Placental Circulation Research Articles

Doppler evaluation of normal and abnormal placenta.

Doppler techniques are needed for the evaluation of the intraplacental circulation and can be of great value in the diagnosis of placental anomalies. Highly sensitive Doppler techniques can differentiate between the maternal (spiral arteries) and fetal (intraplacental branches of the umbilical artery) components of the placental circulation and assist in the evaluation of the placental functional units. A reduced number of placental functional units can be associated with obstetric complications, such as fetal growth restriction. Doppler techniques can also provide information on decidual vessels and blood movement. Abnormal decidual circulation increases the risk of placenta accreta. Doppler evaluation of the placenta greatly contributes to the diagnosis and clinical management of placenta accreta, vasa previa, placental infarcts, placental infarction hematoma, maternal floor infarction, massive perivillous fibrin deposition and placental tumors. However, it has a limited role in the diagnosis and clinical management of placental abruption, placental hematomas, placental mesenchymal dysplasia and mapping of placental anastomoses in monochorionic twin pregnancies. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Physiologically based cord clamping for infants ≥32+0 weeks gestation: A randomised clinical trial and reference percentiles for heart rate and oxygen saturation for infants ≥35+0 weeks gestation.

Globally, the majority of newborns requiring resuscitation at birth are full term or late-preterm infants. These infants typically have their umbilical cord clamped early (ECC) before moving to a resuscitation platform, losing the potential support of the placental circulation. Physiologically based cord clamping (PBCC) is clamping the umbilical cord after establishing lung aeration and holds promise as a readily available means of improving early newborn outcomes. In mechanically ventilated lambs, PBCC improved cardiovascular stability and reduced hypoxia. We hypothesised that PBCC compared to ECC would result in higher heart rate (HR) in infants needing resuscitation, without compromising safety. Between 4 July 2018 and 18 May 2021, infants born at ≥32+0 weeks' gestation with a paediatrician called to attend were enrolled in a parallel-arm randomised trial at 2 Australian perinatal centres. Following initial stimulation, infants requiring further resuscitation were randomised within 60 seconds of birth using a smartphone-accessible web link. The intervention (PBCC) was to establish lung aeration, either via positive pressure ventilation (PPV) or effective spontaneous breathing, prior to cord clamping. The comparator was early cord clamping (ECC) prior to resuscitation. The primary outcome was mean HR between 60 to 120 seconds after birth, measured using 3-lead electrocardiogram, extracted from video recordings blinded to group allocation. Nonrandomised infants had deferred cord clamping (DCC) ≥120 seconds in the observational study arm. Among 508 at-risk infants enrolled, 123 were randomised (n = 63 to PBCC, n = 60 to ECC). Median (interquartile range, IQR) for gestational age was 39.9 (38.3 to 40.7) weeks in PBCC infants and 39.6 (38.4 to 40.4) weeks in ECC infants. Approximately 49% and 50% of the PBCC and ECC infants were female, respectively. Five infants (PBCC = 2, ECC = 3, 4% total) had missing primary outcome data. Cord clamping occurred at a median (IQR) of 136 (126 to 150) seconds in the PBCC arm and 37 (27 to 51) seconds in the ECC arm. Mean HR between 60 to 120 seconds after birth was 154 bpm (beats per minute) for PBCC versus 158 bpm for ECC (adjusted mean difference -6 bpm, 95% confidence interval (CI) -17 to 5 bpm, P = 0.39). Among 31 secondary outcomes, postpartum haemorrhage ≥500 ml occurred in 34% and 32% of mothers in the PBCC and ECC arms, respectively. Two hundred ninety-five nonrandomised infants (55% female) with median (IQR) gestational age of 39.6 (38.6 to 40.6) weeks received DCC. Data from these infants was used to create percentile charts of expected HR and oxygen saturation in vigorous infants receiving DCC. The trial was limited by the small number of infants requiring prolonged or advanced resuscitation. PBCC may provide other important benefits we did not measure, including improved maternal-infant bonding and higher iron stores. In this study, we observed that PBCC resulted in similar mean HR compared to infants receiving ECC. The findings suggest that for infants ≥32+0 weeks' gestation who receive brief, effective resuscitation at closely monitored births, PBCC does not provide additional benefit over ECC (performed after initial drying and stimulation) in terms of key physiological markers of transition. PBCC was feasible using a simple, low-cost strategy at both cesarean and vaginal births. The percentile charts of HR and oxygen saturation may guide clinicians monitoring the transition of at-risk infants who receive DCC. Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618000621213.

Perinatal nicotine exposure alters development of cardiac performance

Perinatal nicotine exposure alters development of brainstem neurons, including those involved in the control of breathing and cardiovascular function. Whether or not perinatal nicotine exposure alters development of cardiac performance is unknown. Pregnant rats were exposed to nicotine plus saccharin in drinking water beginning on the 4thday of gestation. Developing fetuses were exposed via the placental circulation, and exposure continued via breast milk after birth, up until the day of study. Plasma cotinine levels in the nicotine‐exposed pups ranged from 50‐100 ng/ml. Control neonates drank water with saccharin, but no nicotine. Animals aged postnatal day 10‐12 (P10‐P12) were lightly anesthetized with isoflurane, and cardiac function was assessed non‐invasively with echocardiography. Compared to controls (N=13), nicotine‐exposed pups (N=13) had reduced body weight (28.4 ± 1 vs. 21 ± 1 g, P=0.00032), significant reductions in stroke volume (39.1 ± 1 vs. 33.7 ± 1.7 μL/beat, P=0.027) and cardiac output (14.0 ± 0.8 vs. 12.4 ± 1 ml/min, P=0.011), and had significantly slower isovolumetric contraction (15 ± 1 vs. 22 ± 2 ms, P=0.005) and relaxation times (21 ± 1 vs. 33 ± 3 ms, P=0.04). There were also trends toward a lower heart rate (P=0.055), ejection fraction (P=0.065) and left ventricular wall thickness (P=0.059) in the nicotine exposed animals. These are the first data showing that perinatal nicotine exposure alters development of the heart’s pumping capacity.

Obstetric and perinatal pathology in pregnant women who had complications from the group of the Great Obstetrical Syndromes

The objective: to analyze the obstetric and perinatal outcomes of childbirth in pregnant women who had complications from the group of the great obstetrical syndromes.Materials and methods. A retrospective statistical analysis of obstetric and perinatal outcomes of childbirth of 239 pregnant women (the Ist group – main one) who had complications from the group of the great obstetrical syndromes (GOS). They were divided into three subgroups: Ia subgroup included 103 pregnant women with severe preeclampsia (PE), Ib subgroup – 67 pregnant women with placental insufficiency, with clinical manifestation of fetal intrauterine growth retardation (IUGR), Ic subgroup – 69 pregnant women with spontaneous preterm birth in the gestational age 22-36 weeks. The control group (CG) included 56 practically healthy pregnant women with a normal reproductive history and uncomplicated course of this pregnancy.Statistical processing of the study results was performed using standard programs Microsoft Excel 5.0 and Statistica 6.0.Results. The incidence of gestational diabetes mellitus in patients of the I group (28 (11.7 %) women) was higher than in CG (2 (3.6 %) persons). Cervical insufficiency was diagnosed in every fifth patient of Ic subgroup (12 (17.3 %) patients; χ2=15.56, p<0.01; OR=9.25; CI 95%: 2.55–33.54 relative to CG), gestational anemia – in 179 (74.8 %) pregnant women in the I group and 18 (32.1 %) women in CG (p<0.01).A significantly high rate of mild congenital malformations was present in subgroup Ib (7 (10.4 %) of pregnant women; χ2=12.67, p<0.01; OR=7.93; CI 95%: 2.14-29.26). 21 patients in the I group had with antenatal fetal death, 6 (5.8 %) – severe PE, 11 (16.4 %) – IUGR. Five cases of early neonatal mortality was diagnosed in the I group. The rate of perinatal mortality in the I group was high and amounted to 108.7 ‰.The operative delivery in the I group was performed in 127 (53.1 %) patients which is significantly more than in CG (χ2=42.93, p<0.01; OR=4.93; CI 95%: 2.99– 8.13). In 24 (18.9 %) pregnant women in the I group the indication for operative delivery was acute distress, which is significantly more than in CG (2 (3.6 %) women; χ2=7.36, p<0.01; OR=5.17; CI 95%: 1.2–22.28). The mean score on the Apgar scale in newborns in CG was significantly higher compared with the I group (p<0.01).Conclusions. The course of pregnancy and childbirth in women who had complications from the group of the great obstetrical syndromes was accompanied by the development of gestational diabetes, gestational anemia and cervical insufficiency. Complications such as fetal distress, severe preeclampsia, fetal growth retardation with decompensated hemodynamic disorders of the uterine and placental blood circulation, led to a high frequency of cesarean section in these patients.

Crosstalk between foetal vasoactive peptide hormones and placental aminopeptidases regulates placental blood flow: Its significance in preeclampsia.

In pregnancy, placental circulation occurs through two independent circulation systems: foetoplacental and uterine (spiral artery)-placental lake. Crosstalk between the foetal peptide hormones, angiotensin II (A-II) and vasopressin (AVP), and their degrading placental aminopeptidases (APs), aminopeptidase A for A-II and placental leucine aminopeptidase for both AVP and oxytocin, primarily regulate placental circulation. On the other hand, placental circulation represents an arteriovenous shunt. In normal pregnancy, the blood pressure decreases, despite increased cardiac output and plasma volume, probably due to the arteriovenous shunt in the growing placenta. Actually, the foetal vasoactive hormones in the foetoplacental circulation are much higher than those in the maternal circulation throughout pregnancy. In normal pregnancy, AP activity derived from the placenta in maternal blood increases with gestation and placental growth. Foetal hypoxia increases the secretion of foetal both AVP and A-II. Although there is an increase in both AP activities in the maternal blood in normal pregnancy, their activities increase more than those in normal pregnancy during mild preeclampsia. However, both AP activities decline significantly compared than those in severe preeclampsia. This suggests that AP prevents leakage of increased foetal vasoactive hormones into the maternal blood in mild preeclampsia, and its protective role breaks down in severe preeclampsia, leading to a massive leak of the hormones into maternal circulation and consequent marked contraction of both the maternal vessels and the uterus. Consequently, AP activity in both placenta and maternal blood acts as the foeto-maternal barrier for foetal vasoactive hormones and thus contributes to the onset of preeclampsia.

Clinical Correlates of Placental Pathologic Features in Early-Onset Fetal Growth Restriction

Introduction: The purpose of this study was to evaluate the association between placental pathologic features of maternal (MVM) or fetal (FVM) vascular malperfusion and clinical characteristics, sonographic findings and neonatal outcome in a cohort of pregnancies complicated by early-onset (diagnosed before 32 weeks of gestational age) fetal growth restriction (FGR). Methods: A prospective cohort study included 250 singleton early-onset FGR pregnancies diagnosed, followed up and delivered at a single center. Placental pathologic lesions were classified according to standard recommendations. Logistic regression and Cox analysis were used to evaluate outcomes adjusting for confounders. Results: Overall features of severe placental MVM and FVM were observed in 29.6% (74/250) and 12.8% (32/250) of the subjects, respectively. Severe placental MVM lesions were more common among subjects with umbilical artery Doppler Pulsatility Index >95th than ≤95th percentile (50/120 as opposed to 24/130, Adj odds ratio [OR] = 3, 95% CI = 1.6–5.4) and Cerebroplacental ratio <5th than ≥5th percentile (48/115 as opposed to 26/135, Adj OR = 2.7, 95% CI = 1.5–4.9). Mean time from FGR diagnosis to delivery was shorter among subjects with severe MVM (25.5 days, 95% CI = 20.6–30.2, Adj. OR = 1.9, 95% CI = 1.9, 95% CI = 1.4–2.5) when compared to both those with mild/moderate MVM (36.5 days [95% CI = 27.2–45, p = 0.04]) or no MVM (39.4, 95% CI = 35.4–43.4, p < 0.001). Finally, severe FVM was associated with an increased risk of perinatal/neonatal death or severe brain lesions (9/28 in subjects with perinatal/neonatal death/brain lesions as compared to 23/222 in controls, Adj OR = 3, 95% CI = 1.05–8.6) or severe adverse neonatal outcomes (13/46 in subjects with severe adverse outcome as compared to 19/204 among controls, Adj OR = 3.2, 95% CI = 1.2–8.5). Conclusions: In early-onset FGR, placental pathologic features of MVM and FVM are, in different regards, associated to severity of clinical picture, abnormal Doppler markers of placental and fetal circulation and of neonatal outcome, respectively.

Update on Color Flow Imaging in Obstetrics.

Color flow imaging (CFI), being non-invasive, is commonly used in obstetrics to study the fetal and placental circulations. The conventional CFI modes include color Doppler flow imaging (CDFI) and power Doppler imaging (PDI). In recent years, there is increasing use of new modes, including high-definition flow imaging (HDFI), radiant flow, microvascular flow imaging (MVFI), and three-/four-dimensional rendering in glass-body mode. Compared to CDFI, HDFI can show a higher resolution and sensitivity and allow the detection of slower flows. MVFI increases the sensitivity to fine or low-flow vessels while producing little or no motion artifacts. Radiant flow shows the blood flow with a sense of depth and reduces blood overflow. Glass-body mode, showing both gray-scale and color-flow information, can demonstrate the heart-cycle-related flow events and the vessel spatial relationship. In this review, the characteristics and applications of the various CFI modes in obstetrics are discussed. In particular, how these new technologies are integrated in detailed diagnostic and early morphology scans is presented.

Антиоксидантный профиль ретроплацентарной крови при физиологической беременности и преэклампсии

The pathogenesis of pre-eclampsia (PE) is based on the disorders of placental circulation, which develop due to the impaired migration of extravillous trophoblast. Local processes at the maternal-fetal interface can be assessed through the retroplacental blood (RB) which flows during placental separation. Objective. To study the parameters of antioxidant status of RB in uncomplicated pregnancy and PE. Patients and methods. The study included 50 pregnant women: 36 women with uncomplicated pregnancy and 14 women with PE. Total antioxidant capacity (TAC) of plasma was measured by the luminol chemiluminescence method. Results. In uncomplicated pregnancy, total antioxidant capacity of RB was increased compared to peripheral blood (PB) (1236 ± 344 sec vs. 852 ± 246 sec; p &lt; 0.0001), which indicates that RB provides a balance of pro-oxidants and antioxidants at the maternal-placental-fetal interface. The increase in total antioxidant capacity of RB plasma in PE compared to uncomplicated pregnancy (1716 ± 922 sec vs. 1236 ± 344 sec; p = 0.007) may be both compensatory and pathogenetic mechanisms of the disease. Thus, the prevention and treatment of PE with antioxidants should be discussed. The increase in total antioxidant capacity of RB plasma was observed in severe PE (2304 ± 948 sec vs. 1236 ± 344 sec, p &lt; 0.0001), which is associated with an unfavorable prognosis. Conclusion. Our pilot study of the antioxidant defense status of retroplacental blood shows that pre-eclampsia leads to a significant imbalance between pro-oxidants and antioxidants at the maternal-placental-fetal interface. Key words: antioxidants, antioxidant capacity, pre-eclampsia, retroplacental blood, chemiluminescence

MiR-153-3p Targets βII Spectrin to Regulate Formaldehyde-Induced Cardiomyocyte Apoptosis.

Background: Formaldehyde (FA) is ubiquitous in the environment and can be transferred to the fetus through placental circulation, causing miscarriage and congenital heart disease (CHD). Studies have shown that βII spectrin is necessary for cardiomyocyte survival and differentiation, and its loss leads to heart development defects and cardiomyocyte apoptosis. Additionally, previous studies have demonstrated that miRNA is essential in heart development and remodeling. However, whether miRNA regulates FA-induced CHD and cardiomyocyte apoptosis remains unclear.Methods: Using commercially available rat embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis. Real-time quantitative PCR (RT-qPCR) and Western blot were performed to examine the level of miR-153-3p, βII spectrin, caspase 7, cleaved caspase7, Bax, Bcl-2 expression in embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis. Apoptotic cell populations were evaluated by flow cytometry and Tunel. Luciferase activity assay and RNA pull-down assay were used to detect the interaction between miR-153-3p and βII spectrin. Masson's trichrome staining detects the degree of tissue fibrosis. Fluorescence in situ hybridization (FISH) and Immunohistochemistry were used to detect the expression of miR-153-3p and βII spectrin in tissues.Results: Using commercially available rat embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis, our studies indicate that miR-153-3p plays a regulatory role by directly targeting βII spectrin to promote cardiomyocyte apoptosis. miR-153-3p mainly regulates cardiomyocyte apoptosis by regulating the expression of caspase7, further elucidating the importance of apoptosis in heart development. Finally, the results with our animal model revealed that targeting the miR-153-3p/βII spectrin pathway effectively regulated FA-induced damage during heart development. Recovery experiments with miR-153-3p antagomir resulted in the reversal of FA-induced cardiomyocyte apoptosis and fetal cardiac fibrosis.Conclusion: This study investigated the molecular mechanism underpinning the role of βII spectrin in FA-induced CHD and the associated upstream miRNA pathway. The study findings suggest that miR-153-3p may provide a potential target for the clinical diagnosis and treatment of CHD.

Near-Term Cerebroplacental Doppler, Heart Morphology, and Neonatal Biometry in Hypoplastic Left Heart Syndrome.

To analyze near-term cerebroplacental Doppler, heart morphology, and neonatal biometry in isolated hypoplastic left heart syndrome (HLHS) relative to healthy controls. This retrospective study included 55 fetuses with HLHS (29 with mitral valve stenosis [MS]/aortic valve atresia [AA], 14 with MS/aortic valve stenosis, and 12 with mitral valve atresia [MA]/[AA]) diagnosed prenatally between 2010 and 2019 at 2 referral centers and 101 healthy controls. Ultrasound assessment included umbilical artery (UA), middle cerebral artery (MCA) pulsatility index (PI), and cerebroplacental ratio (CPR), with neonatal weight, length, head circumference (HC), Apgar score, and UA pH measured at birth. In total, 32.7% of HLHS fetuses had abnormal MCA-PI and UA-PI, and 38.2% had CPRs below the fifth percentile before birth. All tested Doppler parameters differed from those of the healthy controls (P ≤ .01). Birth weight and length were comparable between HLHS and control fetuses, whereas birth HCs were smaller in the HLHS group than in the control group (P=.018). In both groups, increased UA-PI correlated with lower birth weight, but only HLHS fetuses with UA-PI > the 95th percentile had a lower median HC at birth than those with normal UA-PI (P=.045). The median UA-PI percentile was higher in fetuses with MA than in fetuses with MS (P=.015). The ascending aortic diameter correlated with birth weight (P=.036) and birth length (P=.039). Abnormal cerebroplacental hemodynamics are evident in a high percentage of near-term fetuses with HLHS, and increased placental resistance may contribute to birth weight and HC. Moreover, heart morphology may impact placental circulation and neonatal biometry.

VP52.08: Cardiac output and placental circulation before and after thoracoamniotic shunting in primary fetal hydrothorax

VP52.08: Cardiac output and placental circulation before and after thoracoamniotic shunting in primary fetal hydrothorax

Comparative study of Prophylactic Intravenous Ondansetron in the Attenuation of Post Spinal Hypotension versus Dexamethasone in Parturient Undergoing Caesarean Delivery

Abstract Background Spinal anaesthesia (SA) is the preferred anaesthesia technique for Caesarean section. Hypotension and bradycardia are the most common side effects encountered and are more pronounced in pregnant patients, the incidence being as high as 52.6% and 2.5% in normal patients. The occurrence of hypotension can be dangerous as it compromises placental circulation and can have a detrimental effect on the foetus. Objectives The purpose of this study is to assess the efficacy of ondansetron versus dexamethasone in decreasing incidence of spinal induced hypotension in parturient undergoing cesarean surgery. Patients and Methods This study was conducted at Ain Shams University Hospitals between March 2019 till September 2019. After approval is obtained from the research ethics committee of faculty of medicine, Ain Shams University &amp; patients’ informed consents consent from each patient after full explanation of the procedure possible side effects and complications., 75 healthy parturient, (ASA)physical status I and II undergoing elective cesarean delivery under spinal anesthesia. Results 8 mg ondansetron is more effective than 8 mg dexamethasone in the attenuation of post spinal hypotension. Also, that Dexamethasone 8 mg was as effective as ondansetron 8 mg in providing a simple, safe, cheap, and effective intra and postoperative nausea and emesis prevention method with the advantage of being cheaper decreasing the economic burden. Conclusion The present study demonstrated that, among patients who received spinal anesthesia with bupivacaine and fentanyl as adjuvant for elective for cesarean section, prophylactic intravenous 8 mg ondansetron compared to dexamethasone significantly decreases hypotension, HR fluctuation, yet the need for rescue doses for ephedrine were significantly higher in ondansetron.

Peripheral chemoreflex activation and cardiac function during hypoxemia in near-term fetal sheep without placental compromise.

A drop in arterial oxygen content activates fetal chemoreflex including an increase in sympathetic activity leading to peripheral vasoconstriction and redistribution of blood flow to protect the brain, myocardium, and adrenal glands. By using a chronically instrumented fetal sheep model with intact placental circulation at near-term gestation, we investigated the relationship between peripheral chemoreflex activation induced by hypoxemia and central hemodynamics. A total of 17 Åland landrace sheep fetuses at 115-128/145 gestational days were instrumented. Carotid artery was catheterized in 10 fetuses and descending aorta in 7 fetuses. After a 4-day recovery, baseline measurements of fetal arterial blood pressures, blood gas values, and fetal cardiovascular hemodynamics by pulsed Doppler ultrasonography were obtained under isoflurane anesthesia. Comparable data to baseline were collected 10 min (acute hypoxemia) and 60 min (prolonged hypoxemia) after maternal hypo-oxygenation to saturation level of 70%-80% was achieved. During prolonged hypoxemia, pH and base excess (BE) were lower and lactate levels were higher in the descending aorta than in the carotid artery. During hypoxemia mean arterial blood pressure (MAP) in the descending aorta increased, whereas in the carotid artery, MAP decreased. In addition, right pulmonary artery pulsatility index values increased, and the diastolic component in the aortic isthmus blood flow velocity waveform became more retrograde, thus decreasing the aortic isthmus antegrade/retrograde blood flow (AoI Net Flow) ratio. Both fetal ventricular cardiac outputs were maintained even during prolonged hypoxemia when significant fetal metabolic acidemia developed. Fetal chemoreflex activation induced by hypoxemia decreased the perfusion pressure in the cerebral circulation. Fetal weight-indexed left ventricular cardiac output (LVCO) or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure.NEW & NOTEWORTHY During fetal hypoxemia with intact placental circulation, peripheral chemoreflex was activated, as demonstrated by an increase in the descending aorta blood pressure, pulmonary vasoconstriction, and an increase in retrograde diastolic AoI blood flow, while both ventricular cardiac outputs remained stable. However, perfusion pressure in the cerebral circulation decreased. These changes were seen even during prolonged hypoxemia when significant metabolic acidosis developed. Weight-indexed LVCO or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure.

Maternal but not fetoplacental health can be improved by metformin in a murine diet-induced model of maternal obesity and glucose intolerance.

Maternal obesity is a global problem that increases the risk of short- and long-term adverse outcomes for mother and child, many of which are linked to gestational diabetes mellitus. Effective treatments are essential to prevent the transmission of poor metabolic health from mother to child. Metformin is an effective glucose lowering drug commonly used to treat gestational diabetes mellitus; however, its wider effects on maternal and fetal health are poorly explored. In this study we used a mouse (C57Bl6/J) model of diet-induced (high sugar/high fat) maternal obesity to explore the impact of metformin on maternal and feto-placental health. Metformin (300 mg/kg/day) was given to obese females via the diet and was shown to achieve clinically relevant concentrations in maternal serum (1669±568 nM in late pregnancy). Obese dams developed glucose intolerance during pregnancy and had reduced uterine artery compliance. Metformin treatment of obese dams improved maternal glucose tolerance, reduced maternal fat mass, and restored uterine artery function. Placental efficiency was reduced in obese dams, with increased calcification and reduced labyrinthine area. Consequently, fetuses from obese dams weighed less (p<0.001) at the end of gestation. Despite normalisation of maternal parameters, metformin did not correct placental structure or fetal growth restriction. Metformin levels were substantial in the placenta and fetal circulation (109.7±125.4 nmol/g in the placenta and 2063±2327 nM in fetal plasma). These findings reveal the distinct effects of metformin administration during pregnancy on mother and fetus and highlight the complex balance of risk versus benefits that are weighed in obstetric medical treatments.

Inhibition of the C-X-C Motif Chemokine 12 (CXCL12) and Its Receptor CXCR4 Reduces Utero-Placental Expression of the VEGF System and Increases Utero-Placental Autophagy.

The placenta, a unique organ that only develops during pregnancy, is essential for nutrient, oxygen, and waste exchange between offspring and mother. Yet, despite its importance, the placenta remains one of the least understood organs and knowledge of early placental formation is particularly limited. Abnormalities in placental development result in placental dysfunction or insufficiency whereby normal placental physiology is impaired. Placental dysfunction is a frequent source of pregnancy loss in livestock, inflicting serious economic impact to producers. Though the underlying causes of placental dysfunction are not well-characterized, initiation of disease is thought to occur during establishment of functional fetal and placental circulation. A comprehensive understanding of the mechanisms controlling placental growth and vascularization is necessary to improve reproductive success in livestock. We propose chemokine C-X-C motif ligand 12 (CXCL12) signaling through its receptor CXCR4 functions as a chief coordinator of vascularization through direct actions on fetal trophoblast and maternal endometrial and immune cells. To investigate CXCL12–CXCR4 signaling on uteroplacental vascular remodeling at the fetal–maternal interface, we utilized a CXCR4 antagonist (AMD3100). On day 12 post-breeding in sheep, osmotic pumps were surgically installed and delivered either AMD3100 or saline into the uterine lumen ipsilateral to the corpus luteum for 14 days. On day 35 of ovine pregnancy, fetal/placental and endometrial tissues were collected, snap-frozen in liquid nitrogen, and uterine horn cross sections were preserved for immunofluorescent analysis. Suppressing CXCL12–CXCR4 at the fetal–maternal interface during initial placental vascularization resulted in diminished abundance of select angiogenic factors in fetal and maternal placenta on day 35. Compared to control, less vascular endothelial growth factor (VEGF) and VEFG receptor 2 (KDR) were observed in endometrium when CXCL12–CXCR4 was diminished. Less VEGF was also evident in fetal placenta (cotyledons) in ewes receiving AMD3100 infusion compared to control. Suppressing CXCL12–CXCR4 at the fetal–maternal interface also resulted in greater autophagy induction in fetal and maternal placenta compared to control, suggestive of CXCL12–CXCR4 impacting cell survival. CXCL12–CXCR4 signaling may govern placental homeostasis by serving as a critical upstream mediator of vascularization and cell viability, thereby ensuring appropriate placental development.

Delayed cord clamping in small for gestational age preterm infants

Infants with restricted growth for age are frequently exposed to insufficient placental circulation and are more likely to develop postnatal complications. Delayed cord clamping at birth for these infants requires further exploration. This study aimed to compare the short-term neonatal outcomes of delayed cord clamping with that of early cord clamping in small for gestational age preterm infants and to explore whether the effects of delayed cord clamping in small for gestational age preterm infants are different from that in non-small for gestational age preterm infants. We conducted a national retrospective cohort study, including infants born at <33 weeks' gestation and admitted to the Canadian Neonatal Network units between January 2015 and December 2017. Small for gestational age infants (birthweight of <10th percentile for gestational age and sex) who received delayed cord clamping ≥30 seconds were compared with those who received early cord clamping. In addition, non-small for gestational age infants who received delayed cord clamping were compared with those who received early cord clamping. The main study outcomes included composite outcome of mortality or major morbidity, neonatal morbidity rate, mortality rate, peak serum bilirubin, and number of blood transfusions. Multivariable logistic and linear regression models with a generalized estimation equation approach were used to account for the clustering of infants within centers. Overall, 9722 infants met the inclusion criteria. Of those infants, 1027 (10.6%) were small for gestational age. The median (interquartile range) gestational age was 31 weeks (range, 28-32 weeks). After adjusting for potential confounders, delayed cord clamping in small for gestational age infants was associated with a reduction in the composite outcome of mortality or major morbidity (adjusted odds ratio, 0.60; 95% confidence interval, 0.42-0.86) compared with early cord clamping. There was no difference between the 2 groups in peak serum bilirubin. Many associated benefits of delayed cord clamping in small for gestational age infants were similar to those in non-small for gestational age infants. Delayed cord clamping in small for gestational age preterm infants was associated with decreased odds of mortality or major morbidity. Many of the benefits of delayed cord clamping in the small for gestational age preterm infants were similar to those identified in the non-small for gestational age preterm infants.

Fetal-placental blood flow and neurodevelopment in childhood: population-based neuroimaging study.

ABSTRACTObjectiveAntenatal Doppler measurements of the fetal umbilical and cerebral circulations can predict perinatal complications; however, it is unclear if subtle variations in antenatal Doppler measurements are associated with long‐term neurodevelopmental outcome. In this study, we examined whether antenatal Doppler measurements of the fetal–placental circulation are associated with cognitive and motor abilities and brain morphology in childhood.MethodsTo evaluate differences in long‐term sequelae across the continuum of the umbilical and cerebral artery circulations in the general population, we utilized a population‐based longitudinal cohort study approach. In women from the Generation R study, we measured second‐ and third‐trimester umbilical artery pulsatility index (UA‐PI). Children underwent non‐verbal intelligence testing at 4–8 years of age, and at 8–12 years they underwent finger‐tapping tests to measure fine motor skills, balance beam tests to measure gross motor skills and brain magnetic resonance imaging. We assessed the relationships between prenatal UA‐PI and neurodevelopmental outcome using linear regression. We adjusted for child age and sex, maternal age, education, parity and smoking status.ResultsThe study sample included 2803 pregnancies. Higher third‐trimester UA‐PI was associated with poorer fine motor performance (0.41 (95% CI, 0.11–0.70) fewer taps on the finger‐tapping test per 1 SD higher UA‐PI) and gross motor performance (0.64 (95% CI, 0.20–1.08) fewer steps on the balance beam test per 1 SD higher UA‐PI). One SD higher third‐trimester UA‐PI was also associated with 0.65 (95% CI, 0.04–1.25) points lower intelligence quotient; however, unlike the associations with motor abilities, this finding did not persist after correction for multiple testing. Higher second‐trimester UA‐PI was associated with smaller brain volume (6.1 (95% CI, 1.0–11.3) cm3 reduction per 1 SD higher UA‐PI), but the association did not persist after correction for multiple testing.ConclusionHigher placental vascular resistance may have mild adverse effects on neurodevelopmental outcome at school age. While these effects are subtle at population level, we encourage future research into the role of early circulation in brain development. This information could be used to develop targeted interventions. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Probable Mode of Action of &lt;i&gt;Sita kasmaryadi&lt;/i&gt; Herbal Decoction in Placental Compliance – A Review

The occurrence of IUGR (Intra uterine growth retardation) is estimated to be approximately 5% in the population and it is considered as the third leading cause for perinatal mortality in India. Despite plentiful management options, none is effectively proved in improving placental circulation and foetal weight gain. Indian medicine practices a herbal decoction with &lt;em&gt;Glycyrrhiza glabra&lt;/em&gt; Linn., &lt;em&gt;Gmelina arborea Roxb&lt;/em&gt;. ex. &lt;em&gt;Smith&lt;/em&gt; and sugar. The pharmacological potentials of this decoction was attempted to explore here in this review based on available researches. Thorough internet search was performed to derive the data. Recent researches on detailed chemical composition and its possible pharmacological action also had been detailed. It is an effective formulation in improving placental and umbilical cord circulation, aids in improving foetoplacental circulation to a greater extent with negligible side effects.

Z-Score Reference Ranges for Umbilical Vein Diameter and Blood Flow Volume in Normal Fetuses.

To establish Z-scores for the diameter and blood flow volume of the umbilical vein (UV) in normal fetuses. This was a prospective study involving 907 normal fetuses. We measured the diameter (Duv) of two different segments of the UV (FUV: the free loop of the UV; FIUV: the fetal intra-abdominal UV). Next, we calculated the blood flow volume (Quv). Z-scores were created for both Duv and Quv using gestational age, femur length, and biparietal diameter as independent variables. We successfully acquired 858 (94.6%) normal fetal measurements. Between 20 and 39 weeks, the Duv of the FUV and FIUV increased from 0.38 to 0.80 cm and from 0.33 to 0.70 cm, respectively. The Quv of the FUV and FIUV increased from 32.66 to 381.88 ml/min and from 31.50 to 360.15 ml/min, respectively. Linear or quadratic regression models were best fitted between the parameters of UV and the independent variables. Z-scores were successfully determined for both the Duv and Quv. The calculation of Z-scores for the Duv and Quv is simple by applying standard statistical methods. These Z-scores may be useful to evaluate placental circulation and provide a rationale for monitoring and evaluating the prognosis of fetuses.

Physiopathology of late-onset fetal growth restriction.

Fetal growth restriction (FGR) is defined as the inability of the fetus to reach its potential for genetic determination. FGR can have several causes, including genetic syndromes, chromosomal diseases, and infections; however, a vast majority of cases are probably attributed to impaired uterine and placental circulation. The relationships between abnormal placental development and FGR are complex, and studies are generally few, presenting confounding factors. Damage to the uteroplacental circulation associated with vasculogenesis and villus angiogenesis dysfunction are the main factors involved in subsequent FGR. The main receptors involved in FGR include hypoxia-inducible factor (HIF 1, 2, and 3), vascular endothelial growth factor (VEGF), placental growth factor (PlGF), vascular endothelial growth factor C (VEGF-C), soluble Flt-1, soluble endoglin (Seng), angiopoietin-1 and -2 (Ang-1 and Ang-2), tyrosine kinase receptor 1 (Flt-1), tyrosine kinase receptor 2 (Flt-2), vascular endothelial growth factor receptor (VEGFR) 1, 2 and 3, kinase domain receptor (KDR), and vascular endothelial growth factor receptor A (VEGFR-A). Furthermore, failure in trophoblastic invasion and remodeling of spiral arteries has been associated with FGR owing to poor placental perfusion. There are several possible causes for poor remodeling of spiral arteries, which probably vary on a case-to-case basis. Changes in the placental form, macroscopic and microscopic vascular lesions, inflammation, and genetic changes are also related to FGR. Based on gestational age at diagnosis, FGR can be classified as early- (˂32 weeks) and late-onset (≥32 weeks). Moreover, there exist several theories regarding possible pathophysiological differences between early- and late-onset FGR, with some postulating that it the same disease but at different stages or severity. Another hypothesis suggests that the change in the trophoblastic invasion of spiral arteries would be milder. In this article, we address the main mechanisms described in the pathophysiology of FGR and, later, the specific findings in late-onset FGR.