Gestational Disorders Research Articles

A systematic review and risk of bias analysis of in vitro studies on trophoblast response to immunological triggers

An increasing amount of evidence suggests that immune responses may affect trophoblast functioning, which in turn may play a role in gestational disorders and fetal development. This systematic review offers the first summary of in vitro studies on the trophoblast response to immunological triggers, in conjunction with a risk of bias analysis.A search in Pubmed and Embase yielded 110 relevant studies. Primary trophoblasts were the most commonly used cell type, but trophoblast subtypes were not always defined. Similarly, the exact natures of trophoblast cell lines were sometimes unclear. Cytokines and Toll-like receptor agonists were often used as interventions, but most studies focused on a select few substances such as tumor necrosis factor-α and lipopolysaccharide. In regard to the outcome parameters, some important trophoblast functions, such as hormone production and barrier formation were underrepresented.Whether or not risk of bias was high varied strongly between types of bias. Risk of selection bias, for example, was usually low. However, none of the included studies mentioned blinding or plate randomization. Only a select few studies mentioned passage numbers, use of vehicle control or conflict of interest.In conclusion, better characterization of trophoblast subtypes and a broader range of studied interventions and outcome parameters would contribute to a more complete understanding of trophoblast responses to immune stimuli. Additionally, researchers are encouraged to replicate experiments and pay close attention when setting up and writing down methodologies, in order to improve the reproducibility and translatability of their work.

USO DE SUBSTÂNCIAS PSICOATIVAS E EFEITOS ADVERSOS: DISTÚRBIOS DECORRENTES DO USO DE ÁLCOOL, CAFEÍNA, CANNABIS, COCAÍNA E NICOTINA.

Introduction: Introduction: The frequent use of psychoactive substances causes harm to the health and quality of life of users, due to the activation of the brain’s reward system by such drugs. Objective: Identify the adverse effects caused by the use of the following substances: alcohol, caffeine, cannabis, crack and nicotine. Methodology: This is an integrative review of the literature, with studies published between 2017 and 2023, in Portuguese and English. Results and Discussion: Thirty articles were selected that addressed the effects resulting from the use of the five substances studied, and several damages to the human body were verified with the continuous consumption of these substances. Several adverse reactions were identified, with recurrence of the effects between the different substances. The presence of disorders was found in seven different body systems, and the most affected systems are the nervous, vascular, cardiac, gastrointestinal and respiratory systems, in addition to skin disorders and gestational disorders. Final Considerations: The study made it possible to expand knowledge on the subject, understand the adverse effects resulting from the use of psychoactive substances and how this understanding is of great help to nursing professionals, since they have close contact with patients and can identify symptoms early.

Genetic issues in ICP.

Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disorder with variable global incidence. Genetic susceptibility, combined with hormonal and environmental influences, contributes to ICP aetiology. Adverse pregnancy outcomes linked to elevated serum bile acids highlight the importance of comprehensive risk assessment. ABCB4 and ABCB11 gene variants play a significant role in about 20% of severe ICP cases. Several other genes including ATP8B1, NR1H4, ABCC2, TJP2, SERPINA1, GCKR and HNF4A have also been implicated with ICP. Additionally, ABCB4 variants elevate the risk of drug-induced intrahepatic cholestasis, gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis and abnormal liver function tests. Genetic variations, both rare and common, intricately contribute to ICP susceptibility. Leveraging genetic insights holds promise for personalised management and intervention strategies. Further research is needed to elucidate variant-specific phenotypic expressions and therapeutic implications, advancing precision medicine in ICP management.

Oral exposure to phenanthrene during gestation disorders endocrine and spermatogenesis in F1 adult male mice

Phenanthrene (Phe), a typical low-molecular-weight polycyclic aromatic hydrocarbon (PAH) of three benzene rings, is one of the most abundant PAHs detected in daily diets. Pregnant women and infants are at great risk of Phe exposure. In the present study, Phe was administered to pregnant mice at a dose of 0, 60, or 600 μg/kg body weight six times, and the F1 male mice showed significant reproductive disorders: the testicular weight and testis somatic index were significantly reduced; the levels of serum testosterone, GnRH and SHBG were increased, while the FSH levels were reduced; histological analysis showed that the amount of Sertoli cells and primary spermatocytes in seminiferous tubules was increased, while the amount of secondary spermatocytes and spermatids were decreased in Phe groups. The protein levels of PCNA and androgen receptor were reduced. Differently expressed genes in the testis screened by RNA sequence were enriched in antioxidant capacity, reproduction et al.. Further biochemical tests confirmed that the antioxidant capacity in the F1 testis was significantly inhibited by treatment with Phe during pregnancy. Those results suggested that gestational Phe exposure disordered hypothalamic-pituitary-gonadal (HPG) hormones on the one hand, and on the other hand reduced testicular antioxidant capacity and further arrested cell cycle in F1 adult male mice, which co-caused the inhibition of spermatogenesis.

Ethnic disparities in complete and partial molar pregnancy incidence: a retrospective analysis of arab and jewish women in single medical center

BackgroundMolar pregnancies, encompassing complete and partial moles, represent a rare and enigmatic gestational disorder with potential ethnic variations in incidence. This study aimed to investigate relations of ethnicity with risks of complete and partial molar pregnancies within an Israeli population while accounting for age differences.MethodsA retrospective study was conducted of data recorded during 2007–2021 in an academic medical center in Israel. The study population comprised 167 women diagnosed with complete or partial moles, for whom data were obtained through histological examination and P57 immunostaining. Maternal age and ethnicity were extracted from electronic medical records. Incidence rates were calculated per 10,000 live births, and a nested case-control study compared demographic characteristics and molar pregnancy incidences between Arab and Jewish women. Statistical analyses included age-adjusted comparisons, relative risk calculations and multivariate logistic regression.ResultsThe overall risk of molar pregnancy was 22 per 10,000 live births (95% confidence interval [CI] 18–25). Among Arab women, the overall risk was 21 (95% CI 17–25), and for PM and CM: 14 (95% CI 11–17) and 7 (95% CI 5–10), respectively. Among Jewish women, the overall risk was 23 (95% CI 18–29), and for PM and CM: 12 (95% CI 8–17) and 11 (95% CI 7–16), respectively. Among Arab women compared to Jewish women, the proportion of all the partial moles was higher: (65.3% vs. 51.6%, p = 0.05). The incidence of partial mole was higher among Arab than Jewish women, aged 35–39 years (26 vs. 8 per 10,000, p = 0.041), and did not differ in other age groups. After adjusting for age, the relative risk of partial moles was lower among Jews than Arabs (0.7, 95% CI 0.4-1.0, p = 0.053). For Arab compared to Jewish women, the mean age at molar pregnancies was younger: 31.0 vs. 35.1 years. However, other factors did not differ significantly between Arab and Jewish women with molar pregnancies. In multivariate analysis, Jewish ethnicity was significantly associated with a higher risk of complete molar pregnancies (OR = 2.19, 95% CI 1.09–4.41, p = 0.028).ConclusionThis study highlights ethnic differences in molar pregnancy risk within the Israeli population. Jewish ethnicity was associated with a higher risk of complete molar pregnancies, while Arab women had a significantly higher risk of partial moles. These findings underscore the need to consider ethnicity when studying gestational disorders. Further research should seek to elucidate the underlying factors contributing to these differences.

Developmental origins of exceptional health and survival: A four-generation family cohort study.

Previous researched has demonstrated potent health and survival advantages across three-generations in longevity-enriched families. However, the survival advantage associated with familial longevity may manifest earlier in life than previously thought. We conducted a matched cohort study comparing early health trajectories in third-generation grandchildren (n = 5,637) and fourth-generation great-grandchildren (n = 14,908) of longevity-enriched sibships to demographically matched births (n = 41,090) in Denmark between 1973 and 2018. Lower risk was observed across a range of adverse early life outcomes in the grandchildren, including infant mortality (Hazard Ratio (HR) = 0.53, 95% CI [0.36, 0.77]), preterm birth (Odds Ratio (OR) = 0.82, [0.72, 0.93]), small for gestational age (OR = 0.83, [0.76, 0.90]) and neonatal respiratory disorders (OR = 0.77, [0.67, 0.88]). Relative advantages in parental education and maternal smoking were observed in both generations to a similar degree. However, a much smaller reduction in infant mortality was observed in the great-grandchildren (HR = 0.90, [0.70, 1.17]) and benefits across other outcomes were also less consistent, despite persisting socioeconomic and behavioural advantages. Lastly, maternal, and paternal lines of transmission were equipotent in the transmission of infant survival advantages. Descendants of longevity-enriched sibships exhibit a broad health advantage manifesting as early the perinatal period. However, this effect is strongly diluted over successive generations. Our findings suggest that exceptional health and survival may have early developmental components and implicate heritable genetic and or epigenetic factors in their specific transmission. Previous researched has demonstrated potent health and survival advantages across three-generations in longevity-enriched families. However, the survival advantage associated with familial longevity may manifest earlier in life than previously thought.In our study of third and fourth-generation descendants of longevity-enriched sibships, we observed a broad infant health and survival advantage reflected by protection against a diverse range of adverse birth outcomes.These advantages were strongly attenuated between the third and fourth generations, independent of otherwise stable socioeconomic and behavioural parental advantages, as well as maternal and paternal lines of transmission.Our findings suggest that familial aggregation of exceptional health and survival may have early life developmental components and triangulate to implicate heritable genetic and or epigenetic factors in their transmission.

Genetic analysis of health traits and their associations with longevity, fertility, production, and conformation traits in Holstein cattle

Health traits have high economic values in dairy cattle breeding, which can cause considerable financial loss through involuntary culling. In this study, fourteen health traits were analysed, including five composite health traits: reproductive disorders, udder health (UH), digestive disorders, metabolic disorders, locomotory diseases (LD), and nine independent health traits: gestation disorders and peripartum disorders, irregular estrus cycle and sterility, metritis (ME), mastitis (MA), abomasal displacement (AD), enteritis (EN), and ketosis, claw diseases (CD), laminitis complex. This study analysed variance components for health traits through both single and bivariate repeatability animal models. All health traits showed low heritability, ranging from 0.001 to 0.025. Most of the health traits in five categories showed negative genetic correlations, ranging from −0.012 (CD and EN) to −0.634 (ME and EN). Strong positive genetic correlations appeared within the same category, ranging from 0.469 (EN and AD) to 0.994 (UH and MA, LD and CD). Furthermore, approximate genetic correlations were evaluated between health traits and routinely collected traits (longevity, fertility, production, and conformation). In general, the low to moderate approximate genetic correlations were estimated between health traits and routinely collected traits. The estimated correlations between health traits and longevity, fertility, production, and conformation traits could provide an indirect reference for disease−resistance breeding in Holstein cattle.

Показники ротаційної тромбоеластометрії при передчасних пологах

Disrupted maternal, placental, and/or fetal hemostasis leads to gestational disorders, including preterm birth (PR). A quick and convenient assessment of the coagulation profile is important for a premature newborn. Aim - to compare the indicators of hemostasis in mothers and newborns with different gestational ages using rotational thromboelastometry. Materials and methods. The study analyzed the indicators of the hemostatic profile in women in labor and their newborns using the fib-tem test on the ROTEM® delta device. Three groups of mothers and their newborns were studied: the Group I - at a gestation period of 37-41 weeks, the Group II - 28-34 weeks, the Group III - 22-27 weeks. Results. In the Group III prematures, blood clotting time (257.1±87.29ʺ) is longer than that of the Group I - 43.3±21.48ʺ and the Group II - 52.5±25.03ʺ. Angle α is larger in the Group I and the Group II - 47.6±12.49; 79.9±4.62; 76.7±4.84 (degrees). Amplitudes of contraction (5, 10 min, maximum) of the Group II are lower than the Group I by 10-22%. In the Group III, the amplitudes correlate with the concentration of fibrinogen up to 2 g/l - 4.6±1.39; 8.0±3.00; 7.9±5.56 (mm). The smallest lysis in the Group III (1.8±2.38%) versus the Group I and the Group II (17.1±2.34%, 8.1±2.50%. Maternal indicators of the amplitude of the coagulation are higher at a shorter gestational age. Conclusions. Maternal indicators of the amplitude of coagulation exceed the indicators of newborns by 1.5-2 times - 18.8±7.89 versus 17.4±7.04; 22.0±3.34 vs. 15.2±11.37 and 20.8±9.22 vs. 7.9±5.56 (mm). Blood clotting time of extremely premature newborns (257.1±87.29ʺ s) is longer than that of full-term and moderately premature infants (43.3±21.48ʺ; 52.5±25.03ʺ). Amplitudes of contractions of newborns of the Group III at the 5th minute are three times smaller, and at the 10th minute they are twice as small as in the Group I and the Group II - 4.6±1.39; 13.2±3.34; 16.2±5.38 (mm) and 8.0±3.01; 15.5±4.34; 16.0±7.39 (mm). In the Group III, coagulation lysis is minimal (1.8±2.38% vs. 17.1±2.34%; 8.1±2.50%). The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. The authors declare no conflict of interest.

Liver ChREBP deficiency inhibits fructose-induced insulin resistance in pregnant mice and female offspring

High fructose intake during pregnancy increases insulin resistance (IR) and gestational diabetes mellitus (GDM) risk. IR during pregnancy primarily results from elevated hormone levels. We aim to determine the role of liver carbohydrate response element binding protein (ChREBP) in insulin sensitivity and lipid metabolism in pregnant mice and their offspring. Pregnant C57BL/6J wild-type mice and hepatocyte-specific ChREBP-deficient mice were fed with a high-fructose diet (HFrD) or normal chow diet (NC) pre-delivery. We found that the combination of HFrD with pregnancy excessively activates hepatic ChREBP, stimulating progesterone synthesis by increasing MTTP expression, which exacerbates IR. Increased progesterone levels upregulated hepatic ChREBP via the progesterone-PPARγ axis. Placental progesterone activated the progesterone-ChREBP loop in female offspring, contributing to IR and lipid accumulation. In normal dietary conditions, hepatic ChREBP modestly affected progesterone production and influenced IR during pregnancy. Our findings reveal the role of hepatic ChREBP in regulating insulin sensitivity and lipid homeostasis in both pregnant mice consuming an HFrD and female offspring, and suggest it as a potential target for managing gestational metabolic disorders, including GDM.

Trauma and Posttraumatic Stress Disorder as Important Risk Factors for Gestational Metabolic Dysfunction.

Gestational metabolic diseases adversely impact the health of pregnant persons and their offspring. Pregnant persons of color are impacted disproportionately by gestational metabolic disease, highlighting the need to identify additional risk factors contributing to racial-ethnic pregnancy-related health disparities. Trauma exposure and posttraumatic stress disorder (PTSD) are associated with increased risk for cardiometabolic disorders in nonpregnant persons, making them important factors to consider when identifying contributors to gestational metabolic morbidity and mortality health disparities. Here, we review current literature investigating trauma exposure and posttraumatic stress disorder as psychosocial risk factors for gestational metabolic disorders, inclusive of gestational diabetes, low birth weight and fetal growth restriction, gestational hypertension, and preeclampsia. We also discuss the physiological mechanisms by which trauma and PTSD may contribute to gestational metabolic disorders. Ultimately, understanding the biological underpinnings of how trauma and PTSD, which disproportionately impact people of color, influence risk for gestational metabolic dysfunction is critical to developing therapeutic interventions that reduce complications arising from gestational metabolic disease. KEY POINTS: · Gestational metabolic diseases disproportionately impact the health of pregnant persons of color.. · Trauma and PTSD are associated with increased risk for cardiometabolic disorders in nonpregnant per.. · Trauma and PTSD impact physiological cardiometabolic mechanisms implicated in gestational metabolic..

Aberrant NK cell profile in gestational diabetes mellitus with fetal growth restriction.

Gestational diabetes mellitus (GDM) is a gestational disorder characterized by hyperglycemia, that can lead to dysfunction of diverse cells in the body, especially the immune cells. It has been reported that immune cells, specifically natural killer (NK) cells, play a crucial role in normal pregnancy. However, it remains unknown how hyperglycemia affects NK cell dysfunction thus participates in the development of GDM. In this experiment, GDM mice were induced by an intraperitoneal injection of streptozotocin (STZ) after pregnancy and it has been found that the intrauterine growth restriction occurred in mice with STZ-induced GDM, accompanied by the changed proportion and function of NK cells. The percentage of cytotoxic CD27-CD11b+ NK cells was significantly increased, while the proportion of nourished CD27-CD11b- NK cells was significantly reduced in the decidua of GDM mice. Likewise, the same trend appeared in the peripheral blood NK cell subsets of GDM patients. What's more, after intrauterine reinfusion of NK cells to GDM mice, the fetal growth restriction was alleviated and the proportion of NK cells was restored. Our findings provide a theoretical and experimental basis for further exploring the pathogenesis of GDM.

Updates on thyroid disorders in pregnancy and the postpartum period.

NPs play a pivotal role in caring for pregnant people. This article provides an overview of gestational and postpartum thyroid disorders, including their assessment, management, and indications for referral. The goal of this article is to help providers better assess and manage thyroid disorders during pregnancy and improve patient outcomes.

Pregnancy course and outcomes in patients with non-insulin dependent gestational diabetes mellitus: An observational cohort study

Background. Gestational diabetes mellitus is the most frequent metabolic disorder during pregnancy. Its prevalence is steadily increasing worldwide. In the setting of hyperinsulinism, this pathology may cause various structural and functional changes in the placenta, as well as a reduction in oxygen supply to the fetus. This may result in fetal hypoxia and increased risk of fetal growth restriction. Therefore, research into the specific features of gestation course in patients with gestational diabetes mellitus in order to prevent its complications appears relevant. Objective. To study the specific features of gestation, delivery, and perinatal outcomes in patients with non-insulin dependent gestational diabetes mellitus. Methods. We conducted an observational cohort study of the case histories of 120 women with singleton pregnancies of the second and third trimesters with diagnosed non-insulin dependent gestational diabetes mellitus, their labor and delivery records, and the medical records of the newborns. All the patients were managed at the Ural Research Institute of Maternity and Child Care during 2021–2023. The main group comprised 70 patients whose pregnancy was complicated by sub- and decompensated forms of placental insufficiency. The comparison group comprised 50 pregnant women without pathologies of the fetoplacental complex. The obstetric history, gestation course of the present pregnancy and its outcomes, as well as the condition of the newborns, were analyzed. The obtained data were processed by the methods of variation statistics using Microsoft Excel spreadsheets (Microsoft, USA) and Statistica 13 (DellInc., USA) and MedCalc 15.8 (MedCalcSoftware, Belgium) applications. The null hypothesis was rejected at p > 0.05. Results. Gestational diabetes mellitus in previous pregnancies was statistically significantly less frequent in the main group (2.9% (n = 2)) than in the comparison group (18.0% (n = 9)) ( p > 0.05). Placental insufficiency in the main group was characterized by fetal growth restriction, which was associated with impaired uteroplacental blood flow in 58.6% (n = 41) of the cases. In the main group, the pregnancy ended in preterm delivery in 21.4% (n = 15) of the cases; in 78.6% (n = 55) of the cases, the delivery was at term. There were no preterm births in the comparison group, p > 0.05. Cesarean section was performed in 62.9% (n = 44) of patients in the main group, compared to 20.0% (n = 10) in the comparison group ( p > 0.05). Newborns of the main group required respiratory support more often (p > 0.05). Conclusion. The mechanism of placental insufficiency in patients with non-insulin dependent gestational disorders of carbohydrate metabolism remains to be elucidated. Further research should investigate the predictors of fetoplacental complex pathologies in this group of patients in order to reduce the number of perinatal complications.

Effects of early- and late- neuraxial analgesia on multiparous women: a retrospective monocentric study.

The mechanism underlying maternal fever and prolonged labor progression associated with neuraxial analgesia (NA) remains elusive, raising concerns among certain pregnant women regarding the application of NA during vaginal delivery. This study aimed to investigate the impact of early and late NA on maternal and neonatal outcomes in multiparous women. This retrospective study collected data from 1119 multiparous women with singleton pregnancies, full term and live births at our labor and delivery center between August 1st, 2021 and July 31st, 2022. Based on the timing of NA initiation, participants were categorized into three groups: no-NA, early-NA and late-NA. The no-NA group comprised of 172 women who did not receive NA during vaginal delivery; the early-NA group included 603 women in which NA was initiated when cervical dilation was between 0.5 and 2.0cm; and the late-NA group comprising 344 cases in which NA was initiated at the cervical dilation of ≥ 2cm. Maternal and neonatal outcomes were observed, including durations of the first, second, third and total stage of labor, the rate of intrapartum cesarean delivery (CD), intrapartum fever, postpartum hemorrhage (PPH), transfer to intensive care unit (ICU), admission to the neonatal intensive care unit (NICU), meconium-stained amniotic fluid, and neonatal Apgar scores at 1 and 5min. No differences were noted in the maternal age, body mass index (BMI) on admission, gestations, parity, gestational weeks at delivery and neonatal birth weight, or the rate of gestational diabetes mellitus (GDM) and hypertension disorder did not significantly differ among the three groups (p > 0.05). The no-NA group had shorter durations of first stage, second stage of labor compared to the early-NA or late-NA group (median, 215.0min and 10.0min vs. 300.0min and 12.0min vs. 280.0min and 13.0min) (p < 0.05), but no differences were observed between the early-NA and late-NA group (p > 0.05). There were no differences in the rate of intrapartum CD, intrapartum fever, PPH, maternal transferred to ICU, neonatal transfer to NICU, meconium-stained amniotic fluid, and postpartum stay ≥ 7d, as well as the neonatal the Apgar scores at 1 and 5min among the three groups (p > 0.05). NA is associated with extended durations of the first, second and total stages of labor. However, the early initiation of NA in multiparous women (cervical dilation within 0.5-2.0cm) does not increase the risk of intrapartum CD or intrapartum fever. These findings endorse the secure utilization of early NA for pain relief during labor in multiparous women.

Mesenchymal stem cell-derived exosomes in preeclampsia: A next-generation therapeutic tool.

Preeclampsia (PE) is a major gestational disorder that causes both long- and short-term damage to both the mother and the fetus. Endometrium decidualization and the formation of the placenta are orchestrated by mesenchymal stem cells (MSCs). MSCs obtained from patients with PE exhibit an elevated rate of aging and apoptosis, which impairs the interplay between MSCs and endothelium, trophoblast, and immune cells in the placenta, accelerating the onset of PE. Preclinical and clinical evidence imply that the MSC-based therapy approach for PE is prospective. Importantly, as a novel cell-free approach, MSC-derived exosomes can improve symptoms and maternal-fetal survival in PE models by raising cell metabolism, encouraging angiogenesis balance, and regulating immune responses. Even following allogeneic administration, the likelihood of immune rejection is very limited as a result of the small quantity of exosome membrane-bound proteins. Furthermore, because exosomes do not expand, developing tumors is not probable. As a result, MSC-derived exosomes show superiority over MSCs in terms of safety. For the first time, we outline the properties of MSC-exosomes and highlight their functions and potential as a new paradigm for PE therapy in this review.

Investigating short-stay admission to a neonatal intensive care unit as a risk factor for reduced breast feeding at discharge in infants ≥36 weeks’ gestation: a retrospective cohort study

ObjectiveThis study aims to determine the effect of infant–mother separation following a short-stay (≤72 hours) admission to a Level 5 neonatal unit versus no admission on infant-feeding outcomes at hospital...

Abstract 021: Betamethasone Prevents Preeclamptic Phenotypes By Upregulating Regulator Of G Protein Signaling 2

Preeclampsia (PreE), a prevalent gestational disorder, is characterized by high blood pressure and kidney damage. Currently, the only known treatment for PreE is to deliver the baby. Chronic infusion of AVP in mice has been shown to recapitulate clinical symptoms of preeclampsia including pregnancy-specific hypertension. Corticosteroids are commonly given during pregnancy to promote fetal lung development. However, it is not known whether they can be used to manage PreE. C57Bl6/J mice received 24ng/hr of AVP throughout gestation until necropsy on gestational day 18. Betamethasone, a steroid, was administered at gestational day 7. An increase of 8.093 mmHg (110.72 vs 118.81, p=0.01) in systolic blood pressure was observed in AVP-infused mice compared to saline-infused pregnant mice and addition of BMTZ in AVP-infused mice returned blood pressure to baseline (109.59 mmHg, p=0.030). AVP treated mice had elevated expression of renal collagen 1A (4.99 fold, p=0.01) and TGFβ (2.58 fold, p=0.009) compared to saline infused mice. BMTZ reversed renal collagen 1A (0.98 fold, p=0.03) and TGFβ (0.75 fold, p=0.004) compared to AVP only infused mice. Trophoblast invasion of the uterine spiral arteries early in pregnancy is abnormal in women who develop PreE resulting in poor placental profusion. HTR8, a placental trophoblast cell, was treated with AVP or the combination of AVP and BMTZ. AVP decreased trophoblast migration by 34 units (p&lt;0.001) and BMTZ rescued migration by 42.1 units (p&lt;0.001). Similarly, AVP treatment decreased trophoblast invasion (0.58 vs 0.49 units, p=0.11) and BMTZ rescued invasion (0.62 units vs 0.49 units, p=0.032). Previously published data demonstrated that Regulator of G Protein Signaling 2 (RGS2) is decreased in placentas of PreE patients and RGS2 decreases AVP signaling. Trophoblasts treated with AVP show a 0.49 fold decrease in RGS2 expression and BMTZ rescues RGS2 expression (1.29 fold, p=0.038). Overexpression of RGS2 in AVP treated cells resulted in a 20 unit increase in migration (248.7 vs 268.7, p=0.01). These data demonstrate that BMTZ can prevent PreE phenotypes as well as abnormal trophoblast invasion and migration caused by AVP. RGS2 regulation by BMTZ may be the mechanism by which BMTZ is protective in preclinical models of PreE.

CYP24A1 is associated with fetal mummification in pigs

Mummified piglets are among the leading causes of fertility loss and severely hamper reproductive performance in pigs. However, the contributions of genomic variation to the emergence of mummified piglets (MUM) have rarely been studied. This study aims to (1) elucidate the genetic architecture of MUM in sows of parity 1 - 3 using a single-step genome-wide association study (ssGWAS). The ssGWAS involved genotyping-by-sequencing of Large White and Landrace pig breeds. (2) Explore the biological role of the candidate genes at the cellular level. A total of 185 and 48 genome-wide significant SNPs are associated with MUM in Large White and Landrace pigs, explaining 0.01–36.52% genetic variance for different significant loci, respectively. All the significant SNPs are parity-specific, and the numerous, consecutive significant loci likely generated the nine significant peaks in different parities. Multiple candidate genes (including CYP24A1, FBXO30, and ARHGEF28) are associated with fetal congenital and maternal diseases. Collectively, CYP24A1 regulation contributes to steady-state levels of embryo development genes. CYP24A1 is involved in reproduction and, immune and gestational disorders. Thus, it is associated with known newborn death traits and MUM in Large White sows. Altogether, these results improve the current understanding of the genetic architecture of MUM and expand the knowledge on genetic variations for selecting against mummified piglets in pig breeding.

Plasma lipids are dysregulated preceding diagnosis of preeclampsia or delivery of a growth restricted infant.

Lipids serve as multifunctional metabolites that have important implications for the pregnant mother and developing fetus. Abnormalities in lipids have emerged as potential risk factors for pregnancy diseases, such as preeclampsia and fetal growth restriction. The aim of this study was to assess the potential of lipid metabolites for detection of late-onset preeclampsia and fetal growth restriction. We used a case-cohort of 144 maternal plasma samples at 36 weeks' gestation from patients before the diagnosis of late-onset preeclampsia (n=22), delivery of a fetal growth restricted infant (n=55, defined as <5th birthweight centile), gestation-matched controls (n=72). We performed liquid chromatography-tandem mass spectrometry (LC-QQQ) -based targeted lipidomics to identify 421 lipids, and fitted logistic regression models for each lipid, correcting for maternal age, BMI, smoking, and gestational diabetes. Phosphatidylinositol 32:1 (AUC=0.81) and cholesterol ester 17:1 (AUC=0.71) best predicted the risk of developing preeclampsia or delivering a fetal growth restricted infant, respectively. Five times repeated five-fold cross validation demonstrated the lipids alone did not out-perform existing protein biomarkers, soluble tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) for the prediction of preeclampsia or fetal growth restriction. However, lipids combined with sFlt-1 and PlGF measurements improved disease prediction. This study successfully identified 421 lipids in maternal plasma collected at 36 weeks' gestation from participants who later developed preeclampsia or delivered a fetal growth restricted infant. Our results suggest the predictive capacity of lipid measurements for gestational disorders holds the potential to improve non-invasive assessment of maternal and fetal health. This study was funded by a grant from National Health and Medical Research Council.

An investigation into the role of Notch signaling, altered angiogenesis, and inflammatory-induced preterm delivery and related complications in Northeast Indian patients

IntroductionNotch signaling is crucial during pregnancy with ability to regulate angiogenesis and inflammatory response. Considering the enigmatic importance of Notch signaling in pregnancy including placenta development, gestational disorders and adverse pregnancy; we performed experimental analysis to identify the Notch receptor-ligands association with Preterm delivery (PTD) and linked complication. MethodA total of 245 cases [Term n = 135 and Preterm n = 110] were enrolled for the study from Northeast Indian Population. The differential mRNA expression of Notch receptors , ligands, its downstream target Hes1 and Immune markers (IL-10, IL-12 and TNF-α) was studied by real time polymerase chain reaction. Further the protein study of Notch1 and 4, Hes1, VEGF and TNF-α was performed by immunofluorescence. ResultsPlacental mRNA expression of all the four notch receptors [Notch1 = 2.15 ± 1.02 fold, Notch2 = 6.85 ± 2.70 fold, and Notch3 = 1.74 ± 0.90 fold and Notch4 = 14.15 ± 6.72 fold]; ligands [JAG1 = 2.71 ± 1.22, JAG2 = 4.41 ± 2.31, DLL1 = 3.55 ± 1.38, DLL3 = 4.31 ± 2.82 and DLL4 = 3.07 ± 1.30 folds] and downstream target [Hes1 = 6.09 ± 2.89 folds] was elevated in PTD cases compared to Term delivery (TD) cases. The mRNA expression of pro-inflammatory marker (IL-12 = 3.99 ± 1.02 fold and TNF-α = 16.83 ± 2.97), was upregulated. The upregulated expression of Notch1(p < 0.001), JAG1 (p = 0.006), JAG2 (p = 0.009), DLL1 (p = 0.001), DLL4 (p < 0.001) Hes1 (p < 0.001), TNF-α (p < 0.001) and IL-12 (p = 0.006) were associated with the baby death; and Notch4 significantly inversely correlated with low birth weight (LBW). Consistently higher protein level expression of Notch1, Hes1, VEGFA and TNF-α was observed in preterm with highest expression in negative outcome cases. DiscussionTo conclude, the increased Notch1 expression and angiogenesis linked inflammation holds key in understanding the pathogenesis of PTD and linked complications and underlines its potential as therapeutic target for PTD interventions.