Prenatal stress, anxiety and depression alter transcripts, proteins and pathways associated with immune responses at the maternal-fetal interface†.

During pregnancy, the immune system is modified to allow developmental tolerance of the semi-allogeneic fetus and placenta to term. Pregnant women suffering from stress, anxiety, and depression show dysfunctions of their immune system that may be responsible for fetal and/or newborn disorders, provided that placental gene regulation is compromised. The present study explored the effects of maternal chronic self-perceived stress, anxiety, and depression during pregnancy on the expression of immune-related genes and pathways in term placenta. Pregnancies were clinically monitored with the Beck Anxiety Inventory (BAI) and Edinburgh Postnatal Depression Scale (EPDS). A cutoff threshold for BAI/EPDS of 10 divided patients into two groups: Index group (>10, n = 11) and a Control group (<10, n = 11), whose placentae were sampled at delivery. The placental samples were subjected to RNA-Sequencing, demonstrating that stress, anxiety, and depression during pregnancy induced a major downregulation of placental transcripts related to immune processes such as T-cell regulation, interleukin and cytokine signaling, or innate immune responses. Expression differences of main immune-related genes, such as CD46, CD15, CD8α & ß ILR7α, and CCR4 among others, were found in the Index group (P < 0.05). Moreover, the key immune-like pathway involved in humoral and cellular immunity named "Primary immunodeficiency" was significantly downregulated in the Index group compared with Controls. Our results show that mechanisms ruling immune system functions are compromised at the maternal-fetal interface following self-perceived depressive symptoms and anxiety during pregnancy. These findings may help unveil mechanisms ruling the impact of maternal psychiatric symptoms and lead to new prevention/intervention strategies in complicated pregnancies.

RISK OF PLACENTA-ASSOCIATED COMPLICATIONS AT PREECLAMPSIA IN PREGNANT WOMEN WITH THROMBOPHILIA.

OBJECTIVE: The aim: To study the distribution and influence of coagulation factor gene polymorphisms, endothelial dysfunction, blood pressure regulator on the development of obstetric and perinatal complications in women with preeclampsia (PE). PATIENTS AND METHODS: Materials and methods: The prospective cohort study included 46 women with PE and maternal or fetal complications and 87 pregnant women with PE, without complications. Genetic polymorphisms of coagulation factors and fibrinolysis (1691 G→A FVL, 20210 G→A prothrombin, 675 5G/4G PAI-1, 455 G→A fibrinogen ß), endothelial dysfunction (192 Q→R PON-1, 677 C→T MTHFR) and blood pressure regulator (235 M→T angiotensinogen II) were studied with the help of allele-specific polymerase chain reaction. RESULTS: Results: Markers of predisposition to the development of obstetric and perinatal complications in pregnant women with PE are the following genotypes: 1691 GA by V Leiden factor gene - increases the risk in 2.9 times (95% CI 1.94-4.33), 20210 GA by prothrombin gene - in 2.36 times (95% CI 1.54-3.6), 20210 AA by prothrombin gene - in 3.12 times (95% CI 2.4-4.0). Pathological polymorphisms in the genes of angiotensinogen II 235 M→T, PAI-1 5G/4G, fibrinogen ß 455 G→A, paraoxonase-1 192 Q→R do not significantly affect the development of complications during preeclampsia. CONCLUSION: Conclusions: The development of PE against the background of the existence of acquired and hereditary types of thrombophilia is associated with a more severe course, early-onset and the development of life-threatening complications for a mother and fetus.

The etiology of stillbirth over 30 years: A cross-sectional study in a tertiary referral unit.

INTRODUCTION: Stillbirth remains an often unpredictable and devastating pregnancy outcome, and despite thorough investigation, the number of stillbirths attributable to unexplained causes remains high. Placental examination has become increasingly important where access to perinatal autopsy is limited. We aimed to examine the causes of stillbirth in normally formed infants over 30 years and whether a declining autopsy rate has affected our ability to determine a cause for stillbirths. MATERIAL AND METHODS: All cases of normally formed singleton infants weighing ≥500 g that died prior to the onset of labor from 1989 to 2018 were examined. Trends for specific causes and uptake of perinatal autopsy were analyzed individually. RESULTS: In all, 229 641 infants were delivered, with 840 stillbirths giving a rate of 3.66/1000. The rate of stillbirth declined from 4.84/1000 in 1989 to 2.51 in 2018 (P < .001). There was no difference in the rate of stillbirth between nulliparous and multiparous women (4.25 vs 3.66 per 1000, P = .026). Deaths from placental abruption fell (1.13/1000 in 1989 to 0 in 2018, P < .001) and the relative contribution of placental abruption to the incidence of stillbirth also fell, from 23.3% (7/30) in 1989 to 0.0% (0/19) in 2018 (P < .001). Stillbirth attributed to infection remained static (0.31/1000 in 1989 to 0.13 in 2018, P = .131), while a specific causal organism was found in 79.2% (42/53) of cases. Unexplained stillbirths decreased from 2.58/1000 (16/6200) in 1989 to 0.13 (1/7581) in 2018 (P < .001) despite a fall in the uptake of perinatal autopsy (96.7% [29/30] in 1989 to 36.8% (7/19) in 2018; P < .001). Placental disease emerged as a significant cause of stillbirth from 2004 onwards (89.5% [17/19] in 2018). CONCLUSIONS: The present analysis is one of the largest single-center studies on stillbirth published to date. Stillbirth rates have fallen across the study period across parity. A decrease in deaths secondary to placental abruption contributed largely to this. Infection-related deaths are static; however, in one-fifth of cases a causative organism was not found. Despite a decreasing autopsy rate, the number of unexplained stillbirths continues to fall as the importance of placental pathology is increasingly recognized.

Pathomorphological characteristics and immunohistochemical features of placentae from hiv-positive pregnant women with fetal growth retardation.

OBJECTIVE: The aim: To study the pathomorphological characteristics and immunohistochemical features of placentae from human immunodeficiency virus-positive (HIV-positive) pregnant women with FGR. PATIENTS AND METHODS: Materials and methods: The study material was 32 placentae, including 12 placentae from HIV-positive pregnant women with FGR (study group), 10 placentae from HIVpositivepregnant women without FGR (comparison group) and 10 placentae from HIV-negative women with physiological pregnancy (control group). An immunohistochemical study was performed using monoclonal antibodies (MCA) against CD31+ and vascular endothelial growth factor (VEGF). RESULTS: Results: Pathomorphologic changes of the placentae from HIV-positive pregnant women with FGR were characterized by edema in the umbilical cord tissue, partial dissection of the vascular wall fibers, dysmucoidosis; intracellular edema and hemorrhage in the fetal membrane tissues. In the placentae tissue it was found marked manifestations of degenerative changes in the form of the areas of fibrinoid necrosis, pronounced manifestations of dysmucoidosis, vacuolation of the villi stroma, an increase in the number of avascular villi and immature villi of small caliber with the phenomena of syncytiotrophoblast focal hyperplasia. An immunohistochemical study with MCA against CD31+ revealed the expression (optical density) of the vascular endothelial cells up to 2 points, and the expression level up to 3 points in the isolated areas with the appearance of the expression on the villi surface and in their thickness. During immunohistochemical studies with VEGF the expression level and its optical density increased up to 2-3 points, in some areas the expression of deposits were detected on the villi surface, in their thickness and in the intervillous space. CONCLUSION: Conclusions: The comparative pathomorphological and immunohistochemical study of the placentae demonstrated more significant changes in the group of HIV-positive pregnant women with FGR. In the placentae of HIV-positive pregnant women with FGR immunohistochemical examinations revealed a high level of CD31+ and VEGF expression.

Placental bed research: I. The placental bed: from spiral arteries remodeling to the great obstetrical syndromes.

The term placental bed was coined to describe the maternal-fetal interface (ie, the area in which the placenta attaches itself to the uterus). Appropriate vascularization of this area is of vital importance for the development of the fetus; this is why systematic investigations of this area have now been carried out. Initially, the challenge was the identification and classification of the various successive branching of uterine arteries in this area. These vessels have a unique importance because failure of their physiological transformation is considered to be the anatomical basis for reduced perfusion to the intervillous space in women with preeclampsia, fetal growth restriction, preterm labor, preterm premature rupture of membranes, abruptio placentae, and fetal death. To investigate in depth the pathophysiology of the placental bed, some 60 years ago, a large number of placental bed biopsies, as well as of cesarean hysterectomy specimens with placenta in situ, from both early and late normotensive and hypertensive pregnancies, were carefully dissected and analyzed. Thanks to the presence of a series of specific physiological changes, characterized by the invasion and substitution of the arterial intima by trophoblast, this material allowed the identification in the placental bed of normal pregnancies of the main vessels, the uteroplacental arteries. It was then discovered that preeclampsia is associated with defective or absent transformation of the myometrial segment of the uteroplacental arteries. In addition, in severe hypertensive disease, atherosclerotic lesions were also found in the defective myometrial segment. Finally, in the basal decidua, a unique vascular lesion, coined acute atherosis, was also identified This disorder of deep placentation, coined defective deep placentation, has been associated with the great obstetrical syndromes, grouping together preeclampsia, intrauterine growth restriction, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and abruptio placentae. More recently, simplified techniques of tissue sampling have been also introduced: decidual suction allows to obtain a large number of decidual arteries, although their origin in the placental bed cannot be determined. Biopsies parallel to the surface of the basal plate have been more interesting, making possible to identify the vessels' region (central, paracentral, or peripheral) of origin in the placental bed and providing decidual material for immunohistochemical studies. Finally, histochemical and electron microscopy investigations have now clarified the pathology and pathogenetic mechanisms underlying the impairment of the physiological vascular changes.

Abruptio placentae risk and genetic variations in mitochondrial biogenesis and oxidative phosphorylation: replication of a candidate gene association study.

BACKGROUND: Abruptio placentae is a complex multifactorial disease that is associated with maternal and neonatal death and morbidity. Abruptio placentae's high recurrence rate, high prevalence of heritable thrombophilia among women with abruptio placentae, and aggregation of cases in families of women with the disease support the possibility of a genetic predisposition. Previous genome-wide and candidate gene association studies have identified single nucleotide polymorphisms in mitochondrial biogenesis and oxidative phosphorylation genes that potentially are associated with abruptio placentae risk. Perturbations in mitochondrial biogenesis and oxidative phosphorylation, which results in mitochondrial dysfunction, can lead to the impairment of differentiation and invasion of the trophoblast and to several obstetrics complications that include abruptio placentae. OBJECTIVE: The purpose of this study was to determine whether the results of a candidate genetic association study that indicated a link between DNA variants (implicated in mitochondrial biogenesis and oxidative phosphorylation) and abruptio placentae could be replicated. STUDY DESIGN: The study was conducted among participants (507 abruptio placentae cases and 1090 control subjects) of the Placental Abruption Genetic Epidemiology study. Weighted genetic risk scores were calculated with the use of abruptio placentae risk-increasing alleles of 11 single nucleotide polymorphisms in 9 mitochondrial biogenesis and oxidative phosphorylation genes (CAMK2B, NR1H3, PPARG, PRKCA, THRB, COX5A, NDUFA10, NDUFA12, and NDUFC2), which previously was reported in the Peruvian Abruptio Placentae Epidemiology study, a study with similar design and study population to the Placental Abruption Genetic Epidemiology study. Logistic regression models were fit to examine associations of weighted genetic risk scores (quartile 1, <25th percentile; quartile 2, 25-50th percentile; quartile 3, 50-70th percentile, and quartile 4, >75th percentile) with risk of abruptio placentae, adjusted for population admixture (the first 4 principal components), maternal age, infant sex, and preeclampsia. The weighted genetic risk score was also modeled as a continuous predictor. To assess potential effect modification, analyses were repeated among strata that were defined by preeclampsia status, maternal age (≥35 vs 18-34 years), and infant sex. RESULTS: Abruptio placentae cases were more likely to have preeclampsia, shorter gestational age, and lower infant birthweight. Participants in quartile 2 (score, 12.6-13.8), quartile 3 (score, 13.9-15.0) and quartile 4 (score, ≥15.1) had a genetic risk score of 1.45-fold (95% confidence interval, 1.04-2.02; P=.03), a 1.42-fold (95% confidence interval, 1.02-1.98; P=.04), and a 1.75-fold (95% confidence interval, 1.27-2.42; P=7.0E-04) higher odds of abruptio placentae, respectively, compared with those in quartile 1 (score,<12.6; P-for trend=.0003). The risk of abruptio placentae was 1.12-fold (95% confidence interval, 1.05-1.19; P=3.0×1004) higher per 1-unit increase in the score. Among women with preeclampsia, those in quartile 4 had a 3.92-fold (95% confidence interval, 1.48-10.36; P=.01) higher odds of abruptio placentae compared with women in quartile 1. Among normotensive women, women in quartile 4 had a 1.57-fold (95% confidence interval, 1.11-2.21; P=.01) higher odds of abruptio placentae compared with those in quartile 1 (P-for interaction=.12). We did not observe differences in associations among strata defined by maternal age or infant sex. CONCLUSION: In this study, we replicated previous findings and provide strong evidence for DNA variants that encode for genes that are involved in mitochondrial biogenesis and oxidative phosphorylation pathways, which confers risk for abruptio placentae. These results shed light on the mechanisms that implicate DNA variants that encode for proteins in mitochondrial function that are responsible for abruptio placentae risk. Therapeutic efforts to reduce risk of abruptio placentae can be enhanced by improved biologic understanding of maternal mitochondrial biogenesis/oxidative phosphorylation pathways and identification of women who would be at high risk for abruptio placentae.

Low expression of soluble human leukocyte antigen G in early gestation and subsequent placenta-mediated complications of pregnancy.

AIM: Abnormal placentation is a common pathogenic mechanism of many placenta-mediated complications of late pregnancy, including pre-eclampsia, fetal growth restriction, stillbirth, and placental abruption. During successful placentation, the trophoblast (which is a semi-allograft) is not rejected by decidual immune cells because of maternal immune tolerance, mainly induced by human leukocyte antigen G (HLA-G). Deficient HLA-G expression seems to be associated with the development of complications of pregnancy. The aim of this study was to determine whether low soluble HLA-G (sHLA-G) levels in maternal blood at the beginning of pregnancy may be associated with subsequent placenta-mediated complications. METHODS: For this retrospective case-control study, 117 cases of placenta-mediated complications of pregnancy and 234 controls with uneventful pregnancy were selected. Plasma sHLA-G levels were measured at 11-13 weeks' gestation by the enzyme-linked immunosorbent assay method in blood samples previously obtained at first-trimester prenatal screening for chromosomal fetal abnormalities. RESULTS: Women who subsequently developed placenta-mediated complications had significantly lower sHLA-G levels at the beginning of pregnancy (median, 43.08 IU/mL) than controls (median, 49.10 IU/mL; P = 0.008). An sHLA-G level lower than 43.50 IU/mL at the end of the first trimester was associated with a twofold increased risk of developing a pregnancy complication (odds ratio, 1.82; 95% confidence interval, 1.22-2.73). The strongest association, although only moderately strong, was observed with severe pre-eclampsia (odds ratio, 2.66; 95% confidence interval, 1.08-6.56). CONCLUSION: Placenta-mediated complications of pregnancy may be associated with low sHLA-G levels in the first trimester, suggesting a potential role of sHLA-G in the early stages of placentation.

Aquaporin-1, a New Maternally Expressed Gene, Regulates Placental Development in the Mouse.

Imprinted genes play an important role in placental and embryonic development. Abnormalities in their regulation can result in placental and embryonic dysplasia, leading to congenital diseases. The imprinting state, expression, and function of aquaporin-1 (Aqp1) were explored in knockout mice by imprinting analysis, real-time PCR, and immunohistochemistry. In the present study, Aqp1 was identified as a new, imprinted, and placenta-specific maternally expressed gene in the mouse. Compared with wild-type Aqp1(+/+) mice, there was significant placental and embryonic overgrowth in Aqp1(-/+) (loss of maternal allele) and Aqp1(-/-) mice, but not in Aqp1(+/-) (loss of paternal allele) mice at Embryonic Day (E) 12.5-E18.5. In addition, the masses of Postnatal Day 0 (P0) embryos (Aqp1(-/-) and Aqp1(-/+)) were highest among the four types. In Aqp1(-/+) and Aqp1(-/-) mice, phenotypic analysis indicated that the number and branching of blood vessels, as well as the labyrinth area, increased significantly in placentae of E12.5-E18.5 mice. Moreover, there were abnormalities in the placental junctional zone and the labyrinthine zone at E15.5. Quantitative analysis showed that Aqp1 expression decreased significantly in the placentae of Aqp1(-/+) and Aqp1(-/-) mice at E15.5, and that the AQP1 protein expression signals were detected weakly in the decidual and spongioblast layers. Our results demonstrate that Aqp1 is maternally expressed in the placenta, and that its deficiency resulted in placental abnormalities in the mouse. Aqp1 may have a specific inhibitory role in mouse placental development. These results provide new insights for the treatment of diseases relating to placental and embryonic development.

Renal cortical necrosis is a disappearing entity in obstetric acute kidney injury in developing countries: our three decade of experience from India.

RATIONAL: Obstetrical complications are the commonest causes of Renal Cortical Necrosis (RCN). However, the overall incidence of RCN in obstetric acute kidney injury in developing countries has been decreasing in recent years. OBJECTIVE: The aim of this study was to evaluate the changing profile of RCN in obstetric AKI over the last three decades. METHODS: This single center study included patients with biopsy proven renal cortical necrosis over a period of 32 years from 1982 to 2014. The diagnosis of RCN was suspected in patients with prolonged AKI (>4 weeks) with absolute anuria in the setting of hemorrhage, hypotension and sepsis; and was confirmed by renal biopsy. The changing pattern in the incidence, etiology and outcome of RCN in patients with obstetric AKI was compared in the three study periods, namely 1982-1991, 1992-2002 and 2003-2014. RESULTS: Over a period of 32 years, RCN was diagnosed in 15/259(5.8%) cases of obstetric AKI. Diffuse and patchy cortical necrosis were noted in 8(53.3%) and 7(46.7%) patients, respectively. RCN occurred in 17%(11/65), 2.4%(3/125) and 1.44%(1/69) patients in 1982-1991, 1992-2002 and 2003-2014, respectively. Septic abortion was commonest cause of RCN in the first two study periods but no case was observed in last decade. The decrease in incidence of RCN over the three decades was statistically significant (p-value < 0.001). Maternal mortality decreased to zero in 2003-2014 from 72.7% in 1982-1991. CONCLUSIONS: The incidence of RCN in obstetric AKI in developing countries has declined low enough to label it as a disappearing entity.

Prospective risk of abruptio placentae.

AIM: The aim of this study was to better characterize the nature of abruptio placentae (AP) with regard to the timing of onset. MATERIAL AND METHODS: Prevalence and prospective risk of AP according to gestational week (GW) were determined among 293,899 women who gave birth to singleton infants at and after GW 30. The prospective risk of AP at gestational week N was defined as the number of all women who experienced an AP at ≥GW N divided by the number of all women who gave birth at ≥GW N. RESULTS: AP developed in 2649 (0.90%) women. The prevalence of AP (6.7% among women who gave birth at GW 30-33) sharply decreased with advancing GW at delivery to 0.9% for GW 37 and 0.1% for ≥GW 42. The highest prospective risk of AP, 9 per 1000 women at GW 30, decreased linearly with advancing gestation to 1 per 1000 women at ≥GW 42. AP accounted for 4.7% (1591/33,725) of all preterm births at GW <37, while prevalence of AP was 0.41% (1058/260,174) among term births. Preterm AP accounted for 60.1% (1591/2649) of all AP. CONCLUSION: Our figures indicate that AP is more common in preterm births than in term birth and may be helpful for better understanding the epidemiology of this condition.

Adverse perinatal and neonatal outcomes in patients with chronic abruption-oligohydramnios sequence.

AIM: Chronic abruption-oligohydramnios sequence (CAOS) is a clinical condition with lasting vaginal bleeding and oligohydramnios because of chronic placental abruption, which seems to cause preterm labor and neonatal chronic lung disease (CLD). This prompted us to explore the correlation between perinatal/neonatal outcomes and CAOS. METHODS: Patients with suspected risk of abortion with recurrent vaginal bleeding were divided into CAOS and non-CAOS groups, and we compared the perinatal/neonatal outcomes between these two groups. To examine the impact of chorioamnionitis (CAM) on the prognosis of CAOS, we also compared outcomes between the CAOS group and gestational-age-matched preterm labor due to CAM (CAM group). RESULTS: In the CAOS and non-CAOS groups, initial vaginal bleeding was seen at the first trimester. However, its duration was significantly longer in the CAOS group. Additionally, neonatal birthweight was lower, and small-for-gestational-age (SGA) incidence was higher in the CAOS group. CLD was observed in most infants from CAOS patients. In the comparison between CAOS and CAM groups, birthweight was lower and SGA incidence was higher in the CAOS group. Moreover, CLD incidence and neonatal mortality were significantly higher, despite the lower incidence of severe CAM in the CAOS group. Finally, multivariate analysis demonstrated that duration of bleeding was a significant predictive factor for CAOS. CONCLUSIONS: Our observations demonstrated that patients with CAOS were a high-risk group for poor perinatal/neonatal outcomes. Moreover, episodes of recurrent and prolonged uterine bleeding were predictive factors for CAOS. During the first trimester, prolonged bleeding is an important sign as one symptom of CAOS.

Clinical implications of a Couvelaire uterus with placental abruption: A retrospective study.

OBJECTIVE: This study aimed to clarify the maternal and neonatal outcomes based on the presence or absence of a Couvelaire uterus with placental abruption. METHODS: This single-center retrospective study was conducted at a tertiary perinatal center in Japan, including patients diagnosed with acute placental abruption who delivered live births via cesarean section between 2016 and 2023. Patients were divided into two groups based on the presence or absence of a Couvelaire uterus during surgery: the Couvelaire and normal uterus groups. Maternal and neonatal outcomes were assessed. RESULTS: This study included 76 patients: 24 in the Couvelaire group and 52 in the normal uterus group. No patients underwent hysterectomies. The Couvelaire group had significantly higher intraoperative blood loss (median 1152 vs 948 g, P = 0.010), blood transfusion rates (58% vs 31%, P = 0.022), fibrinogen administration rates (38% vs 13%, P = 0.038), intensive care unit/high care unit admission rates (29% vs 7.7%, P = 0.013), and disseminated intravascular coagulation complication rates (25% vs 7.7%, P = 0.038). There were no differences in birth weight, gestational age (median 2387 vs 2065 g, P = 0.082), Apgar score <4 at 5 min (4.2% vs 3.9%, P = 0.95), umbilical artery blood pH <7.1 (25% vs 22%, P = 0.82), and neonatal death (4.2% vs 1.9%, P = 0.57). CONCLUSION: A Couvelaire uterus indicated adverse maternal outcomes but not neonatal ones. Its presence necessitates preparation for blood transfusions and/or intensive patient follow-up.

Expectant management of severe preeclampsia remote from term: the MEXPRE Latin Study, a randomized, multicenter clinical trial.

OBJECTIVE: The objective of the study was to determine whether expectant management of severe preeclampsia prior to 34 weeks of gestation results in improved neonatal outcome in countries with limited resources. STUDY DESIGN: This was a randomized clinical trial performed in 8 tertiary hospitals in Latin America. Criteria of randomization included gestational age between 28 and 33 weeks' gestation and the presence of severe hypertensive disorders. Patients were randomized to steroids with prompt delivery (PD group) after 48 hours vs steroids and expectant management (EXM group). The primary outcome was perinatal mortality. RESULTS: A total of 267 patients were randomized, 133 to the PD group and 134 to the EXM group. Pregnancy prolongation was 2.2 days for the PD group vs 10.3 days for the EXM group (P = .0001). The rate of perinatal mortality (9.4% vs 8.7%; P = .81; relative risk [RR], 0.91; 95% confidence interval [CI], 0.34-1.93) was not improved with expectant management, and neither was the composite of neonatal morbidities (56.4% vs 55.6%; P = .89; RR, 01.01; 95% CI, 0.81-1.26). There was no significant difference in maternal morbidity in the EXM group compared with the PD group (25.2% vs 20.3%; P = .34; RR, 1.24; 95% CI, 0.79-1.94). However, small gestational age (21.7% vs 9.4%; P = .005; RR, 2.27; 95% CI, 1.21-4.14) and abruption were more common with expectant management (RR, 5.07; 95% CI, 1.13-22.7; P = .01). There were no maternal deaths. CONCLUSION: This study does not demonstrate neonatal benefit with expectant management of severe preeclampsia from 28 to 34 weeks. Additionally, a conservative approach may increase the risk of abruption and small for gestational age.

Epigenetic modifications appear in the human placenta following anxiety and depression during pregnancy.

INTRODUCTION: The future health of the offspring can be influenced by longstanding maternal anxiety and depression disorders during pregnancy. The present study aimed to explore the effect of psychiatric disorders during pregnancy on placental epigenetics. METHODS: We measured DNA methylation patterns in term-placentas of women either suffering longstanding anxiety and depression symptoms (Index group, with overt symptoms), or a healthy population (Control, none/only mild symptoms). Whole genome DNA methylation profiling was performed using the TruSeq® Methyl Capture EPIC Library Prep Kit (Illumina, San Diego, CA, USA) for library preparation and NGS technology for genomic DNA sequencing. RESULTS: The results of high-throughput DNA methylation analysis revealed that the Index group had differential DNA methylation at epigenome-wide significance (p < 0.05) in 226 genes in the placenta. Targeted enrichment analyses identified hypermethylation of genes associated with psychiatric disorders (BRINP1, PUM1), and ion homeostasis (COMMD1), among others. The ECM (extracellular matrix)-receptor interaction pathway was significantly dysregulated in the Index group compared to the Control. In addition, DNA methylation/mRNA integration analyses revealed that four genes with key roles in neurodevelopment and other important processes (EPB41L4B, BMPR2, KLHL18, and UBAP2) were dysregulated at both, DNA methylation and transcriptome levels in the Index group compared to Control. DISCUSSION: The presented results increase our understanding of how maternal psychiatric disorders may affect the newborn through placental differential epigenome, suggesting DNA methylation status as a biomarker when aiming to design new preventive techniques and interventions.

Reverse diastolic flow of the fetal middle cerebral artery associated with placental chorangiomatosis and asymptomatic concealed placental abruption.

Reverse diastolic flow of the fetal middle cerebral artery is a rare, yet ominous finding which has been associated with adverse perinatal outcomes including: intracranial hemorrhage, growth restriction, fetal-maternal hemorrhage, severe anemia, hydrops, hepatic anomaly, subsequent stillbirth, and early neonatal death. We report a case in which following notation of a nonreassuring fetal heart rate at 32 weeks' gestation, sonographic documentation of persistent reverse diastolic flow of the fetal middle cerebral artery was noted in association with sonographic findings of vascular placental dysmorphology and an asymptomatic concealed placental abruption. Subsequent fetal heart rate tracing consistent with uteroplacental insufficiency led to immediate Cesarean birth of an anemic yet nonacidotic, nonhypoxic neonate, who did well following management of respiratory distress syndrome and partial exchange transfusion. Placental abruption was confirmed at delivery. Histopathology of the placenta confirmed the presence of localized chorangiomatosis ("wandering" chorangioma). The association of reverse diastolic flow of the fetal middle cerebral artery, placental chorangiomatosis and placental abruption has not been reported previously. We conclude that in the presence of prenatal sonographic findings of placental dysmorphology and or placental abruption, insonation of the fetal middle cerebral artery should be performed to assess the possibility of increased peak systolic velocity and possible reverse diastolic flow, both associated with fetal anemia and increased likelihood of an adverse perinatal outcome.

A Five-Year Review of Feto-Maternal Outcome of Antepartum Haemorrhage in a Tertiary Center.

Background: Pregnancies complicated with antepartum-haemorrhage is high risk pregnancies associated with adverse maternal, fetal-and-perinatal-outcomes. It contributes significantly to fetal and maternal mortality especially in the developing countries. Proper antenatal care and prompt intervention is necessary to forestall adverse and improve outcome. Objective: To determine the prevalence, sociodemographic characteristics, risk factors, fetomaternal outcome of pregnancies with antepartum haemorrhage. Methods: The case files of the patients were retrieved from the medical records department. The total number of deliveries within the study period was obtained from the labour ward records. The feto-maternal-outcome-measures were; prevalence of caesarean-section, postpartum-haemorrhage, hysterectomy, need for blood-transfusion, maternal-death, prematurity, need for admission in intensive-care-unit and still births. The data was analysed using SPSS version 21. Chi-square was used to test for significance. Results: Within the 5-year period under review, out of a total of 6974 deliveries, 234 had antepartum-haemorrhage (3.4% prevalence rate). Abruptio-placentae was the commonest cause and accounted for 69.5% of the cases (prevalence of 2.1%) while placenta praevia accounted for 28.2% of the cases (prevalence rate of 0.9%). The mean age of the women was 31.8±5.3 years. The mean parity was 3.4±1.7 and majority (63.8%) of the women were unbooked. The commonest identifiable risk factors were multiparity and advanced maternal age. One-hundred-and sixty-six (77.9%) women were delivered through the abdominal route. Postpartum-haemorrhage occurred in 22.1% (47) of the cases while prematurity was the commonest fetal complications. Maternal mortality was 0.47% (1) while still birth was 44.1% (94). Conclusion: There is high prevalence of antepartum-haemorrhage in our environment. Abruptio-placentae was the commonest cause and associated with significant adverse fetomaternal-outcome when compared with placenta-praevia. Thus, good and quality antenatal care as well as high index of suspicion, prompt diagnosis and treatment remain the key to forestall these complications and improve fetomaternal-outcome.

Case Report: Abruptio placentae and epileptic seizure after occurrence of perinatal hyperglycaemia in woman with gestational diabetes mellitus and hypertriglyceridemia-induced acute pancreatitis.

Hypertriglyceridemia-induced acute pancreatitis seldom occurs in the second trimester of pregnancy with gestational diabetes mellitus. For these patients, the existing knowledge on concomitant hyperglycemia is not sufficient. We report a case of abruptio placentae and epileptic seizure following perinatal hyperglycaemia in woman with gestational diabetes mellitus and hypertriglyceridemia-induced acute pancreatitis. The occurrence of abruptio placentae and epileptic seizure may be associated with concomitant hyperglycemia, and the epileptic seizure was terminated after she underwent treatment with insulin. We should pay more attention to the adverse effects of perinatal hyperglycemia and continue to give appropriate insulin treatment even if patients have passed the acute phase of hypertriglyceridemia-induced acute pancreatitis.

Plasma Homocysteine, Folic Acid and Vitamin B12 in Abruptio Placentae: A Cross-Sectional Study of Their Role and Feto-Maternal Outcome.

Background Out of the many causes of abruptio placentae, the micronutrient association with its occurrence and severity has not been researched extensively till now. We aim to measure the serum levels of homocysteine, folic acid and vitamin B12 in patients with abruptio placentae in the third trimester of pregnancy and compare the levels with those without the complication. We also propose to compare the feto-maternal outcome between the groups. Methods The cross-sectional study was undertaken in 50 pregnant women with abruption before or during delivery and 50 controls with uncomplicated pregnancy over 28 weeks of gestation. Serum levels of homocysteine, folic acid, and vitamin B12 were determined and feto-maternal outcome was compared between the groups Results Mean age of the cases and controls are 26.82 ± 5.5 and 28.82 ± 4.88 years respectively. Obstetric characteristics have significant difference between the groups in terms of gravidity, mode of delivery, timing of delivery, proportion of stillbirths and blood transfusion. The mean concentration of homocysteine and vitamin B12 between the groups also have a significant difference . The serum level of homocysteine is significantly correlated with serum vitamin B12 level (Pearson correlation= -0.601, P=0.000). However, folic acid concentration between the groups remains comparable. Conclusion Hence we conclude that vitamin B12 and homocysteine are significant determinants of abruptio placentae in pregnant women. Supplementation with the vitamin in the high-risk Indian population can avert a number of obstetric complications occurring due to raised homocysteine.

The impact of SARS-CoV-2 infection on term placentae.

Background: Coronavirus 2019 infection (COVID 19) is an ongoing pandemic caused by pathogenic RNA viruses called severe acute respiratory syndrome coronavirus-2 (SARS-COV-2). It has affected people of all ages, with high morbidity and mortality among the elderly and immunocompromised population. Limited information is available on the effects of COVID-19 infection on pregnancy. Aim: To describe the histopathological changes in the placental tissue of SARS-CoV-2 infected term mothers with no comorbidities and to correlate with neonatal outcome. Materials and Methods: This observational study was conducted in the Department of Pathology, KMCH institute of health sciences and research, Coimbatore from May 1, 2020 to November 30, 2020 for 6 months. Placental tissues of all COVID-19-positive term mothers with no comorbidities were included in this study. Histopathological examination of placentae was carried out and clinical data of mothers and newborn babies were obtained from medical records. Results: Histopathological examination of 64 placental tissue of COVID-19 mothers showed predominantly the features of fetal vascular malperfusion like stem villi vasculature thrombus, villous congestion, and avascular villi. No significant correlation was obtained in comparison with parity and symptomatic status of the mothers. However, histopathological changes were more prominent among symptomatic patients. The newborn babies born to these mothers showed no adverse outcome. Conclusion: This study concluded that though COVID-19 infection in normal term pregnant women was associated with increased prevalence of features of fetal vascular malperfusion, there was no significant morbidity in the health status of both COVID-19 mothers and their neonates.

Corrigendum: Case report: Abruptio placentae and epileptic seizure after occurrence of perinatal hyperglycaemia in woman with gestational diabetes mellitus and hypertriglyceridemia-induced acute pancreatitis.

[This corrects the article DOI: 10.3389/fendo.2023.1220957.].