across a continuum, with the most severe form visible upon gross dissection. Additionally, some Mtrr gt/gt conceptuses display twinning. Therefore, we implicate folate metabolism in blastocyst orientation and spacing at implantation. Skewed growth likely influences embryo development since developmental delay and heart malformations (but not defects in neural tube closure or trophoblast differentiation) associate with severe misalignment of Mtrr gt/gt conceptuses. Typically, the uterus is thought to guide conceptus orientation. To investigate a uterine effect of the Mtrr gt allele, we manipulate the maternal Mtrr genotype. Misaligned conceptuses were observed in litters of Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt mothers. While progesterone and/or BMP2 signalling might be disrupted, normal decidual morphology, patterning, and blood perfusion are evident at E6.5 regardless of conceptus orientation. These observations argue against a post-implantation uterine defect as a cause of conceptus misalignment. Since litters of Mtrr +/+ mothers display conceptus misalignment, a grandparental effect is explored. Multigenerational phenotype inheritance is characteristic of the Mtrr gt model, though the mechanism remains unclear. Genetic pedigree analysis reveals that severe conceptus skewing associates with the Mtrr genotype of either maternal grandparent. Moreover, the presence of conceptus skewing after embryo transfer into a control uterus indicates that misalignment is independent of the peri- and/or post-implantation uterus and instead is likely attributed to an embryonic mechanism that is epigenetically inherited. Overall, our data indicates that abnormal folate metabolism influences conceptus orientation over multiple generations with implications for subsequent development. This study casts light on the complex role of folate metabolism during development beyond a direct maternal effect.

Overview of Human HtrA Family Proteases and Their Distinctive Physiological Roles and Unique Involvement in Diseases, Especially Cancer and Pregnancy Complications.

The mammalian high temperature requirement A (HtrA) proteins are a family of evolutionarily conserved serine proteases, consisting of four homologs (HtrA1-4) that are involved in many cellular processes such as growth, unfolded protein stress response and programmed cell death. In humans, while HtrA1, 2 and 3 are widely expressed in multiple tissues with variable levels, HtrA4 expression is largely restricted to the placenta with the protein released into maternal circulation during pregnancy. This limited expression sets HtrA4 apart from the rest of the family. All four HtrAs are active proteases, and their specific cellular and physiological roles depend on tissue type. The dysregulation of HtrAs has been implicated in many human diseases such as cancer, arthritis, neurogenerative ailments and reproductive disorders. This review first discusses HtrAs broadly and then focuses on the current knowledge of key molecular characteristics of individual human HtrAs, their similarities and differences and their reported physiological functions. HtrAs in other species are also briefly mentioned in the context of understanding the human HtrAs. It then reviews the distinctive involvement of each HtrA in various human diseases, especially cancer and pregnancy complications. It is noteworthy that HtrA4 expression has not yet been reported in any primary tumour samples, suggesting an unlikely involvement of this HtrA in cancer. Collectively, we accentuate that a better understanding of tissue-specific regulation and distinctive physiological and pathological roles of each HtrA will improve our knowledge of many processes that are critical for human health.

Systematic review and meta-analysis on influence of human papillomavirus infection during pregnancy on premature rupture of membranes and premature delivery.

The increasing infection rate of human papillomavirus (HPV) has resulted in various complex pregnancy-related complications in recent years. HPV can directly pass through the placenta to cause intrauterine infection, leading to premature delivery or the premature rupture of membranes (PROM). English databases were searched for randomized control trials (RCTs) on HPV infection and premature delivery and PROM, including PubMed, Medline, Embase, and Cochrane Central Register. The search time was from inception to March 1st 2021, with human papillomavirus, rupture, pregnancy, preterm birth, viral infection, and pregnancy complications as search terms. RevMan5.3 provided by the Cochrane Collaboration was used to perform bias risk assessment. A total of 7 studies were identified, involving 45,603 patients, including 22,799 cases in the control group, and 22,799 cases in an HPV infection group. The odds ratio (OR) and 95% confidence interval (95% CI) were used to express the results. HPV infection increased the probability of premature delivery (OR =1.81, 95% CI: 1.25-2.62, Z=3.16, P=0.002) and PROM (OR =1.74, 95% CI: 1.45-2.10, Z=5.84, P<0.00001). The P values were all less than 0.05, and the difference was statistically significant. A total of 7 articles were included in this meta-analysis. HPV infection affects the physiology of pregnant women and may lead to PROM and premature delivery.

The promise of placental extracellular vesicles: models and challenges for diagnosing placental dysfunction in utero†.

Monitoring the health of a pregnancy is of utmost importance to both the fetus and the mother. The diagnosis of pregnancy complications typically occurs after the manifestation of symptoms, and limited preventative measures or effective treatments are available. Traditionally, pregnancy health is evaluated by analyzing maternal serum hormone levels, genetic testing, ultrasonographic imaging, and monitoring maternal symptoms. However, researchers have reported a difference in extracellular vesicle (EV) quantity and cargo between healthy and at-risk pregnancies. Thus, placental EVs (PEVs) may help to understand normal and aberrant placental development, monitor pregnancy health in terms of developing placental pathologies, and assess the impact of environmental influences, such as infection, on pregnancy. The diagnostic potential of PEVs could allow for earlier detection of pregnancy complications via noninvasive sampling and frequent monitoring. Understanding how PEVs serve as a means of communication with maternal cells and recognizing their potential utility as a readout of placental health have sparked a growing interest in basic and translational research. However, to date, PEV research with animal models lags behind human studies. The strength of animal pregnancy models is that they can be used to assess placental pathologies in conjunction with isolation of PEVs from fluid samples at different time points throughout gestation. Assessing PEV cargo in animals within normal and complicated pregnancies will accelerate the translation of PEV analysis into the clinic for potential use in prognostics. We propose that appropriate animal models of human pregnancy complications must be established in the PEV field.

Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis.

BACKGROUNDAlthough spontaneous miscarriage is the most common complication of human pregnancy, potential contributing factors are not fully understood. Advanced maternal age has long been recognised as a major risk factor for miscarriage, being strongly related with fetal chromosomal abnormalities. The relation between paternal age and the risk of miscarriage is less evident, yet it is biologically plausible that an increasing number of genetic and epigenetic sperm abnormalities in older males may contribute to miscarriage. Previous meta-analyses showed associations between advanced paternal age and a broad spectrum of perinatal and paediatric outcomes. This is the first systematic review and meta-analysis on paternal age and spontaneous miscarriage.OBJECTIVE AND RATIONALEThe aim of this systematic review and meta-analysis is to evaluate the effect of paternal age on the risk of spontaneous miscarriage.SEARCH METHODSPubMed, Embase and Cochrane databases were searched to identify relevant studies up to August 2019. The following free text and MeSH terms were used: paternal age, father’s age, male age, husband’s age, spontaneous abortion, spontaneous miscarriage, abortion, miscarriage, pregnancy loss, fetal loss and fetal death. PRISMA guidelines for systematic reviews and meta-analysis were followed. Original research articles in English language addressing the relation between paternal age and spontaneous miscarriage were included. Exclusion criteria were studies that solely focused on pregnancy outcomes following artificial reproductive technology (ART) and studies that did not adjust their effect estimates for at least maternal age. Risk of bias was qualitatively described for three domains: bias due to confounding, information bias and selection bias.OUTCOMESThe search resulted in 975 original articles. Ten studies met the inclusion criteria and were included in the qualitative synthesis. Nine of these studies were included in the quantitative synthesis (meta-analysis). Advanced paternal age was found to be associated with an increased risk of miscarriage. Pooled risk estimates for miscarriage for age categories 30–34, 35–39, 40–44 and ≥45 years of age were 1.04 (95% CI 0.90, 1.21), 1.15 (0.92, 1.43), 1.23 (1.06, 1.43) and 1.43 (1.13, 1.81) respectively (reference category 25–29 years). A second meta-analysis was performed for the subgroup of studies investigating first trimester miscarriage. This showed similar pooled risk estimates for the first three age categories and a slightly higher pooled risk estimate for age category ≥45 years (1.74; 95% CI 1.26, 2.41).WIDER IMPLICATIONSOver the last decades, childbearing at later ages has become more common. It is known that frequencies of adverse reproductive outcomes, including spontaneous miscarriage, are higher in women with advanced age. We show that advanced paternal age is also associated with an increased risk of spontaneous miscarriage. Although the paternal age effect is less pronounced than that observed with advanced maternal age and residual confounding by maternal age cannot be excluded, it may have implications for preconception counselling of couples comprising an older aged male.

Elevated circulating HtrA4 in preeclampsia may alter endothelial expression of senescence genes

IntroductionPreeclampsia (PE) is a serious complication of human pregnancy. Women who have had PE, especially early-onset PE (EPE), have an increased risk of cardiovascular disease (CVD) later in life. However, how PE is linked to CVD is not well understood. We previously reported that HtrA4, a placenta-specific protease, is significantly elevated in EPE, and inhibits the proliferation of endothelial cells as well as endothelial progenitor cells (EPCs). This can potentially impair endothelial repair and regeneration, leading to endothelial aging, which is a major risk factor of CVD. In this study, we examined whether HtrA4 can alter endothelial expression of senescence genes. MethodsHuman umbilical vein endothelial cells (HUVECs) and primary EPCs isolated from cord blood of healthy pregnancies were used as in vitro models. Firstly, HUVECs were treated with HtrA4 at the highest levels detected in EPE for 48h and screened with a senescence PCR array. The results were then validated by RT-PCR and ELISA in HUVECs and EPCs treated with HtrA4 for 24 and 48h. ResultsWe observed that HtrA4 significantly up-regulated IGFBP3, SERPINE1 and SERPINB2, which all promote senescence. IGFBP-3 protein was also significantly elevated in the media of HtrA4-treated HUVECs. Conversely, a number of genes including CDKN2C, PCNA, CALR, CHEK2 and NOX4 were downregulated by HtrA4. Many of these genes also showed a similar trend of change in EPCs following HtrA4 treatment. DiscussionElevation of placenta-derived HtrA4 in PE alters the expression of endothelial genes to promote cellular senescence and may contribute to premature endothelial aging.

A top priority in pre-eclampsia research: development of a reliable and inexpensive urinary screening test

Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity worldwide, with an estimated 60 000 pre-eclampsia-related maternal deaths per year.1 This complication of human pregnancy has increased in incidence in the past decade and can be avoided by timely and effective care (secondary prevention).2 Pre-eclampsia is defined by new hypertension and organ damage (mainly involving the kidney and sometimes the liver) that can evolve into eclamptic seizures, maternal stroke, and abruptio placentae.

HtrA4 may play a major role in inhibiting endothelial repair in pregnancy complication preeclampsia

Preeclampsia (PE) is a life-threatening complication of human pregnancy with no effective treatment other than premature delivery. It is hallmarked by systemic endothelial injury/dysfunction which is believed to be caused by abnormal levels/types of placenta-derived factors that are circulating in the maternal blood. Emerging evidence suggests that endothelial repair is also dysregulated in PE, as circulating endothelial progenitor cells (EPCs) critical for endothelial regeneration are reduced in number and functionality. However, the underlying mechanisms are poorly understood. HtrA4 is a placenta-specific protease that is secreted into the circulation and significantly elevated in early-onset PE. Here we investigated the impact of HtrA4 on endothelial proliferation and repair. We demonstrated that high levels of HtrA4 halted endothelial cell proliferation and significantly down-regulated a number of genes that are critical for cell cycle progression, including CDKN3, BIRC5, CDK1 and MKI67. Furthermore, HtrA4 significantly inhibited the proliferation of primary EPCs isolated from term human umbilical cord blood and impeded their differentiation into mature endothelial cells. Our data thus suggests that elevated levels of HtrA4 in the early-onset PE circulation may impair endothelial cell repair, not only by halting endothelial cell proliferation, but also by inhibiting the proliferation and differentiation of circulating EPCs.

Selenium, Selenoproteins, and Female Reproduction: A Review.

Selenium (Se) is an essential micronutrient that has several important functions in animal and human health. The biological functions of Se are carried out by selenoproteins (encoded by twenty-five genes in human and twenty-four in mice), which are reportedly present in all three domains of life. As a component of selenoproteins, Se has structural and enzymatic functions; in the latter context it is best recognized for its catalytic and antioxidant activities. In this review, we highlight the biological functions of Se and selenoproteins followed by an elaborated review of the relationship between Se and female reproductive function. Data pertaining to Se status and female fertility and reproduction are sparse, with most such studies focusing on the role of Se in pregnancy. Only recently has some light been shed on its potential role in ovarian physiology. The exact underlying molecular and biochemical mechanisms through which Se or selenoproteins modulate female reproduction are largely unknown; their role in human pregnancy and related complications is not yet sufficiently understood. Properly powered, randomized, controlled trials (intervention vs. control) in populations of relatively low Se status will be essential to clarify their role. In the meantime, studies elucidating the potential effect of Se supplementation and selenoproteins (i.e., GPX1, SELENOP, and SELENOS) in ovarian function and overall female reproductive efficiency would be of great value.

Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia.

Preeclampsia and fetal growth restriction (FGR) are major causes of the more than 5 million perinatal and infant deaths occurring globally each year, and both are associated with placental dysfunction. The risk of perinatal and infant death is greater in males, but the mechanisms are unclear. We studied data and biological samples from the Pregnancy Outcome Prediction (POP) study, a prospective cohort study that followed 4,212 women having first pregnancies from their dating ultrasound scan through delivery. We tested the hypothesis that fetal sex would be associated with altered placental function using multiomic and targeted analyses. We found that spermine synthase (SMS) escapes X-chromosome inactivation (XCI) in the placenta and is expressed at lower levels in male primary trophoblast cells, and male cells were more sensitive to polyamine depletion. The spermine metabolite N1,N12-diacetylspermine (DiAcSpm) was higher in the female placenta and in the serum of women pregnant with a female fetus. Higher maternal serum levels of DiAcSpm increased the risk of preeclampsia but decreased the risk of FGR. To our knowledge, DiAcSpm is the first maternal biomarker to demonstrate opposite associations with preeclampsia and FGR, and this is the first evidence to implicate polyamine metabolism in sex-related differences in placentally related complications of human pregnancy.

Regulation of maternal-fetal heart rates and coupling in mice fetuses.

The aim of this preliminary study is to investigate if there is any evidence of maternal-fetal heart rate coupling in mice fetuses and how the coupling patterns are regulated by vagal nervous system on beat by beat. Total of 6 pregnant female mice were divided into two groups [control (N=3) and vagal blockade (N=3)]. On 17.5-day beat-to-beat heart rates of mothers and fetuses (MHR and FHR) were simultaneously measured for 20 minutes (10 minutes under normal condition and 10 minutes with saline (to control group) and atropine (to the vagal blockade group)) solution by using an invasive maternal and fetal electrocardiogram techniques with needle electrodes. Results show that occasional strong maternal-fetal heart rate coupling (strength was measured by $\lambda$) appeared and its patterns changed with atropine infusion (no change with saline). Additionally, fisher's exact test shows that changes (increase/decrease from pre to post injection values) in mean, rmssd and power spectral density (PSD) (2~4 Hz) of MHR, rmssd FHR and PSD (2~4 Hz) of${\lambda }$were found to be significantly (p<0.05) associated with treatment types (saline/ atropine). The presented results and protocol allow for the first time in the assessment of autonomic regulation of maternal and fetal heart and their interactions, which will further enhance the value of the mouse as a murine model of heritable human pregnancy and perinatal complications due to maternal conditions.

Serum heat shock protein 70 in preeclampsia and normal pregnancy: A systematic review and meta-analysis

Preeclampsia, a severe complication of human pregnancy is one of the main causes of maternal, fetal, and neonatal morbidity and mortality with unclear pathogenesis. Heat shock protein 70 (HSP70) is one of the factors that can mediate cytoprotective, antiapoptotic, and immune regulatory effects. This meta-analysis was performed with aim to evaluate HSP70 in preeclampsia and normal pregnancy. The original publications reporting the serum HSP70 levels in preeclampsia and normal pregnancies published before November 2015 were identified by searching PubMed Central, Scopus, and ISI Web of Knowledge databases by two researchers, separately. The keywords were" preeclampsia" and "HSP70" or "Heat shock protein 70" Statistical analyses were performed using STATA software (version 11). Out of 127 studies, seven eligible case-control studies were identified which consists of 350 preeclampsia and 429 normal pregnancies. Our pooled analysis of data from 7 studies which met the inclusion criteria, provides evidence that there is a significant association between HSP70 and preeclampsia. Cochran's test results showed the heterogeneity of the studies (p<0.001) and the I2 index was 91%. The standardized mean differences (SMD) based on a random effect model with trim and fill method was 0.92 (95% CI: 0.33-1.51); also there was a significant association between HSP70 and preeclampsia (Z=3.07, p=0.002). The results showed that serum HSP70 concentration was significantly higher in preeclamptic patients than the control group. Therefore HSP70 may be identified as a diagnostic factor.