Evidence from human placenta, ER-stressed trophoblasts and transgenic mice links transthyretin proteinopathy to preeclampsia

We have demonstrated that protein aggregation plays a pivotal role in the pathophysiology of preeclampsia (PE) and identified several aggregated proteins in the circulation of PE patients, most significantly the serum protein transthyretin (TTR). Here we show robust accumulation of TTR aggregates in the placentas of women with early-onset PE (e-PE). TTR aggregation was inducible in primary human trophoblasts (PHTs) and the TCL-1 trophoblast cell line by ER stress inducers or autophagy-lysosomal disruptors. Hypoxia/reoxygenation (H/R) of cultured PHTs increased intracellular BiP, phosphorylated IRE1alpha, PDI and Ero-1, all markers of the UPR, and the apoptosis mediator caspase-3. Blockade of IRE1alpha inhibited H/R-induced upregulation of Ero-1 in PHTs. Excessive UPR was observed in the PE placenta. Further, pregnant mice, overexpressing transgene encoded wild type human TTR, displayed aggregated TTR in the junctional zone of the placenta and PE-like features including hypertension, proteinuria, intrauterine growth restriction, kidney injury, and elevated levels of the PE biomarkers serum sFlt-1 and endoglin. High Resolution Ultrasound analysis revealed low blood flow in uterine and umbilical arteries compared to that found in wild type pregnant mice. On the other hand, loss of mouse TTR function did not cause any pregnancy abnormalities in Ttr-/- mice. These observations in the PE placenta, cultured trophoblast cells and TTR transgenic mice indicate that TTR aggregation is an important causal contributor to PE pathophysiology.

Discordant umbilical arteries in the umbilical cord entanglement: a light microscope study

Objective The present study aimed to examine the histopathological diagnosis of the umbilical artery discordance in cases with single or multiple umbilical cord entanglement and pregnancy outcomes. Methods The vascular structure of the umbilical cord, histopathological findings of the placenta and obstetric outcomes were retrospectively examined in 50 cases. The cases were divided into two groups by the number of cord entanglement (single-multiple) and their histopathological findings and neonatal Apgar scores were assessed. Results Out of 50 cases, 38 (76%) had single and 12 (24%) had multiple cord entanglement. In 50 cases, the mean gestational age was 39.16±1.06 weeks, neonatal Apgar scores were 8.7±0.58 at 1 minute and 9.64±0.56 at 5 minute. No statistically significant difference was detected between single and multiple groups in terms of gestational age (p=0.79), 1-minute Apgar score (p=0.832) and 5-minute Apgar score (p=0.656). In histopathological examination, the diameters of umbilical arteries 1 and 2 were found to be 0.11±0.12, 0.09±0.05 µm, respectively in the single group (p=0.756) and 0.13±0.14, 0.06±0.02 µm, respectively in the multiple group (p=0.131). When the umbilical arterial diameters were compared by group, the diameter of the umbilical artery 2 was detected 0.09±0.05 µm in the single and 0.06±0.02 µm in the multiple group and statistically significant difference was detected (p=0.037). Out of 50 cases, placental hypoxia finding was detected as chorangiosis only in 10 cases (2 multiple, 8 single). Conclusion Umbilical artery discordance was detected in cases with multiple umbilical cord entanglement. However, poor pregnancy outcome was not observed in any of the cases. When multiple cord entanglement is seen during obstetric examination, umbilical artery discordance must be remembered and investigated, and also maternal-fetal condition should be considered.

Analysis of Ultrasound Clinical Early Warning System in Hyper-Coiling Umbilical Cord

Background： Umbilical coiling index（UCI）can not be used to predict pregnancy outcomes. Whether there are other abnormal ultrasound indicators in the hyper-coiling cord (HC) that can give early warning of adverse pregnancy still needs to be further explored.Objective: To establish an ultrasonic early warning system for clinical intervention in patients with the hyper-coiling umbilical cord.Study Design: Retrospectively analyzed 29 patients’ characteristics with hyper-coiling cord (HC) diagnosed by ultrasound in our hospital from January 2019 to March 2021. According to whether the following high-risk factors were combined ①High resistance of umbilical arteries beside the bladder, ②fetal growth restriction (FGR), ③increased diastolic peak blood flow of middle cerebral artery, ④oligohydramnios, ⑤enhanced echo of the cerebral parenchyma, ⑥reversed A wave of the venous catheter ( VC). It could be divided into two types: simple type and complex type, and then divided into three groups according to the delivery situation of patients, as terminated pregnancy group, intervention group, and non-intervention group. At last, according to the distribution of high-risk factors in each group, established an ultrasonic early warning system which affected the clinical intervention and pregnancy outcome of complex HC patients.Results: compared with 9 cases in the simple HC group and 20 cases in the complex HC group, the intervention ratio of complex HC patients was higher (p=0.027), the average delivery gestational weeks was smaller (p=0.034), the abnormal rate of fetal heart monitoring was higher (p=0.027), and there were statistical differences in above. Compared in the three groups (terminated pregnancy group, intervention group, and the non-intervention group), there were statistical differences in the number of high-risk factors (P=0.000) and the distribution proportion of six high-risk factors (P = 0.012, 0.011, 0.000, 0.026, 0.028, 0.000).Conclusion: the monitoring of six high-risk factors by ultrasound could establish an ultrasound early warning system for HC to influence the clinical intervention and pregnancy outcome. In this early warning system, the monitoring of fetal intrauterine safety was often needed for complex HC patients. High resistance of umbilical arteries beside the bladder and FGR were the earliest warning signs. Once timely clinical intervention was carried out, the prognosis of pregnancy could be improved.

Ultrastructure of Hyrtl's Anastomosis of Pregnancy Induced Hypertensive Umbilical Arteries

BACKGROUND The human umbilical arteries form an important component involved in the exchange of materials between the foetus and the mother. Hypertensive disorders in pregnancy are responsible for a significant amount of maternal and perinatal morbidity and mortality. It complicates about 6 - 20 % of all pregnancies. Although PIH (Pregnancy-induced hypertension) is one of the major causes of maternal death, especially in developing countries; its perinatal outcomes are also not so favourable. We wanted to study the ultrastructure of Hyrtl’s anastomosis between the normotensive and hypertensive placentas. METHODS A cross-sectional study was carried out to assess the variable anatomy in Hyrtl’s anastomosis and determine the alterations of the Hyrtl’s anastomosis in the case of pregnancy-induced hypertension from the year 2017-2018 at Sikkim Manipal Institute of Medical Sciences. For TEM (transmission electron microscopy) the portion of the Hyrtl’s anastomosis was carefully dissected out and processed. The study included women with pregnancy-induced hypertension if their arterial blood pressure with systolic as ≥ 140 mm Hg and diastolic ≥ 90 mm Hg measured on two or more occasions at least after the 20th week of gestation with or without oedema. Due to an inadequate number of cases essential hypertensive cases were excluded. RESULTS From the study conducted, transmission electron microscopy revealed a disrupted muscular layer in pregnancy-induced hypertension when compared to normal Hyrtl’s anastomosis. Thickening of the muscular layer was observed in the pregnancy-induced Hyrtl’s anastomosis. Statistical Analysis - Independent t-test was considered in the analysis for continuous among the ultrastructure of the Hyrtl’s anastomosis between the normotensive and hypertensive groups. P ≤ 0.05 was considered significant. SPSS 20.0 was used for data analysis. CONCLUSIONS The effect of hypertension brought about structural changes in the blood vessel which might probably have an effect on the fetoplacental circulation and therefore adversely affecting the foetal outcome. KEY WORDS Hyrtl’s Anastomosis, Pregnancy- Induced Hypertension

Fetal Sex and Fetal Environment Interact to Alter Diameter, Myogenic Tone, and Contractile Response to Thromboxane Analog in Rat Umbilical Cord Vessels

Fetal growth needs adequate blood perfusion from both sides of the placenta, on the maternal side through the uterine vessels and on the fetal side through the umbilical cord. In a model of intrauterine growth restriction (IUGR) induced by reduced blood volume expansion, uterine artery remodeling was blunted. The aim of this study is to determine if IUGR and fetus sex alter the functional and mechanical parameters of umbilical cord blood vessels. Pregnant rats were given a low sodium (IUGR) or a control diet for the last 7 days of pregnancy. Umbilical arteries and veins from term (22 day) fetal rats were isolated and set-up in wire myographs. Myogenic tone, diameter, length tension curve and contractile response to thromboxane analog U46619 and serotonin (5-HT) were measured. In arteries from IUGR fetuses, myogenic tone was increased in both sexes while diameter was significantly greater only in male fetuses. In umbilical arteries collected from the control group, the maximal contraction to U46619 was lower in females than males. Compared to the control groups, the maximal response decreased in IUGR male arteries and increased in female ones, thus abolishing the sexual dimorphism observed in the control groups. Reduced contractile response to U46619 was observed in the IUGR vein of both sexes. No difference between groups was observed in response to 5HT in arteries. In conclusion, the change in parameters of the umbilical cord blood vessels in response to a mild insult seems to show adaptation that favors better exchange of deoxygenated and wasted blood from the fetus to the placenta with increased myogenic tone.

A case report of sirenomelia with two umbilical arteries: an unusual finding in a rare case

Sirenomelia also known as Mermaid syndrome is a rarely encountered fusion anomaly of the caudal region of body often associated with Potter’s facies, single umbilical artery and various visceral abnormalities which make it irreconcilable with life. Here we report a case of sirenomelia delivered in our tertiary care hospital by lower segment cesarean section to a 24 year old third gravida with no previous live issues. No high risk factors could be identified with the mother including diabetes mellitus. Baby was born alive with Potter’s facies. Both the lower limbs were merging into each other like a mermaid’s tail (hence called mermaid syndrome). Sex of the baby could not be identified and the urogenital and anal orifices were absent. Umbilical cord stump had two umbilical arteries. The baby died after 20 hours of life. There appears to be no definitive modality for diagnosing sirenomelia in the antenatal period. However, if a patient has consistently low AFI without any history of leaking per vaginum, high resolution USG or colour Doppler should be done at the earliest to look for the cause.

Pathogenesis of Anorectal Malformations in Retinoic Acid Receptor Knockout Mice Studied by HREM

Anorectal malformations (ARMs) are relatively common congenital abnormalities, but their pathogenesis is poorly understood. Previous gene knockout studies indicated that the signalling pathway mediated by the retinoic acid receptors (RAR) is instrumental to the formation of the anorectal canal and of various urogenital structures. Here, we show that simultaneous ablation of the three RARs in the mouse embryo results in a spectrum of malformations of the pelvic organs in which anorectal and urinary bladder ageneses are consistently associated. We found that these ageneses could be accounted for by defects in the processes of growth and migration of the cloaca, the embryonic structure from which the anorectal canal and urinary bladder originate. We further show that these defects are preceded by a failure of the lateral shift of the umbilical arteries and propose vascular abnormalities as a possible cause of ARM. Through the comparisons of these phenotypes with those of other mutant mice and of human patients, we would like to suggest that morphological data may provide a solid base to test molecular as well as clinical hypotheses.

An incidental rare finding of a TRAP sequence during a caesarean section: A case report

Twin reversed arterial perfusion (TRAP) sequence is an anomaly of monochorionic twin pregnancies where one twin has an absent, non-functioning or rudimentary heart while the other twin may be normal. The condition occurs because of early development of arterio -arterial anastomoses between the umbilical arteries of twin foetuses that share a fused placenta. In this condition, the affected anomalous (acardiac twin) is perfused by the normal twin (pump twin) via an arterio-arterial anastomosis. The affected twin (acardiac twin) presents with malformations such as absent (acradia) or rudimentary heart, underdeveloped or missing head, upper body and limbs. As pump twin has to provide circulation to itself as well as the perfused twin, this increased burden to perfuse acardiac twin increases the risk of developing cardiac failure in pump twin. Here we present such a case of 22-year-old, which was diagnosed per operatively during caesarean section at department of obstetrics & gynecology, Rukshamaniben General Hospital, Ahmedabad.

The expression of ATP-sensitive potassium channels in human umbilical arteries with severe pre-eclampsia

The aim of this study is to establish the expression of ATP-sensitive potassium channels(KATP) in human umbilical arteries with severe pre-eclampsia. Real-time quantitative PCR and western blotting were used to detect the mRNA and protein expression levels of KATP channel subunits Kir6.1 and SUR2B in human umbilical arteries from normal pregnant and those with severe pre-eclampsia, early onset severe pre-eclampsia and late onset severe pre-eclampsia. The mRNA and protein levels of SUR2B in the severe pre-eclampsia group were lower than those in the normal group (P < 0.001), and the expression of Kir6.1 was not statistically significant between the two groups (P > 0.05). The mRNA and protein levels of SUR2B in early onset severe pre-eclampsia group were lower than those in late onset severe pre-eclampsia group (P < 0.001). There was no significant difference in expression of Kir6.1 between the two groups (P > 0.05). The mRNA and protein expression levels of SUR2B in pregnant women with severe pre-eclampsia were lower than those in normal pregnant women, suggesting that the expression of the SUR2B of the KATP channel may be related to the occurrence and development of severe pre-eclampsia. Compared with late onset severe pre-eclampsia, the mRNA and protein expression levels of SUR2B were lower in the umbilical arteries of women with early onset severe pre-eclampsia, suggesting that the occurrence time of severe pre-eclampsia may be related to the extent reduced expression of the SUR2B of the KATP channel.

Sex differences in fetal Doppler parameters during gestation

Background Fetal sex is known to affect pregnancy outcomes. In current clinical practice, monitoring of fetal well-being is based on Doppler ultrasound measurements of major placental and fetal vessels. The objective of this study was to investigate the effect of fetal sex on Doppler parameters throughout gestation in healthy pregnancy. Methods A prospective study was conducted in 240 pregnant women with ultrasound examinations at a 4-weekly interval between 12 and 38 weeks of gestation. Pulsed Doppler spectra were collected for the umbilical arteries (UAs), middle cerebral artery (MCA), descending abdominal aorta (DAo), and ductus venosus (DV). Linear mixed effects models were used to determine if the pulsatility indices (PIs) of these vessels depended on gestational age and fetal sex. Results While there were no differences in the MCA PI and DV PIV over gestation between female and male fetuses, the trajectory of the UA and DAo PIs differed by fetal sex (p = 0.02 and p = 0.01, respectively). Conclusions Doppler ultrasound parameters were found to be dependent on fetal sex for some vessels and not for others in healthy pregnancies. Further investigations are needed to understand the physiological mechanisms for these sex differences and the relevance for disease processes in pregnancy.