Maternal Circulation Research Articles

Plasma metabolites are altered before and after diagnosis of preeclampsia or fetal growth restriction

Metabolomics is the study of small molecules (metabolites), within cells, tissues and biofluids. Maternal metabolites can provide important insight into the health and development of both mother and fetus throughout pregnancy. This study assessed metabolic profiles in the maternal circulation prior to and at the time of diagnosis of preeclampsia and fetal growth restriction. Maternal plasma samples were collected from two independent cohorts: (1) Established disease cohort: 50 participants diagnosed with early-onset preeclampsia (< 34 weeks’ gestation), 14 with early-onset fetal growth restriction, and 25 gestation-matched controls. (2) Prospective cohort, collected at 36 weeks’ gestation before diagnosis: 17 participants later developed preeclampsia, 49 delivered infants with fetal growth restriction (birthweight < 5th centile), and 72 randomly selected controls. Metabolic evaluation was performed by Metabolomics Australia on the Agilent 6545 QTOF Mass Spectrometer. In the established disease cohort, 77 metabolites were altered in circulation from participants with preeclampsia – increased l-cysteine (3.73-fold), l-cystine (3.28-fold), l-acetylcarnitine (2.57-fold), and carnitine (1.53-fold) (p < 0.05). There were 53 metabolites dysregulated in participants who delivered a fetal growth restriction infant—including increased levulinic acid, citric acid (1.93-fold), and creatine (1.14-fold) (p < 0.05). In the prospective cohort, 30 metabolites were altered in participants who later developed preeclampsia at term – reduced glutaric acid (0.85-fold), porphobilinogen (0.77-fold) and amininohippuric acid (0.82-fold) (p < 0.05) was observed. There were 5 metabolites altered in participants who later delivered a fetal growth restriction infant – including reduced 3-methoxybenzenepropanoic acid (p < 0.05). Downstream pathway analysis revealed aminoacyl-tRNA biosynthesis to be most significantly altered in the established cohort in preeclampsia (13/48 hits, p < 0.001) and fetal growth restriction (7/48 hits, p < 0.001). The predictive cohort showed no significant pathway alterations. This study observed altered metabolites in maternal plasma collected before and after diagnosis of a preeclampsia or fetal growth restriction. While a significant number of metabolites were altered with established disease, few changes were observed in the predictive cohort. Thus, metabolites measured in this study may not be useful as predictors of preeclampsia or fetal growth restriction.

Cord Blood Hemoglobin Levels in Full Term Neonates of Mothers with Iron Deficiency Anemia

Abstract Background Iron is a critical micronutrient for tissue oxygenation, cellular metabolism, energy generation, and the metabolism of toxins. Iron transfer from mother to fetus is a regulated process involving iron status in the maternal circulation, its transport across the placenta and subsequent transfer into the fetal circulation. Objective To evaluate cord blood Hemoglobin (Hb) levels in neonates of mothers with iron deficiency anemia (IDA). Patients and Methods This prospective case-control study was conducted at Ain Shams University Hospitals. It included 60 full terms newborn who were born at Obstetrics and Gynecology Hospital. The study population included full term neonates delivered at ≥ completed 37 weeks of gestation which was divided into two groups according to maternal risk factor: Case: full term neonates with maternal risk factor. Control: full term neonates without maternal risk factor. Thorough clinical examination and investigations were performed including cord blood samples collected for measurement of the level of complete blood count (CBC; (Hb, MCV and MCH). For the mothers, venous blood samples were withdrawn with standard precautions and strict sterile conditions for CBC, transferrin saturation and serum ferritin. Results In comparison between cases and controls as regard RBCS parameter, there was no significant difference between cases and controls regarding neonatal hemoglobin( 14.93±1.14 vs 15.44 ±1.35(g/dL), p = 0.12) and MCH (32.51±2.9 vs33.57 ±1.9 (pg), p = 0.10), but there was significantly lower MCV in cases compared to controls (104.07± 7.36 vs 109.60±4.93 (fL), p = 0.001). There was no significant difference between cases and controls as regard maternal clinical characteristics including (age, weight, height, maternal diseases, gravidity, consanguinity and mode of delivery, p &amp;gt; 0.05 for all). Also, there was no significant difference between cases and controls regarding neonatal weight, Z score for weight, length (cm), head circumference (cm) and gestational age by Ballord Score and Apgar Score in 1-minute and 5-minute score p &amp;gt; 0.05 for all). Conclusion There was no relation between the maternal Hb deficient levels and neonatal Hb. The first sign of iron deficiency in neonates reflected in lower MCV in cases, but not reached to decrease Hb levels in neonates.

Short-term effects of antenatal betamethasone on fetal cardiovascular and circulation status: A quasi-experimental observational (before-after) study.

The administration of antenatal corticosteroid is a standard treatment to reduce the rate of perinatal mortality and morbidity; however, there is limited evidence regarding the potential effects of betamethasone on the constriction of the ductus arteriosus (DA). This study aimed to investigate the short-term effects of antenatal betamethasone on fetal cardiovascular and circulation status. This quasi-experimental observational (before-after) study was conducted on 32 singleton fetuses. The participants were healthy pregnant women with a diagnosis of placenta accreta spectrum who were eligible for 2 doses of betamethasone and referred to prenatal care clinic, Vali-E-Asr hospital, Tehran, Iran from January 2021-May 2022. The results of fetal echocardiography and Doppler sonography were compared before and after the administration of antenatal corticosteroid therapy. Following betamethasone injection, significant increases were observed in peak systolic and diastolic velocity of the DA without constriction of the DA (p 0.001, p = 0.002 respectively). However, no significant changes were observed in right ventricular function, tricuspid valve function, Doppler of ductus venous, and peak systolic velocity of the aortic isthmus (p 0.05). Doppler examination of the uterine, umbilical, and middle cerebral arteries also showed no significant changes (p 0.05). Considering the benefits of antenatal corticosteroid therapy, its administration seems reasonable in preterm births. The transient changes in ductal blood flow are not prohibitive.

A review of neonatal lupus syndrome.

This review article discusses neonatal lupus syndrome (NLS), an immune-mediated disease caused by maternal antibodies. Maternal antibodies in the fetal circulation are mostly but not always protective. NLS is a disease caused by pathogenic maternal autoantibodies in the fetal circulation. The passive immunization of the fetus by NLS-causing maternal antibodies may occur in the absence of a previously known maternal systemic autoimmune rheumatic disease (SARD). Screening for NLS-related antibodies in patients with related SARD or those in whom there is a risk of NLS including first-degree relatives should occur before pregnancy. This screening is best performed as part of a collaborative relationship between obstetrics and rheumatology. Pregnancy preparations in those with SARD include transitioning to pregnancy-safe medications. The symptoms of NLS range from minor skin rashes to fetal demise from heart block. Fetal screening allows for maternal therapeutic interventions that may be beneficial, as well as the use of fetal pacemakers in the more severe cases that include cardiac NLS.

Predominance of Cephalic Presentation at Birth: An Oxygen Delivery-Based Concept

Background: Fetuses closer to term present predominantly as cephalic, and by the time of delivery 96-97% of them are born headfirst. To date, no coherent hypothesis has been put forth to explain the phenomenon. Observation: As pregnancy advances, there is a progressive increase in cephalic presentation; by 25 weeks, 60% are cephalic, at 35 weeks 90% cephalic and at term only less than 3-4% remain breech. Hypothesis: Oxygen delivery to the fetus comes from the environment through the parturient and it must traverse a very long passage to get to the fetal tissues making oxygen delivery a very precarious process. The fetus develops several compensatory mechanisms to enhance the delivery of oxygen—higher hemoglobin level, hemoglobin with greater affinity for oxygen, the double Bohr phenomenon to improve the diffusion of oxygen from the parturient and lastly redesign of the fetal circulation to increase flow to the brain whilst in the state of near chronic hypoxia whilst in utero. The better flow of blood to the head and therefore more oxygen to the brain makes this organ the densest causing it to progressively present cephalic as pregnancy advances. Implications: The hypothesis aligns well with not only the observed progressive cephalic phenomenon but also the long-term subtle cognitive deficits and neurological sequelae observed in several studies of those born breech. Conclusion: Cephalic presentation at birth is driven by better blood flow to the brain as another compensatory mechanism to cope with hypoxia.

Placental Protein 13 and Syncytiotrophoblast Basement Membrane Ultrastructures in Preeclampsia.

Background and Objectives: Preeclampsia has been linked to an inflammatory response that may be brought on by endothelial cell dysfunction. This paper investigates the pathomechanism of syncytiotrophoblast basement membrane (STBM) damage and Placental Protein 13 (PP13) release, which may have a role in systemic endothelial dysfunction in preeclampsia. Materials and Methods: This comparative cross-sectional study involves 54 preeclampsia patients (27 early-onset preeclampsia and 27 late-onset preeclampsia) and 27 pregnant women with normal blood pressure. An enzyme-linked immunosorbent assay was performed to evaluate maternal blood levels of PP13. Following birth, a portion of the placenta was collected for transmission electron microscope (TEM) and immunohistochemical (IHC) analysis. The data were analyzed using STATA version 15. Results: PP13 expression in the placental syncytiotrophoblast was significantly lower in the early-onset preeclampsia, compared to late-onset preeclampsia and normotensive pregnancy, group (p < 0.001). In contrast, serum PP13 levels were found to be the highest in the early-onset preeclampsia group, although no significant difference were found in mean maternal serum levels of PP13 between the three groups. The decreased PP13 expression in placental syncytiotrophoblast can be attributed to the greater extent of damage in the STBM in early-onset preeclampsia that leads to the release of a larger amount of PP13 into maternal circulation. The hypothesis aligns with the TEM analysis results. Preeclamptic pregnancies showed placental syncytiotrophoblast aponeurosis, whereas normotensive pregnancies did not. Placental lesions and STBM shedding were found to be more pronounced in early-onset preeclampsia compared to late-onset preeclampsia. Conclusions: PP13 and STBM damage may play a role in systemic endothelial dysfunction in preeclampsia.

Коагуляційні характеристики пуповинної крові при затримці росту плода

Fetal growth restriction (FGR) is a common complication of pregnancy associated with severe perinatal consequences, a significant part of which is hemorrhagic and thrombotic disorders. Fetuses with FGR have thrombocytopenia, platelet dysfunction, and distortion of standard coagulation tests. There are few studies of the coagulation system in such newborns in vivo in the literature. Аim - to assess the relationship between the Doppler criteria of FGR and the kinetic manifestations of umbilical artery blood coagulation and fibrinolysis according to rotational thromboelastometry. Materials and methods. Prenatal Doppler parameters and postpartum kinetic parameters of blood coagulation and fibrinolysis in 118 newborns from singleton births were analyzed: the Group I - 67 newborns with FGR; the Group II - 51 full-term newborns from healthy mothers. Results. A significant decrease in the uterine and umbilical arteries resistance and blood flow velocity in FGR cases has been established. Thromboelastometric tests in the umbilical cord blood of the Group I newborns showed faster than in the Group II the blood clot formation, its greater firmness and delayed fibrinolysis. Comparison using rank correlation showed a relationship of average strength between the velocity of blood flow in the umbilical cord arteries and the blood clot firmness. Correlation between blood flow velocity in the midbrain and uterine arteries and coagulation indicators are weak. Conclusions. Reduced resistance index in the middle cerebral artery of fetuses with FGR indicates reduced resistance in these vessels, which should be regarded as signs of decentralization of fetal circulation. The blood of newborns with FGR is dominated by the processes of increased coagulation and slowing down of fibrinolysis, regardless of the date of birth. An increase in the pulsation index in the umbilical cord arteries during pregnancy can be considered a prognostically favorable hemodynamic characteristic in FGR. The study was carried out in accordance with the principles of the Helsinki Declaration. The research protocol was approved by the Local Ethics Committee of the institution mentioned in the work. The authors declare that there is no conflict of interest.

Is Feto-Maternal Transfusion after Cesarean Delivery Different in Singleton and Twin Pregnancy?

Background: The aim of the study was to investigate if feto-maternal transfusion was related to the size of the fetal-maternal interface, and, therefore, was larger in twin pregnancy in comparison with singleton pregnancy. Methods: Blood samples from women with singleton (n = 11), and monochorionic (n = 11) and dichorionic (n = 13) twin gestations were tested. Flow cytometry tests with hemoglobin F, glycophorin A, and hemoglobin F and carbonic anhydrase simultaneous staining were used to detect fetal red blood cells and maternal F cells. Results: In all cases, the volume of feto-maternal transfusion was estimated to be low. The highest rate of fetal red blood cells in the maternal circulation was observed in the blood of women with dichorionic twin gestations both before and after delivery. An increase in fetal red blood cells was observed after cesarean section in singletons and twins. The median rate of maternal F cells was 2.23% in singleton, 2.1% in monochorionic and 3.95% in dichorionic pregnancy. Conclusions: Feto-maternal transfusion during pregnancy may be related to the multiplicity and chorionicity of pregnancy.

Norepinephrine or phenylephrine for the prevention of post-spinal hypotension after caesarean section: A double-blinded, randomized, controlled study of fetal heart rate and fetal cardiac output

Study objectiveSpinal anesthesia often causes hypotension, with consequent risk to the fetus. The use of vasopressor agents has been highly recommended for the prevention of spinal anesthesia-induced hypotension during caesarean delivery. Many studies have shown that norepinephrine can provide more stable maternal hemodynamics than phenylephrine. We therefore tested the hypothesis that norepinephrine preserves fetal circulation better than phenylephrine when used to treat maternal hypotension consequent to spinal anesthesia. DesignProspective, randomized, double-blinded study. SettingOperating room. PatientsWe recruited 223 parturients with uncomplicated singleton pregnancies who were scheduled for elective caesarean section under combined spinal-epidural anesthesia. InterventionsThe patients received prophylactic intravenous infusion of either 0.08 μg/kg/min norepinephrine or 0.5 μg/kg/min phenylephrine for prevention of spinal anesthesia-induced hypotension. MeasurementsChanges in fetal heart rate and fetal cardiac output before and after spinal anesthesia were measured using noninvasive Doppler ultrasound. Main results90 subjects who received norepinephrine infusion and 93 subjects who received phenylephrine infusion were ultimately analyzed in the present study. The effects of norepinephrine and phenylephrine on the change of fetal heart rate and fetal cardiac output at 3 and 6 min after spinal block were similar. Although there was a statistically significant decrease in fetal cardiac output at 6 min after subarachnoid block initiation in both the norepinephrine group (mean difference 0.02 L/min; 95% CI, 0–0.04 L/min; P = 0.03) and the phenylephrine group (mean difference 0.02 L/min; 95% CI, 0–0.04 L/min; P = 0.02), it remained within the normal range. ConclusionsProphylactic infusion of comparable doses of phenylephrine or norepinephrine has similar effects on fetal heart rate and cardiac output changes after spinal anesthesia. Neither phenylephrine nor norepinephrine has meaningful detrimental effects on fetal circulation or neonatal outcomes.

Placental Expression of Glucose and Zinc Transporters in Women with Gestational Diabetes

Background/Objectives: Gestational diabetes (GDM) is a metabolic disorder with altered glucose levels diagnosed in pregnant women. The pathogenesis of GDM is not fully known, but it is thought to be caused by impaired insulin production and insulin resistance induced by diabetogenic factors. The placenta may play an important role in the development of GDM. Glucose transporters (GLUTs) are responsible for the delivery of glucose into the foetal circulation. Placental zinc transporters regulate insulin and glucagon secretion, as well as gluconeogenesis and glycolysis. The aim of this study was to investigate the placental expression of GLUT3, GLUT4, GLUT7 and SLC30A8 in women with GDM. Furthermore, we evaluated whether the expression profiles of these transporters were correlated with clinical parameters. Methods: This study included 26 patients with GDM and 28 patients with normal glucose tolerance (NGT). Results: The placental expression of GLUT3 was significantly reduced in the GDM group, while the placental expression of GLUT4, GLUT7 and SLC30A8 was significantly upregulated in the GDM group. GLUT3 expression correlated significantly with body mass index (BMI) increase during pregnancy and body mass increase during pregnancy, while GLUT4 expression correlated negatively with BMI at birth. Conclusions: These results suggest the involvement of GLUT3 and GLUT4, GLUT7 and SLC30A8 in the pathogenesis of GDM.

Middle Cerebral Artery Doppler before and after Fetal Spina Bifida Repair: An Indirect Sign of Hindbrain Compression and Decompression?

Reduced middle cerebral artery resistance indices (MCA-RI) in fetuses with spina bifida (fSB) are commonly observed. Compression of neuronal pathways in the brainstem due to hindbrain herniation (HH) and disturbed cerebrospinal fluid circulation likely cause an imbalance of the autonomic nervous system. This may increase systemic vasoconstriction and compensatory increase cerebral vasodilation (like brain sparing). The aim of this study was to systematically analyze all fetal MCA-RI before and after fSB repair and to compare their correlation with the presence and postsurgical resolution of HH. 173 patients were included. Standardized ultrasound examinations including MCA and umbilical artery (UA) Doppler as well as assessment of HH presence and regression were performed. Fetuses with MCA-RI &lt;5th percentile (P) before fetal surgery were compared to the group with normal MCA-RI and correlated to the presence of HH before and its regression after fSB repair. 30% (49/161) fetuses showed RI's &lt;5th P before fSB repair. All fetuses had normal UA-RI. 99.4% of fetuses (160/161) showed normal of MCA-RI before delivery. Normalization occurred within a mean of 1.3 ± 1.2 weeks. HH regression was observed in 97% in the group with normal MCA-RI and in 96% in the group with MCA-RI &lt;5th P before surgery (p = 0.59). Time lapse to HH regression after fSB repair was 1.8 ± 1.7 and 1.9 ± 1.6 weeks, respectively. In fetuses with MCA-RIs &lt;5 P before fSB repair, a parallel timely course of MCA-RI normalization and HH regression was noted. To suggest common pathogenic factor(s), more studies are needed. However, normalization of the fetal cerebral circulation could be a further benefit of fSB repair.

The predictors of successful methotrexate treatment of tubal ectopic pregnancy

Background The pre-treatment characteristics of the patient and ectopic pregnancy to determine the patients who are likely to successfully respond to methotrexate (MTX) therapy remain controversial. This study investigated the outcomes of ectopic pregnancy after one and two MTX doses and their independent predictors. Methods Retrospective cross-sectional study of women who consented to MTX treatment in 2017–2018 at our institution (N = 317). Of these, patients with Caesarean scar pregnancies were excluded because they require different treatment protocols (n = 25). All patients were treated according to our institution’s protocol based on international guidelines and standardised across the three hospitals included in the current study. We retrieved patients’ demographics, laboratory, ultrasonography, and clinical characteristics from our hospital database. Serum β-human chorionic gonadotropin (β-hCG) was measured using electrochemiluminescence immunoassay; ectopic pregnancy was diagnosed using ultrasonography (transvaginal probe). Results Two ninety-two patients were included in the current analysis. Age, pre-treatment β-hCG levels, sonographic presence of yolk sac, presence of foetal cardiac activity, and pelvic pain were significantly different between patients with successful and unsuccessful outcomes. Younger age (adjusted odds ratio [aOR] 2.33, 95% confidence interval (CI) 1.16–4.66, p = .017), no pelvic pain (aOR 2.65, 95%CI 1.03–6.83, p = .043), lower initial β-hCG level (aOR 1.32, 95%CI 1.08–1.59, p = .005), and absence of foetal cardiac activity (aOR 12.63; 95% CI 1.04–153.6; p = .047) were independently associated with success. Treatment failure odds were >2 folds higher for each 10-year age increase (p = .017), 32% higher for each 1000 IU/L increase in initial β-hCG level (p = .005), and >2 folds higher in presence of pelvic pain (p = .043). Conclusions MTX is effective in most patients, averting invasive surgery, which might affect fertility. Pre-treatment β-hCG levels, age, pelvic pain, and foetal cardiac activity was independently associated with outcomes. Research should assess the relationship between the ectopic pregnancy size and treatment outcomes and refine β-hCG titres where treatment would be ineffective.

Acute-on-chronic: using magnetic resonance imaging to disentangle the haemodynamic responses to acute and chronic fetal hypoxaemia.

The fetal haemodynamic response to acute episodes of hypoxaemia are well characterised. However, how these responses change when the hypoxaemia becomes more chronic in nature such as that associated with fetal growth restriction (FGR), is less well understood. Herein, we utilised a combination of clinically relevant MRI techniques to comprehensively characterize and differentiate the haemodynamic responses occurring during acute and chronic periods of fetal hypoxaemia. Prior to conception, carunclectomy surgery was performed on non-pregnant ewes to induce FGR. At 108-110 days (d) gestational age (GA), pregnant ewes bearing control (n = 12) and FGR (n = 9) fetuses underwent fetal catheterisation surgery. At 117-119 days GA, ewes underwent MRI sessions where phase-contrast (PC) and T2 oximetry were used to measure blood flow and oxygenation, respectively, throughout the fetal circulation during a normoxia and then an acute hypoxia state. Fetal oxygen delivery (DO2) was lower in FGR fetuses than controls during the normoxia state but cerebral DO2 remained similar between fetal groups. Acute hypoxia reduced both overall fetal and cerebral DO2. FGR increased ductus venosus (DV) and foramen ovale (FO) blood flow during both the normoxia and acute hypoxia states. Pulmonary blood flow (PBF) was lower in FGR fetuses during the normoxia state but similar to controls during the acute hypoxia state when PBF in controls was decreased. Despite a prevailing level of chronic hypoxaemia, the FGR fetus upregulates the preferential streaming of oxygen-rich blood via the DV-FO pathway to maintain cerebral DO2. However, this upregulation is unable to maintain cerebral DO2 during further exposure to an acute episode of hypoxaemia. The haemodynamic alterations required at the level of the liver and lung to allow the DV-FO pathway to maintain cerebral DO2, may have lasting consequences on hepatic function and pulmonary vascular regulation after birth.

Research progress on the effects of exposure to major persistent organic pollutants during pregnancy on the functional development of nervous system in children

Persistent Organic Pollutants (POPs) have the characteristics of resistance to environmental degradation, bioaccumulation and long-distance migration potential. Maternal exposure to POPs during pregnancy can enter the fetal blood circulation through the placental barrier, and have a potential impact on the functional development of the nervous system of the offspring. This in turn leads to the occurrence and development of neurological defects and diseases in adulthood. The purpose of this paper is to elucidate the effects of exposure to three major POPs (organochlorine compounds, perfluoroalkyl and polyfluoroalkyl substances, and polybrominated diphenyl ethers) during pregnancy on the functional development of the nervous system (social emotions, cognition, language, exercise, and adaptability) in children, and to provide reference for subsequent studies.

Small RNAs in the pathogenesis of preeclampsia

Preeclampsia is a major contributor to maternal and fetal morbidity and mortality. The disorder can be classified into early- and late-onset subtypes, both of which evolve in two stages. The first stage comprises the development of pre-clinical, utero-placental malperfusion. Early and late utero-placental malperfusion have different causes and time courses. Early-onset preeclampsia (20 % of cases) is driven by dysfunctional placentation in the first half of pregnancy. In late-onset preeclampsia (80 % of cases), malperfusion is a consequence of placental compression within the confines of a limited uterine cavity. In both subtypes, the malperfused placenta releases stress signals into the maternal circulation. These stress signals trigger onset of the clinical syndrome (the second stage). Small RNA molecules, which are implicated in cellular stress responses in general, may be involved at different stages. Micro RNAs contribute to abnormal trophoblast invasion, immune dysregulation, angiogenic imbalance, and syncytiotrophoblast-derived extracellular vesicle signalling in preeclampsia. Transfer RNA fragments are placental signals known to be specifically involved in cell stress responses. Disorder-specific differences in small nucleolar RNAs and piwi-interacting RNAs have also been reported. Here, we summarise key small RNA advances in preeclampsia pathogenesis. We propose that existing small RNA classifications are unhelpful and that non-biased assessment of RNA expression, incorporation of non-annotated molecules and consideration of chemical modifications to RNAs may be important in elucidating preeclampsia pathogenesis.

Kisspeptin signalling and its correlation with placental ultrastructure and clinical outcomes in pregnant South African women with obesity and gestational diabetes

IntroductionGestational diabetes mellitus (GDM) is a major pregnancy metabolic disorder and is strongly linked with obesity. Kisspeptin is a hormone that increases several thousand-fold in the maternal circulation during human pregnancy, with placenta as its main source. Studies have suggested that kisspeptin regulates trophoblast invasion and promotes pancreatic insulin secretion and peripheral insulin sensitivity. MethodsIn a well-characterized cohort of pregnant South African women and molecular and histological techniques, this study explored the impact and interaction of maternal obesity and GDM on kisspeptin (KISS1) signalling in relation to placental morphology and maternal and neonatal parameters. ResultsWe found that GDM had no effect on placental KISS1 and KISS1R (KISS1 receptor) mRNA and/or protein expression. However, obesity reduced placental KISS1R mRNA expression even though overall KISS1 protein abundance or localization was not different from the non-obese group. Maternal and cord circulating KISS1 concentrations did not vary with obesity or GDM, but maternal circulating KISS1 was positively correlated with placenta weight in non-GDM obese women, and negatively correlated with placental intervillous space volume in non-GDM non-obese women. Cord serum KISS1 was positively correlated with infant weight in GDM obese women, but negatively correlated with maternal BMI in the non-obese GDM group. Placental syncytiotrophoblast extracellular vesicles exhibited detectable KISS1 and its abundance was ∼50 % lower in those from obese GDM compared to non-GDM women. DiscussionThis study shows maternal obesity and GDM can modulate placental kisspeptin signalling and placental morphological development with potential pathophysiological implications for clinically-relevant pregnancy and perinatal outcomes.

Patent Foramen Ovale Closure in Special Clinical Situations: More Questions Than Answers?

Patent foramen ovale (PFO) is a remnant of the foetal circulation resulting from incomplete occlusion of the septum primum and septum secundum. Although prevalent in about 25% of the population, it mainly remains asymptomatic. However, its clinical significance in situations such as cryptogenic stroke, migraine, and decompression illness (DCI) has been well described. Recent randomised clinical trials (RCTs) have demonstrated the efficacy of percutaneous PFO closure over pharmacological therapy alone for secondary stroke prevention in carefully selected patients. Notably, these trials have excluded older patients or those with concurrent thrombophilia. Furthermore, the role of closure in other clinical conditions associated with PFO, like decompression sickness (DCS) and migraines, remains under investigation. Our review aims to summarise the existing literature regarding epidemiology, pathophysiological mechanisms, optimal management, and closure indications for these special patient groups.

Analysis of fetal heart rate fluctuations in women diagnosed with preeclampsia during the latent phase of labor

IntroductionFetal heart rate variability (fHRV) is a tool used to investigate the functioning of the fetal autonomic nervous system. Despite the significance of preeclampsia, fHRV during the latent phase of labor has not been extensively studied. This study aimed to evaluate fetal cardiac autonomic activity by using linear and nonlinear indices of fHRV analysis in women diagnosed with preeclampsia without hypertensive treatment during gestation, compared to normotensive women during the latent phase of labor.MethodsA cross-sectional and exploratory study was conducted among pregnant women in the latent phase of labor, forming three study groups: normotensive or control (C, 38.8 ± 1.3 weeks of pregnancy, n = 22), preeclampsia with moderate features (P, 37.6 ± 1.4 weeks of pregnancy n = 10), and preeclampsia with severe features (SP, 36.9 ± 1.2 weeks of pregnancy, n = 12). None of the participants received anti-hypertensive treatment during their pregnancy. Linear and nonlinear features of beat-to-beat fHRV, including temporal, frequency, symbolic dynamics, and entropy measures, were analyzed to compare normotensive and preeclamptic groups.ResultsSignificantly lower values of multiscale entropy (MSE) and short-term complexity index (Ci) were observed in the preeclamptic groups compared to the C group (p &amp;lt; 0.05). Additionally, higher values of SDNN (standard deviation of R-R intervals) and higher values of low-frequency power (LF) were found in the P group compared to the C group.ConclusionOur findings indicate that changes in the complexity of fetal heart rate fluctuations may indicate possible disruptions in the autonomic nervous system of fetuses in groups affected by undiagnosed preeclampsia during pregnancy. Reduced complexity and shifts in fetal autonomic cardiac activity could be associated with preeclampsia’s pathophysiological mechanisms during the latent phase of labor.

Two novel in vitro assays to screen chemicals for their capacity to inhibit thyroid hormone transmembrane transporter proteins OATP1C1 and OAT4

Early brain development depends on adequate transport of thyroid hormones (THs) from the maternal circulation to the fetus. To reach the fetal brain, THs have to cross several physiological barriers, including the placenta, blood–brain-barrier and blood–cerebrospinal fluid-barrier. Transport across these barriers is facilitated by thyroid hormone transmembrane transporters (THTMTs). Some endocrine disrupting chemicals (EDCs) can interfere with the transport of THs by THTMTs. To screen chemicals for their capacity to disrupt THTMT facilitated TH transport, in vitro screening assays are required. In this study, we developed assays for two THTMTs, organic anion transporter polypeptide 1C1 (OATP1C1) and organic anion transporter 4 (OAT4), both known to play a role in the transport of THs across barriers. We used overexpressing cell models for both OATP1C1 and OAT4, which showed an increased uptake of radiolabeled T4 compared to control cell lines. Using these models, we screened various reference and environmental chemicals for their ability to inhibit T4 uptake by OATP1C1 and OAT4. Tetrabromobisphenol A (TBBPA) was identified as an OATP1C1 inhibitor, more potent than any of the reference chemicals tested. Additionally perfluorooctanesulfonic acid (PFOS), perfluoroctanic acid (PFOA), pentachlorophenol and quercetin were identified as OATP1C1 inhibitors in a similar range of potency to the reference chemicals tested. Bromosulfophthalein, TBBPA, PFOA and PFOS were identified as potent OAT4 inhibitors. These results demonstrate that EDCs commonly found in our environment can disrupt TH transport by THTMTs, and contribute to the identification of molecular mechanisms underlying TH system disruption chemicals.

Placental Drug Delivery to Treat Pre-Eclampsia and Fetal Growth Restriction.

Pre-eclampsia and fetal growth restriction (FGR) continue to cause unacceptably high levels of morbidity and mortality, despite significant pharmaceutical and technological advances in other disease areas. The recent pandemic has also impacted obstetric care, as COVID-19 infection increases the risk of poor pregnancy outcomes. This review explores the reasons why it lacks effective drug treatments for the placental dysfunction that underlies many common obstetric conditions and describes how nanomedicines and targeted drug delivery approaches may provide the solution to the current drug drought. The ever-increasing range of biocompatible nanoparticle formulations available is now making it possible to selectively deliver drugs to uterine and placental tissues and dramatically limit fetal drug transfer. Formulations that are refractory to placental uptake offer the possibility of retaining drugs within the maternal circulation, allowing pregnant individuals to take medicines previously considered too harmful to the developing baby. Liposomes, ionizable lipid nanoparticles, polymeric nanoparticles, and adenoviral vectors have all been used to create efficacious drug delivery systems for use in pregnancy, although each approach offers distinct advantages and limitations. It is imperative that recent advances continue to be built upon and that there is an overdue investment of intellectual and financial capital in this field.