Oxycodone does not affect placental circulatory physiology during the early first stage of labor-A randomized trial.

INTRODUCTION: Opioids are used for pain relief during the first stage of labor. Oxycodone can cause maternal hypotension that may modify utero- and fetoplacental circulatory physiology. We hypothesized that maternal intravenous (i.v.) oxycodone has no detrimental effect on utero- and fetoplacental hemodynamics during the early first stage of labor. MATERIAL AND METHODS: Twenty-two parturients requiring pain relief during the first stage of labor were randomized in a double-blinded and placebo-controlled study. By Doppler ultrasonography, both uterine artery (Ut) and umbilical vein (UV) volume blood flows (Q), Ut pulsatility index (PI), and Ut vascular resistance (RUt) were calculated. Blood flow velocity waveforms were obtained between uterine contractions. After baseline measurements, women received oxycodone 0.05 mg/kg or a placebo intravenous. Doppler ultrasonography was repeated up to 120 min after the first drug administration. The second dose of oxycodone 0.05 mg/kg was allowed at 60 min to all parturients with contraction pain ≥5/10. Maternal plasma samples were collected at each study phase and after delivery with umbilical cord plasma samples, to measure oxycodone concentrations. CLINICALTRIALS: gov identifier (NCT no. NCT02573831). RESULTS: At baseline, mean QUt and QUV did not differ significantly between the placebo-first (478 mL/min and 57 mL/min/kg) and the oxycodone-first (561 mL/min and 71 mL/min/kg) groups. In addition, RUt and Ut PI were comparable between the groups. Following oxycodone at 60 min, mean QUt and QUV (714 mL/min and 52 mL/min/kg) were similar to the placebo-first (520 mL/min and 55 mL/min/kg) group. Furthermore, all the measured parameters were comparable to the baseline values. At 60 min after the first study drug administration, all the parturients in the placebo-first group needed intravenous oxycodone 0.05 mg/kg. At 120 min, we found no statistically significant change in any of the measured parameters. No significant correlation was found between maternal oxycodone concentration and QUt or QUV. Furthermore, newborn oxycodone concentration did not correlate with QUV. CONCLUSIONS: Oxycodone did not have any detrimental effect on either utero- or fetoplacental circulatory physiology during the early first stage of labor. Maternal plasma oxycodone did not correlate with utero- and fetoplacental hemodynamics. No correlation was found between newborn oxycodone concentration and fetoplacental hemodynamics.

Accuracy of fetal echocardiography diagnosis and anticipated perinatal and early postnatal care in congenital heart disease in mid-gestation.

INTRODUCTION: The aim of this study was to determine discrepancies in fetal congenital heart disease (CHD) diagnoses and anticipated early postnatal care and outcomes. MATERIAL AND METHODS: A retrospective review of 462 randomly selected cases (23% of all cases) referred to a fetal cardiac assessment during the second trimester (mean 26 weeks) at the Children's Hospital in Helsinki between October 2010 and December 2020. Discrepancy between prenatal and postnatal CHD case evaluations was assessed with independently provided cardiac severity and surgical complexity scores. RESULTS: In all, 250 cases, 181 CHD and 69 normal, with complete prenatal and postnatal live birth data as well as seven fetal autopsy reports available were included in the analysis. There were 12 false normal and seven false abnormal prenatal assessments. The prenatally anticipated level of early neonatal care was actualized in 62% and prostaglandin infusion in 95%. In total, 32.7% (84/257) cardiac severity scores were discrepant and in 12,4% (32/257) cases the discrepancies were considered significant (≥ +/- 2 scores). Among significant discrepancies, CHD severity score was overestimated in 13 and underestimated in 19 in fetal assessment. Progression of CHD severity after mid-gestation and during early neonatal phase explained eight of 19 underestimated fetal assessments. The most common discrepant diagnostic categories included ventricular septal defects (n = 7), borderline ventricles (n = 7; 5 left heart, 1 right heart and 1 double outlet right ventricle/transposition of the great arteries), arch anomalies including coarctations (n = 5) and tricuspid valve dysplasias (n = 4) with a significant change in postnatal diagnoses and treatment. CONCLUSIONS: Although fetal CHD diagnosis and counseling is accurate and reliable in general, the study elaborates specific areas of uncertainty in clinical fetal cardiology practice that may be important to consider in fetal CHD evaluation and counseling provided in mid-gestation.

Nifedipine disturbs fetal cardiac function during hypoxemia in a chronic sheep model at near term gestation.

BACKGROUND: Nifedipine is a widely used drug in pregnancies complicated by maternal hypertensive disorders that can be associated with placental insufficiency and fetal hypoxemia. The evidence regarding fetal myocardial responses to nifedipine in hypoxemia is limited. OBJECTIVE: We hypothesized that nifedipine would not impair fetal sheep cardiac function under hypoxemic environment. In particular, we investigated the effects of nifedipine on fetal ventricular functional parameters and cardiac output. STUDY DESIGN: A total of 21 chronically instrumented fetal sheep at 122 to 134 gestational days (term, 145 days) were included in this study. Fetal cardiac function was evaluated by measuring global longitudinal strain, indices describing ventricular systolic and diastolic function, and cardiac outputs using two-dimensional speckle tracking and tissue and spectral pulsed-wave Doppler echocardiography. Fetal carotid artery blood pressure and blood gas values were invasively monitored. After baseline data collection, fetal hypoxemia was induced by maternal hyperoxygenation. After hypoxemia phase data collection, 9 fetuses received nifedipine infusion, and 12 fetuses received saline infusion. Data were collected 30 and 120 minutes after the infusion was started. After 120 minutes of data collection, maternal and fetal oxygenation were normalized, and normoxemia phase data were collected, while infusion was continued. RESULTS: Hypoxemia decreased fetal carotid artery mean arterial pressure from 40 (8) mm Hg to 35 (8) mm Hg (P<.007), and left ventricular global longitudinal strain showed less deformation than at baseline (P=.001). Under hypoxemia, nifedipine caused a reduction in right ventricular global longitudinal strain (P<.05), a decrease in right ventricular isovolumic relaxation velocity and its deceleration (P<.01) indicating diastolic dysfunction, and a drop in right ventricular cardiac output (P<.05). Nifedipine did not alter fetal left ventricular functional parameters or cardiac output. When normoxemia was restored, fetal right ventricular functional parameters and cardiac output returned to baseline level. CONCLUSION: In hypoxemic fetus, nifedipine impaired right ventricular function and reduced its cardiac output. The detrimental effects of nifedipine on fetal right ventricular function were abolished, when normoxemia was restored. Our findings suggest that in a hypoxemic environment nifedipine triggers detrimental effects on fetal right ventricular function.

Fetal cardiovascular hemodynamics in type 1 diabetic pregnancies at near-term gestation.

INTRODUCTION: Poor glycemic control in maternal type 1 diabetes mellitus during pregnancy can affect fetal cardiac and placental function. However, studies concerning fetal central hemodynamics have revealed conflicting results. We hypothesized that in pregnancies complicated by maternal type 1 diabetes, fetal cardiovascular and placental hemodynamics are comparable to the control fetuses at near-term gestation. In addition, we investigated the relation between newborn serum biomarkers of cardiac function and fetal cardiovascular and placental hemodynamics. Furthermore, we studied whether maternal diabetes is associated with placental inflammation. MATERIAL AND METHODS: In this prospective case-control study, fetal central and peripheral hemodynamics were assessed by ultrasonography in 33 women with type 1 diabetes and in 67 controls with singleton pregnancies between 34+2 and 40+2 gestational weeks. Newborn umbilical cord serum was collected to analyze cardiac natriuretic peptides (atrial and B-type natriuretic peptides) and troponin T concentrations. Placental tissue samples were obtained for cytokine analyses. RESULTS: Fetal ventricular wall thicknesses were greater and weight-adjusted stroke volumes and cardiac outputs were lower in the type 1 diabetes group than in the control group. Pulsatility in the aortic isthmus and inferior vena cava blood flow velocity waveforms was greater in the type 1 diabetes group fetuses than in the controls. A positive correlation was found between branch pulmonary artery and aortic isthmus pulsatility index values. Umbilical artery pulsatility indices were comparable between the groups. Umbilical cord serum natriuretic peptide and troponin T concentrations were elevated in the type 1 diabetes fetuses. These cardiac biomarkers correlated significantly with cardiovascular hemodynamics. Placental cytokine levels were not different between the groups. CONCLUSIONS: In maternal type 1 diabetes pregnancies, fetal cardiovascular hemodynamics is impaired. Maternal type 1 diabetes does not seem to alter placental vascular impedance or induce placental inflammation.

Maternal azithromycin therapy for Ureaplasma parvum intraamniotic infection improves fetal hemodynamics in a nonhuman primate model.

BACKGROUND: Ureaplasma parvum infection is a prevalent cause of intrauterine infection associated with preterm birth, preterm premature rupture of membranes, fetal inflammatory response syndrome, and adverse postnatal sequelae. Elucidation of diagnostic and treatment strategies for infection-associated preterm labor may improve perinatal and long-term outcomes for these cases. OBJECTIVE: This study assessed the effect of intraamniotic Ureaplasma infection on fetal hemodynamic and cardiac function and the effect of maternal antibiotic treatment on these outcomes. STUDY DESIGN: Chronically catheterized pregnant rhesus monkeys were assigned to control (n=6), intraamniotic inoculation with Ureaplasma parvum (107 colony-forming units/mL, n=15), and intraamniotic infection plus azithromycin treatment (12.5 mg/kg twice a day intravenously, n=8) groups. At approximately 135 days' gestation (term=165 days), pulsed and color Doppler ultrasonography was used to obtain measurements of fetal hemodynamics (pulsatility index of umbilical artery, ductus venosus, descending aorta, ductus arteriosus, aortic isthmus, right pulmonary artery, middle cerebral artery and cerebroplacental ratio, and left and right ventricular cardiac outputs) and cardiac function (ratio of peak early vs late transmitral flow velocity [marker of ventricular function], Tei index [myocardial performance index]). These indices were stratified by amniotic fluid proinflammatory mediator levels and cardiac histology. RESULTS: Umbilical and fetal pulmonary artery vascular impedances were significantly increased in animals from the intraamniotic inoculation with Ureaplasma parvum group (P<.05). Azithromycin treatment restored values to control levels. Amniotic fluid prostaglandin F2 alpha levels were significantly higher in animals with abnormal umbilical artery pulsatility index (>1.1) than in those with normal blood flow (P<.05; Spearman ρ=0.6, P<.05). In the intraamniotic inoculation with Ureaplasma parvum group, left ventricular cardiac output was significantly decreased (P<.001), and more animals had abnormal right-to-left ventricular cardiac output ratios (defined as >1.6, P<.05). Amniotic fluid interleukin-6 concentrations were elevated in cases of abnormal right-to-left ventricular cardiac output ratios compared with those in normal cases (P<.05). CONCLUSION: Fetal hemodynamic alterations were associated with intraamniotic Ureaplasma infection and ameliorated after maternal antibiotic treatment. Doppler ultrasonographic measurements merit continuing investigation as a diagnostic method to identify fetal cardiovascular and hemodynamic compromise associated with intrauterine infection or inflammation and in the evaluation of therapeutic interventions or clinical management of preterm labor.

Perinatal and perioperative factors associated with mortality and an increased need for hospital care in infants with transposition of the great arteries: A nationwide 11-year population-based cohort.

INTRODUCTION: Newborn infants with transposition of the great arteries (d-TGA) need immediate care for an optimal outcome. This study comprised a nationwide 11-year population-based cohort of d-TGA infants, and assessed whether the implementation of a nationwide systematic fetal screening program, or other perinatal, or perioperative factors, are associated with mortality or an increased need for hospital care. MATERIAL AND METHODS: The national cohort consisted of all live-born infants with simple d-TGA (TGA ± small ventricular septal defect, n = 127) born in Finland during 2004-2014. Data were collected from six national registries. Prenatal diagnosis and perinatal and perioperative factors associated with mortality and length of hospitalization were evaluated. RESULTS: Preoperative mortality was 7.9%, and the total mortality was 8.7%. The prenatal detection rate increased after introducing systematic fetal anomaly screening from 5.0% to 37.7% during the study period (P < .0001), but the total mortality rate remained unchanged. All prenatally diagnosed infants (n = 27) survived. Lower gestational age (odds ratio 0.68, P = .012) and higher maternal age at birth (odds ratio 1.16, P = .036) were associated with increased mortality in multivariable analysis. Older infant age at time of operation (P = .002), longer aortic clamp time (P < .001), and higher maternal body mass index (P = .027) were associated with longer initial hospital stay. An extended need for hospital care during the first year of life was multi-factorial. CONCLUSIONS: In our cohort, none of the prenatally diagnosed d-TGA infants died. As a result of the limited prenatal detection rates, however, the sample size was insufficient to reach statistical significance. The d-TGA infants born with lower gestational age and to older mothers had increased mortality.

Foramen ovale blood flow and cardiac function after main pulmonary artery occlusion in fetal sheep.

NEW FINDINGS: What is the central question of this study? At near-term gestation, foramen ovale blood flow accounts for a significant proportion of fetal left ventricular output. Can the foramen ovale increase its volume blood flow when right ventricular afterload is increased by main pulmonary artery occlusion? What is the main finding and its importance? Foramen ovale volume blood flow increased during main pulmonary artery occlusion. However, this increase was attributable to an increase in fetal heart rate, because left ventricular stroke volume remained unchanged. These findings suggest that the foramen ovale has a limited capacity to increase its volume blood flow. ABSTRACT: The foramen ovale (FO) accounts for the majority of fetal left ventricular (LV) output. Increased right ventricular afterload can cause a redistribution of combined cardiac output between the ventricles. To understand the capability of the FO to increase its volume blood flow and thus LV output, we mechanically occluded the main pulmonary artery in seven chronically instrumented near-term sheep fetuses. We hypothesized that FO volume blood flow and LV output would increase during main pulmonary artery occlusion. Fetal cardiac function and haemodynamics were assessed by pulsed and tissue Doppler at baseline, 15 and 60 min after occlusion of the main pulmonary artery and 15 min after occlusion was released. Fetal ascending aorta and central venous pressures and blood gas values were monitored. Main pulmonary artery occlusion initially increased fetal heart rate (P < 0.05) from [mean (SD)] 158 (7) to 188 (23) beats min-1 and LV cardiac output (P < 0.0001) from 629 (198) to 776 (283) ml min-1 . Combined cardiac output fell (P < 0.0001) from 1524 (341) to 720 (273) ml min-1 . During main pulmonary artery occlusion, FO volume blood flow increased (P < 0.001) from 507 (181) to 776 (283) ml min-1 . This increase was related to fetal tachycardia, because LV stroke volume did not change. Fetal ascending aortic blood pressure remained stable. Central venous pressure was higher (P < 0.05) during the occlusion than after it was released. During the occlusion, fetal pH decreased and P C O 2 increased. Left ventricular systolic dysfunction developed while LV diastolic function was preserved. Right ventricular systolic and diastolic function deteriorated after the occlusion. In conclusion, the FO has a limited capacity to increase its volume blood flow at near-term gestation.

Fetal sheep central haemodynamics and cardiac function during occlusion of the ascending aorta.

NEW FINDINGS: What is the central question of this study? The fetal aortic isthmus has an important physiological role, allowing communication between the left and right ventricular outputs, which are arranged in parallel. Can the aortic isthmus provide unrestrictive communication between the left and right ventricular circulations during occlusion of the ascending aorta? What is the main finding and its importance? During occlusion of the ascending aorta, fetal carotid artery perfusion pressure fell significantly, showing that the aortic isthmus failed to redirect blood flow and pressure from the ductus arteriosus to the aortic arch. This suggests that the aortic isthmus cannot provide unrestrictive communication between left and right ventricular circulations. The fetal aortic isthmus (AoI) allows communication between left (LV) and right ventricular (RV) outputs and represents an arterial watershed between the brachiocephalic (brain) and subdiaphragmatic (placenta) circulations. To understand the capability of the AoI to maintain the balance between the upper and lower body circulations, we performed a complete occlusion of the fetal ascending aorta in nine chronically instrumented sheep at near term gestation. We hypothesized that the occlusion would significantly decrease LV output and concomitantly increase RV output in order to maintain adequate systemic cardiac output and perfusion pressure to the fetal brain circulation through retrograde filling of the AoI. Fetal cardiac function and haemodynamics were assessed by pulsed and tissue Doppler at baseline, 15 and 60 min after occlusion of the ascending aorta and 15 min after occlusion was released. Carotid artery and jugular vein pressures were monitored. Occlusion of the ascending aorta increased (P < 0.002) RV output from [mean (SD)] 684 (369) to 907 (414) ml min-1 and decreased (P < 0.0001) LV output from 440 (136) to 40 (16) ml min-1 . Combined cardiac output decreased (P < 0.02) from 1125 (494) to 946 (417) ml min-1 . During occlusion, carotid artery mean pressure decreased from 32 (7) to 12 (7) mmHg (P < 0.0001). Systemic venous pressure was unaffected. Left ventricular systolic and diastolic function deteriorated during occlusion. Right ventricular systolic function improved, while diastolic dysfunction developed. Fetal carotid artery perfusion pressure decreased significantly during occlusion of the ascending aorta, demonstrating that AoI failed to redirect blood flow and pressure from the ductus arteriosus to the aortic arch. Our finding suggests that at near term gestation the aortic AoI cannot provide unrestrictive communication between LV and RV circulations.

Congenital diaphragmatic hernia with heart defect has a high risk for hypoplastic left heart syndrome and major extra-cardiac malformations: 10-year national cohort from Finland.

INTRODUCTION: Congenital diaphragmatic hernia (CDH) has a well-known risk of congenital heart defects with poor prognosis. This study was conducted to determine the national total prevalence and prenatal detection rates of CDH with heart defects and its association with major extra-cardiac malformations and to further evaluate the impact of the heart defect severity on survival. MATERIAL AND METHODS: A 10-year national cohort was derived from four national registries, including live births, stillbirths, and terminations of pregnancy for fetal anomalies. The study cohort was sorted according to cardiac defect severity. RESULTS: The total prevalence of CDH with heart defects was 0.6/10 000 births and live birth prevalence 0.3/10 000 live births. Of 145 cases with CDH, 37 (26%) had a concurrent heart defect. The overall prenatal detection rate of heart defects was 41%. The total prevalence (483/10 000) and live birth prevalence (500/10 000) of hypoplastic left heart syndrome were 124 and 250 times higher than in the general population in Finland, respectively. Additional major extra-cardiac malformations were found in 68% of cases. The survival rate for CDH with major heart defects was 11 and 38% with minor heart defects. CONCLUSIONS: The total prevalence of hypoplastic left heart syndrome was significantly higher in CDH patients than in the general population in Finland. Prenatal detection rate for heart defects in CDH patients was 41%. Major extra-cardiac malformations were more common than previously reported. The prognosis of CDH with major heart defects remained poor.

Oxycodone pharmacokinetics and fetal exposure after intravenous or epidural administration to the ewe.

INTRODUCTION: There are limited data on oxycodone pharmacokinetics during pregnancy and on fetal exposure after maternal administration. The present study describes the pharmacokinetics of intravenous (i.v.) oxycodone in pregnant sheep and fetal exposure after intravenous and epidural administration. MATERIAL AND METHODS: Ten pregnant sheep received 0.1 mg·kg-1 oxycodone intravenously, and blood samples were collected up to 24 hours. Seven days later, the ewes were randomized to receive 0.5 mg·kg-1 oxycodone intravenously (n = 5) or epidurally (n = 5) as a single bolus, before laparotomy for placement of catheters into the fetal superior vena cava and carotid artery. Paired maternal and fetal blood samples were taken when the fetal arterial catheter was in place and at the end of surgery. Maternal blood samples were taken up to 24 hours. RESULTS: After 0.1 mg·kg-1 oxycodone intravenously, the median clearance was 5.2 L·h-1 ·kg-1 (range 4.6-6.2), but the volume of distribution varied between 1.5 and 4.7 L·kg-1 . The area under the curve was 17 h·ng·mL-1 (range 14-19) and the plasma concentration at 2 minutes 60 ng·mL-1 (range 50-74). Following administration of 0.5 mg·kg-1 intravenously or epidurally, oxycodone concentrations were similar in the maternal and the fetal plasma. Accumulation of oxymorphone in the fetus occurred; fetal-to-maternal ratios were 1.3-3.5 (median 2.1) in the i.v.-group and 0.9-3.0 (1.3) in the Epidural-group. CONCLUSIONS: We determined the pharmacokinetics of oxycodone in pregnant sheep. We showed accumulation of oxymorphone, which an active metabolite of oxycodone, in the fetus. Further studies in human pregnancies are required to evaluate the safety of oxycodone.

Gestational hyperglycemia reprograms cardiac gene expression in rat offspring.

BackgroundRat fetuses with maternal pregestational hyperglycemia develop cardiac dysfunction, and their cardiac gene expression differs from that of healthy control fetuses near term. We hypothesized that cardiac gene expression and morphologic abnormalities of rat fetuses with maternal pregestational hyperglycemia become normal after birth.MethodsNine rats were preconceptually injected with streptozotocin to induce maternal hyperglycemia and nine rats served as controls. The hyperglycemia group comprised 82 mice and the control group 74 offspring fed by euglycemic dams. Hearts of the offspring were collected on postnatal days 0, 7, and 14, and processed for histologic and gene expression analyses.ResultsOn day 0, heart weight was increased, and expression of cardiac genes involved in contractility, growth, and metabolism was decreased in the hyperglycemia group. On day 7, although cardiomyocyte apoptosis was enhanced, most of the changes in gene expression had normalized in the hyperglycemia group. By day 14, the expression of genes important for myocardial growth, function, and metabolism was again abnormal in the hyperglycemia group.ConclusionMost cardiac gene expression abnormalities become transiently normal during the first week of life of offspring to hyperglycemic rats. However, by day 14, cardiac expressions of genes involved in growth, function, and metabolism are again abnormal in relation to control offspring.

Fetal hemodynamics and adverse outcome in primary school-aged children with fetal growth restriction: a prospective longitudinal study.

INTRODUCTION: Fetal growth restriction is associated with short-term and long-term mortality and morbidity. We hypothesized that adverse outcome in children with fetal growth restriction at primary school age is associated with fetoplacental circulatory abnormalities. MATERIAL AND METHODS: Comprehensive ultrasonographic assessment of fetoplacental hemodynamics was performed in 72 growth-restricted fetuses prenatally, and short-term outcome data were collected. At the median age of 9 years, mortality and morbidity were determined using medical charts and questionnaires. The impact of abnormal fetoplacental hemodynamics on mortality and morbidity with significant developmental disorders or delay were studied. RESULTS: Fetal growth restriction children with adverse long-term outcome were delivered earlier and with lower birthweights than were those with non-compromised outcome. Seventy percent of the fetal growth restriction group showed non-compromised long-term outcomes and participated in mainstream education at the appropriate age level. Absent/retrograde diastolic flow in the umbilical artery (p < 0.001), negative A-wave in the ductus venosus (p = 0.006), cardiomegaly (p = 0.02), hydrops (p = 0.006) and cardiovascular profile score <6 (p = 0.002) were associated with increased risk of adverse outcome. After adjustment for gestational age, these parameters demonstrated hazard ratios of 5.0-16.5 for adverse long-term outcome; increased systemic venous pulsatility and low cardiovascular profile score had the highest predictive power. CONCLUSIONS: Absent or reversed end-diastolic flow in the umbilical artery, reversed A-wave in the ductus venosus, cardiomegaly, hydrops, and low cardiovascular profile score are associated with adverse outcomes at primary school age in fetal growth restriction children. These fetal parameters play a significant role in the prediction of long-term outcomes for fetal growth restriction children.

Hemodynamic aspects of normal human feto-placental (umbilical) circulation.

Understanding the changes in normal circulatory dynamics that occur during the course of pregnancy is essential for improving our knowledge of pathophysiological mechanisms associated with feto-placental diseases. The umbilical circulation is the lifeline of the fetus, and it is accessible for noninvasive assessment. However, not all hemodynamic parameters can be reliably measured in utero using currently available technology. Experimental animal studies have been crucial in validating major concepts related to feto-placental circulatory physiology, but caution is required in directly translating the findings of such studies into humans due to species differences. Furthermore, it is important to establish normal reference ranges and take into account gestational age associated changes while interpreting the results of clinical investigation. Therefore, it is necessary to critically evaluate, synthesize and summarize the knowledge available from the studies performed on human pregnancies to be able to appropriately apply them in clinical practice. This narrative review is an attempt to present contemporary concepts on hemodynamics of feto-placental circulation based on human studies.

Species-Specific Differences in the in Vitro Metabolism of Lasiocarpine.

There are species-related differences in the toxicity of pyrrolizidine alkaloids (PAs) partly attributable to the hepatic metabolism of these alkaloids. In this study, the metabolism of lasiocarpine, a potent hepatotoxic and carcinogenic food contaminant, was examined in vitro with human, pig, rat, mouse, rabbit, and sheep liver microsomes. A total of 12 metabolites (M1-M12) were detected with the human liver microsomes, of which M1, M2, M4, and M6 were unstable in the presence of reduced glutathione (GSH). With the exception of M3 and M8, the formation of all metabolites of lasiocarpine was catalyzed by CYP3A4 in humans. Tandem mass spectra (MS/MS) detected several new metabolites, termed M4-M7; their toxicological significance is unknown. M9 (m/z 398), identified as a demethylation product, was the main metabolite in all species, although the relative dominance of this metabolite was lower in humans. The level of the reactive metabolites, as measured by M1 ((3H-pyrrolizin-7-yl)methanol) and the GSH conjugate, was higher with the liver microsomes of susceptible species (human, pig, rat, and mouse) than with the species (rabbit and sheep) resistant to PA intoxication. In general, in addition to the new metabolites (M4-M7) that could make humans more susceptible to lasiocarpine-induced toxicity, the overall metabolite fingerprint detected with the human liver microsomes differed from that of all other species, yielding high levels of GSH-reactive metabolites.

Maternal serum glycosylated fibronectin as a point-of-care biomarker for assessment of preeclampsia.

OBJECTIVE: We assessed the association of glycosylated fibronectin (GlyFn) with preeclampsia and its performance in a point-of-care (POC) test. STUDY DESIGN: GlyFn, placental growth factor (PlGF), and soluble vascular endothelial growth factor receptor 1 (sFlt1) levels were determined in serum samples from 107 pregnant women. In all, 45 were normotensive and 62 were diagnosed with preeclampsia. The ability of GlyFn to assess preeclampsia status and relationships between GlyFn and maternal characteristics and pregnancy outcomes were analyzed. RESULTS: GlyFn serum levels in the first trimester were significantly higher in women with preeclampsia (P < .01) and remained higher throughout pregnancy (P < .01). GlyFn, sFlt1, PlGF, and the sFlt1/PlGF ratio were significantly associated (P < .01) with preeclampsia status, and the classification performance of these analytes represented by area under the receiver operating characteristic curve was 0.99, 0.96, 0.94, and 0.98, respectively, with 95% confidence intervals of 0.98-1.00, 0.89-1.00, 0.86-1.00, and 0.94-1.00, respectively. Increased GlyFn levels were significantly associated with gestational age at delivery (P < .01), blood pressure (P = .04), and small-for-gestational-age neonates. Repeated-measures analysis of the difference in weekly GlyFn change in the third trimester demonstrated that mild preeclampsia was associated with a weekly change of 81.7 µg/mL (SE 94.1) vs 195.2 µg/mL (SE 88.2) for severe preeclampsia. The GlyFn POC demonstrated similar performance to a plate assay with an area under the receiver operating characteristic curve of 0.93 and 95% confidence interval of 0.85-1.00. CONCLUSION: GlyFn is a robust biomarker for monitoring of preeclampsia in both a standard and POC format, which supports its utility in diverse settings.

Vitamin C supplementation ameliorates the adverse effects of nicotine on placental hemodynamics and histology in nonhuman primates.

OBJECTIVE: We previously demonstrated that prenatal nicotine exposure decreases neonatal pulmonary function in nonhuman primates, and maternal vitamin C supplementation attenuates these deleterious effects. However, the effect of nicotine on placental perfusion and development is not fully understood. This study utilizes noninvasive imaging techniques and histological analysis in a nonhuman primate model to test the hypothesis that prenatal nicotine exposure adversely effects placental hemodynamics and development but is ameliorated by vitamin C. STUDY DESIGN: Time-mated macaques (n = 27) were divided into 4 treatment groups: control (n = 5), nicotine only (n = 4), vitamin C only (n = 9), and nicotine plus vitamin C (n = 9). Nicotine animals received 2 mg/kg per day of nicotine bitartrate (approximately 0.7 mg/kg per day free nicotine levels in pregnant human smokers) from days 26 to 160 (term, 168 days). Vitamin C groups received ascorbic acid at 50, 100, or 250 mg/kg per day with or without nicotine. All underwent placental dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) at 135-140 days and Doppler ultrasound at 155 days to measure uterine artery and umbilical vein velocimetry and diameter to calculate uterine artery volume blood flow and placental volume blood flow. Animals were delivered by cesarean delivery at 160 days. A novel DCE-MRI protocol was utilized to calculate placental perfusion from maternal spiral arteries. Placental tissue was processed for histopathology. RESULTS: Placental volume blood flow was significantly reduced in nicotine-only animals compared with controls and nicotine plus vitamin C groups (P = .03). Maternal placental blood flow was not different between experimental groups by DCE-MRI, ranging from 0.75 to 1.94 mL/mL per minute (P = .93). Placental histology showed increased numbers of villous cytotrophoblast cell islands (P < .05) and increased syncytiotrophoblast sprouting (P < .001) in nicotine-only animals, which was mitigated by vitamin C. CONCLUSION: Prenatal nicotine exposure significantly decreased fetal blood supply via reduced placental volume blood flow, which corresponded with placental histological findings previously associated with cigarette smoking. Vitamin C supplementation mitigated the harmful effects of prenatal nicotine exposure on placental hemodynamics and development, suggesting that its use may limit some of the adverse effects associated with smoking during pregnancy.

Maternal hyperglycemia leads to fetal cardiac hyperplasia and dysfunction in a rat model.

Accelerated fetal myocardial growth with altered cardiac function is a well-documented complication of human diabetic pregnancy, but its pathophysiology is still largely unknown. Our aim was to explore the mechanisms of fetal cardiac remodeling and cardiovascular hemodynamics in a rat model of maternal pregestational streptozotocin-induced hyperglycemia. The hyperglycemic group comprised 107 fetuses (10 dams) and the control group 219 fetuses (20 dams). Fetal cardiac function was assessed serially by Doppler ultrasonography. Fetal cardiac to thoracic area ratio, newborn heart weight, myocardial cell proliferative and apoptotic activities, and cardiac gene expression patterns were determined. Maternal hyperglycemia was associated with increased cardiac size, proliferative, apoptotic and mitotic activities, upregulation of genes encoding A- and B-type natriuretic peptides, myosin heavy chain types 2 and 3, uncoupling proteins 2 and 3, and the angiogenetic tumor necrosis factor receptor superfamily member 12A. The genes encoding Kv channel-interacting protein 2, a regulator of electrical cardiac phenotype, and the insulin-regulated glucose transporter 4 were downregulated. The heart rate was lower in fetuses of hyperglycemic dams. At 13-14 gestational days, 98% of fetuses of hyperglycemic dams had holosystolic atrioventricular valve regurgitation and decreased outflow mean velocity, indicating diminished cardiac output. Maternal hyperglycemia may lead to accelerated fetal myocardial growth by cardiomyocyte hyperplasia. In fetuses of hyperglycemic dams, expression of key genes that control and regulate cardiomyocyte electrophysiological properties, contractility, and metabolism are altered and may lead to major functional and clinical implications on the fetal heart.