Increasing placental perfusion (PP) could improve outcomes of growth-restricted fetuses. One way of increasing PP may be by using phosphodiesterase (PDE)-5 inhibitors, which induce vasodilatation of vascular beds. We used a combination of clinically relevant magnetic resonance imaging (MRI) techniques to characterize the impact that tadalafil infusion has on maternal, placental and fetal circulations. At 116-117 days\' gestational age (dGA; term, 150 days), pregnant ewes (n = 6) underwent fetal catheterization surgery. At 120-123 dGA ewes were anaesthetized and MRI scans were performed during three acquisition windows: a basal state and then ∼15-75 min (TAD 1) and ∼75-135 min (TAD 2) post maternal administration (24 mg; intravenous bolus) of tadalafil. Phase contrast MRI and T2 oximetry were used to measure blood flow and oxygen delivery. Placental diffusion and PP were assessed using the Diffusion-Relaxation Combined Imaging for Detailed Placental Evaluation-\'DECIDE\' technique. Uterine artery (UtA) blood flow when normalized to maternal left ventricular cardiac output (LVCO) was reduced in both TAD periods. DECIDE imaging found no impact of tadalafil on placental diffusivity or fetoplacental blood volume fraction. Maternal-placental blood volume fraction was increased in the TAD 2 period. Fetal D O 2 ${D_{{{\\mathrm{O}}_2}}}$ and V ̇ O 2 ${\\dot V_{{{\\mathrm{O}}_2}}}$ were not affected by maternal tadalafil administration. Maternal tadalafil administration did not increase UtA blood flow and thus may not be an effective vasodilator at the level of the UtAs. The increased maternal-placental blood volume fraction may indicate local vasodilatation of the maternal intervillous space, which may have compensated for the reduced proportion of UtA D O 2 ${D_{{{\\mathrm{O}}_2}}}$ .

The ex vivo human placenta perfusion model has proven to be clinically relevant to study transfer- and fetal exposure of various drugs. Although the method has existed for a long period, the setup of the perfusion model has not been generalized yet. This review aims to summarize the setups of ex vivo placental perfusion models used to examine drug transfer across the placenta to identify generalized properties and differences across setups. A literature search was carried out in PubMed September 26, 2022. Studies were labeled as relevant when information was reported, between 2000 and 2022, on the setups of ex vivo placental perfusion models used to study drug transfer across the placenta. The placenta perfusion process, and the data extraction, was divided into phases of preparation, control, drug, and experimental reflecting the chronological timeline of the different phases during the entire placental perfusion process. 135 studies describing an ex vivo human placental perfusion experiment were included. Among included studies, the majority (78.5%) analyzed drug perfusion in maternal to fetal direction, 18% evaluated bi-directional drug perfusion, 3% under equilibrium conditions, and one study investigated drug perfusion in fetal to maternal direction. This literature review facilitates the comparison of studies that employ similar placenta perfusion protocols for drug transfer studies and reveals significant disparities in the setup of these ex vivo placental perfusion models. Due to interlaboratory variability, perfusion studies are not readily comparable or interchangeable. Therefore, a stepwise protocol with multiple checkpoints for validating placental perfusion is needed.

This is a follow-up study to the pentaerythrityl tetranitrate randomized controlled multicenter trial that reports neonatal outcome data of newborns admitted to neonatal intensive care units and outcome data of the offspring at 12 months of age.
We present data on adverse events reported during the study to document the safety of pentaerythrityl tetranitrate treatment during pregnancy. To further evaluate the effects of pentaerythrityl tetranitrate on neonatal and long-term outcomes, we present follow up data from of 240 children at 12 months of age, including information on height, weight, head circumference, developmental milestones, and the presence of chronic disease and of 144 newborns admitted to the neonatal intensive care unit during the trial.
The pentaerythrityl tetranitrate trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of the nitric oxide-donor pentaerythrityl tetranitrate in the prevention of fetal growth restriction and perinatal death in pregnancies complicated by abnormal placental perfusion.
Results at 12 months demonstrated that significantly more children were age appropriately developed without impairments in the pentaerythrityl tetranitrate group (P=.018). In addition, the presence of chronic disease was lower in the pentaerythrityl tetranitrate group (P=.041). Outcome data of the 144 newborns admitted to the neonatal intensive care unit did not reveal differences between the treatment and placebo groups. There were no differences in the number or nature of reported adverse events between the study groups.
The analysis shows that study children born in the pentaerythrityl tetranitrate cohort have a clear advantage compared with the placebo group at the age of 12 months, as evidenced by the increased incidence of normal development without the presence of chronic disease. Although safety has been proven, further follow-up studies are necessary to justify pentaerythrityl tetranitrate treatment during pregnancies complicated by impaired uterine perfusion.

Safe medications for mild mental diseases in pregnancy are needed. Phytomedicines from St. John\'s wort and valerian are valid candidates, but safety data in pregnancy are lacking. The transplacental transport of hyperforin and hypericin (from St. John\'s wort), and valerenic acid (from valerian) was evaluated using the ex vivo cotyledon perfusion model (4 h perfusions, term placentae) and, in part, the in vitro Transwell assay with BeWo b30 cells. Antipyrine was used for comparison in both models. U(H)PLC-MS/MS bioanalytical methods were developed to quantify the compounds. Perfusion data obtained with term placentae showed that only minor amounts of hyperforin passed into the fetal circuit, while hypericin did not cross the placental barrier and valerenic acid equilibrated between the maternal and fetal compartments. None of the investigated compounds affected metabolic, functional, and histopathological parameters of the placenta during the perfusion experiments. Data from the Transwell model suggested that valerenic acid does not cross the placental cell layer. Taken together, our data suggest that throughout the pregnancy the potential fetal exposure to hypericin and hyperforin - but not to valerenic acid - is likely to be minimal.

Although Doppler ultrasonography (USG) is frequently used in human medicine to evaluate placental function and fetal well-being, studies in veterinary medicine are limited. Thus, this study aimed to determine the relationship between placentome perfusion and echotexture and endocrine changes during the last stages of pregnancy in cows using B-mode/Doppler USG and reveal the effects of hormonal changes on placentome and uterine artery hemodynamics. The animals consisted of 12 pregnant Swiss Brown cows 3.8 ± 0.34 years old with at least one birth. Imaging with USG was continued for 1 month, thrice weekly, until delivery. To determine serum progesterone (P4), total estrogen, and cortisol levels, blood was drawn from the tail vein immediately after USG examinations. Contrast (CON), homogeneity (HOM), and mean gray value (MGV) were determined by placentome echotexture analysis. Color Doppler perfusion areas (A mix) and power Doppler perfusion areas (A red) of the placentome, pulse rate (PR), pulsatility index (PI), resistance index (RI), blood flow velocity (BFVe), blood flow volume (BFVo), and diameter (DM) in the spectral analysis of uterine artery values were collected. ImageJ was used to analyze the B-mode images, and PixelFlux (Chameleon® Software, Münster, Germany) was used to calculate the placentome perfusion values and hemodynamic parameters of the uterine artery in Doppler images. In the last month of pregnancy, there was no statistical difference in the placentome echotexture values CON and HOM. However, MGV increased close to birth (P < 0.001). Placentome perfusion level and area did not change significantly but were found to decrease numerically 2 days before delivery (P > 0.05). Uterine artery PR increased from 62.36 bpm on day 25 prepartum to 81.42 bpm at birth (P < 0.05). The P4 concentration decreased in the last month of pregnancy, whereas an increase was detected in estrogen and cortisol during this period (P < 0.05). In the uterine artery of pregnant cornu, RI and PI were negatively correlated with BFVe (P < 0.01). Based on this study, echotextural differences were observed in placentomes in the last stage of pregnancy in cows, and there were significant changes in placental and uterine artery blood flow. These changes may be related to placental maturation, especially on the days close to birth.

Fetal growth restriction is strongly associated with impaired placentation and abnormal uteroplacental blood flow. Nitric oxide donors such as pentaerythritol tetranitrate are strong vasodilators and protect the endothelium. Recently, we demonstrated in a randomized controlled pilot study a 38% relative risk reduction for the development of fetal growth restriction or perinatal death following administration of pentaerythritol tetranitrate to pregnant women at risk, identified by impaired uterine perfusion at midgestation. Results of this monocenter study prompted the hypothesis that pentaerythritol tetranitrate might have an effect in pregnancies with compromised placental function as a secondary prophylaxis.
This study aimed to test the hypothesis that the nitric oxide donor pentaerythritol tetranitrate reduces fetal growth restriction and perinatal death in pregnant women with impaired placental perfusion at midgestation in a multicenter trial.
In this multicenter, randomized, double-blind, placebo-controlled trial, 2 parallel groups of pregnant women presenting with a mean uterine artery pulsatility index >95th percentile at 19+0 to 22+6 weeks of gestation were randomized to 50-mg Pentalong or placebo twice daily. Participants were assigned to high- or low-risk groups according to their medical history before randomization was performed block-wise with a fixed block length stratified by center and risk group. The primary efficacy endpoint was the composite outcome of perinatal death or development of fetal growth restriction. Secondary endpoints were neonatal and maternal outcome parameters.
Between August 2017 and March 2020, 317 participants were included in the study and 307 were analyzed. The cumulative incidence of the primary outcome was 41.1% in the pentaerythritol tetranitrate group and 45.5% in the placebo group (unadjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; adjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; P=.43). Secondary outcomes such as preterm birth (unadjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; adjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; P=.01) and pregnancy-induced hypertension (unadjusted relative risk, 0.65; 95% confidence interval, 0.46-0.93; adjusted relative risk, 0.65; 95% confidence interval, 0.46-0.92; P=0.01) were reduced.
Our study failed to show an impact of pentaerythritol tetranitrate on the development of fetal growth restriction and perinatal death in pregnant women with impaired uterine perfusion at midgestation. Pentaerythritol tetranitrate significantly reduced secondary outcome parameters such as the incidence of preterm birth and pregnancy-induced hypertension in these pregnancies.

The present study aimed to investigate placental hemodynamics to determine quantitative and qualitative parameters for pregnant brachycephalic bitches as well as describe placental vascularization and perfusion in females with fetal abnormalities close to delivery. Forty-four healthy fetuses from 22 brachycephalic bitches and 9 fetuses with gestational abnormalities (anasarca and hydrocephalus) from 8 brachycephalic bitches were evaluated. All female dogs were artificially inseminated intravaginally and underwent cesarean section at the end of gestation. Pregnancy diagnosis was made on the 25th day and experimental evaluations were performed on Days 25 (M1), 45 (M2), and 58 (M3) of gestation in normal pregnancies. Fetuses with gestational abnormalities were evaluated at the last time point. Biometric values of the fetuses were determined by B-mode and vascular indices by Doppler fluxometry of the umbilical artery, whereas qualitative assessment of contrast filling and quantitative parameters of placental perfusion were performed using CEUS. Parameter comparisons among the examined fetuses (normal and abnormal) and between the moments (M1, M2, and M3) were performed by Student\'s t-test and ANOVA tests, and then correlated using the Spearman test. In healthy fetuses, systolic and diastolic velocities as well as the time averages of minimum and maximum velocities increased significantly from M2 to M3 (P < 0.05), whereas the pulsatility index (P < 0.043) and vascular resistance (P < 0.001) decreased. Contrast distribution was always homogeneous in placental tissues and CEUS filling parameters remained constant during the evaluated periods (P < 0.05). In fetuses with hydrops, Doppler values were similar to those obtained in healthy subjects (P > 0.05), but CEUS evaluation demonstrated a heterogeneous distribution with lower intensity of placental tissue filling and a delay in perfusion time (P < 0.05) with a diagnostic accuracy of 75%. The association of dopplerfluxometry and CEUS allowed evaluation of qualitative and quantitative parameters of physiological pregnancy hemodynamics in all gestational thirds without evidence of significant changes in the physiology of the maternal-fetal binomial, and CEUS was shown to be applicable in the detection of failures in placental vascular filling (tissue dysfunction) in fetuses with anasarca and hydrocephaly.

Investigation of the maternal to fetal transfer of oxytocin across the dually perfused term human placenta.
Human placentae obtained from term singleton pregnancies were utilized in a dual recirculating model of ex vivo placental perfusion. Six placentae from women delivering by elective cesarean at term were perfused, one blank and five with the test substance synthetic oxytocin (0.8 ng/mL) (OX) added to the maternal perfusate for 180 min. Antipyrine was used as positive control to validate overlap of the maternal and fetal circuits. The concentration of OX was determined by radioimmunoassay.
A fall in maternal concentration of OX was seen throughout the experiment. At 90 min of perfusion a state of equilibrium was reached between maternal and fetal concentrations; however after 180 min the fetal concentration of OX was higher than that of the maternal. 31 % of the test substance was accounted for at the end of the experiment - suggesting OX protein binding and a high degree of oxytocinase activity.
The ex vivo perfusion experiments revealed low transfer of OX to the fetal circuit below physiologically relevant concentrations.

The association between maternal hypotension and poor fetal growth has not been well studied.
We hypothesized that the presence of persistent maternal hypotension will reflect a chronic reduction of uteroplacental blood flow, leading to placental hypoperfusion and subsequent poor fetal growth. We aimed to evaluate whether persistent hypotension is associated with the risk of having a small for gestational age neonate. A secondary aim was to evaluate whether transient hypotension is associated with the same risk of having a small for gestational age neonate.
We performed a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be data, a large prospective cohort study of nulliparous women. The inclusion criteria included delivery of subjects with singleton pregnancies at ≥24 weeks\' gestation who had systolic and diastolic blood pressure data at 3 antenatal visits between 6 0/7 and 29 6/7 weeks\' gestation. Univariable analyses were performed to evaluate the association among persistent hypotension (systolic blood pressure of <100 mm Hg and or diastolic blood pressure of <60 mm Hg at 3 antenatal visits), transient hypotension (systolic blood pressure <100 mm Hg and diastolic blood pressure <60 mm Hg at any 1 of 3 aforementioned visits but not all 3), maternal characteristics and small for gestational age neonates. Variables found to be significant (P<.05) were included in multivariable logistic regression.
Here, 164 of 7233 participants (2.3%) had persistent hypotension. In univariable analyses, subjects with persistent hypotension compared with those without were significantly more likely to have small for gestational age neonates (21.3% vs 11.6%; P<.001). When adjusting for confounders, persistent hypotension remained significantly associated with an increased risk of having a small for gestational age neonate (adjusted odds ratio, 1.65; 95% confidence interval, 1.11-2.44). In multivariable analysis, transient hypotension was not associated with an increased risk of having a small for gestational age neonate.
Persistent hypotension was significantly associated with small for gestational age among neonates born to low-risk nulliparous women.

OBJECTIVE: To establish Z-scores for the diameter and blood flow volume of the umbilical vein (UV) in normal fetuses.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.