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.

Central nervous system distribution of buprenorphine in pregnant sheep, fetuses and newborn lambs after continuous transdermal and single subcutaneous extended-release dosing.

Buprenorphine is used during pregnancy for the treatment of opioid use disorder. Limited data exist on the central nervous system (CNS) permeation and distribution, and on the fetal exposure to buprenorphine. The aim of our study was to determine the extent of buprenorphine distribution to CNS in the pregnant sheep, and their fetus at steady-state, and their newborn lambs postdelivery, using three different dosing regimens. Twenty-eight pregnant ewes in late gestation received buprenorphine via 7-day transdermal patch releasing buprenorphine 20 µg/h (n=9) or 40 µg/h (n=11), or an extended-release 8 mg/week subcutaneous injection (n=8). Plasma, cerebrospinal fluid, and CNS tissue samples were collected at steady-state from ewes and fetuses, and from lambs 0.33 - 45 hours after delivery. High accumulation of buprenorphine was observed in all CNS tissues. The median CNS/plasma concentration -ratios of buprenorphine in different CNS areas ranged between 13 and 50 in the ewes, and between 26 and 198 in the fetuses. In the ewes the CNS/plasma -ratios were similar after the three dosing regimens, but higher in the fetuses in the 40 µg/h dosing group, medians 65 - 122, than in the 20 µg/h group, medians 26 - 54. The subcutaneous injection (theoretical release rate 47.6 µg/h) produced higher concentrations than observed after 40 µg/h transdermal patch dosing. The median fetal/maternal concentration -ratios in different dosing groups ranged between 0.21 and 0.54 in plasma, and between 0.38 and 1.3 in CNS tissues, respectively, with the highest ratios observed in the spinal cord. Buprenorphine concentrations in the cerebrospinal fluid were 8 - 13 % of the concurrent plasma concentration in the ewes and 28 % in the fetuses. Buprenorphine was quantifiable in the newborn lambs' plasma and CNS tissues two days postdelivery. Norbuprenorphine was analyzed from all plasma, cerebrospinal fluid, and CNS tissue samples but was nondetectable or below the LLOQ in most. The current study demonstrates that buprenorphine accumulates into CNS tissues at much higher concentrations than in plasma in pregnant sheep, fetuses, and their newborn lambs even 45 hours after delivery.

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.

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 AND FETAL BUPRENORPHINE PHARMACOKINETICS IN PREGNANT SHEEP DURING TRANSDERMAL PATCH DOSING: Buprenorphine pharmacokinetics in pregnant sheep.

BACKGROUND: Buprenorphine is used in the opioid maintenance treatment for opioid dependent patients, including pregnant women. Despite the wide use, limited data exists on buprenorphine pharmacokinetics and fetal exposure during pregnancy. The aim of our study was to determine the buprenorphine pharmacokinetics during transdermal patch dosing to pregnant sheep and, to determine the extent of transplacental transfer of buprenorphine to the fetus. METHODS: Pregnant sheep in late gestation (n=50) received 20, 25 or 40 µg/h of buprenorphine as a 7-day extended-release transdermal patch. Plasma samples were collected from the ewe and the fetus on days 1 - 6, and buprenorphine and norbuprenorphine concentrations were determined. During the exposure period the sheep had a surgical procedure on the second day, a recovery phase, and an experimental procedure on the sixth day. In the experiment, hypoxia was induced under anesthesia for 18 sheep to investigate if decreased fetal pH would cause ion-trapping of buprenorphine in the fetus. The fetal/maternal plasma concentration ratio was determined on the second and on the sixth exposure day at baseline and during hypoxia. Maternal pharmacokinetics were modelled with a population pharmacokinetic method using the data from this study and our previous intravenous administration study. RESULTS: The transdermal patch provided an extended release of buprenorphine throughout the exposure period, but the release rate declined approximately 20 h after patch placement. The median fetal/maternal plasma concentration ratio was 13 - 27 % throughout the exposure period at baseline. A ratio over 100 % was observed for four sheep on the sixth exposure day (102 - 269 %). A minor increase was seen in the median fetal/maternal-ratios during maternal hypoxia. Norbuprenorphine was undetected in all plasma samples. CONCLUSIONS: The low transplacental passage of less than one fourth of the ewe's exposure supports buprenorphine as an alternative to methadone in opioid maintenance therapy during pregnancy.

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.

Pharmacokinetics of buprenorphine in pregnant sheep after intravenous injection.

Buprenorphine is a semi-synthetic opioid, widely used in the maintenance treatment for opioid-dependent pregnant women. Limited data exist on the pharmacokinetics of buprenorphine in pregnancy. We conducted a pharmacokinetic study to determine the pharmacokinetics of intravenous buprenorphine in pregnant sheep. Fourteen pregnant sheep in late gestation received 10 µg/kg of buprenorphine as an intravenous bolus injection. Plasma samples were collected up to 48 h after administration. Buprenorphine and its metabolite, norbuprenorphine, were quantified from plasma using a LC/MS/MS method, with lower limits of quantification of 0.01 µg/L and 0.04 µg/L for buprenorphine and norbuprenorphine, respectively. The pharmacokinetic parameters were calculated using noncompartmental analysis. The pharmacokinetic parameters, median (minimum-maximum), were Cmax 4.31 µg/L (1.93-15.5), AUCinf 2.89 h*µg/L (1.72-40.2), CL 3.39 L/h/kg (0.25-6.02), terminal t½ 1.75 h (1.07-31.0), Vss 8.04 L/kg (1.05-49.3). Norbuprenorphine was undetected in all plasma samples. The median clearance in pregnant sheep was higher than previously reported for nonpregnant sheep and human (male) subjects. Our sensitive analytical method was able to detect long terminal half-lives for six subjects, and a wide between-subject variability in the study population. Significance statement: Buprenorphine is widely used for the treatment of opioid use disorder in pregnancy. However, limited data exist on the pharmacokinetics of buprenorphine during pregnancy. As this type of study cannot be done in humans due to ethical reasons, we conducted a study in pregnant sheep. This study provides pharmacokinetic data on buprenorphine in pregnant sheep and helps us to understand the pharmacokinetics of the drug in humans.

Antenatal hemodynamic findings and heart rate variability in early school-age children born with fetal growth restriction.

BACKGROUND: According to epidemiological studies, impaired intrauterine growth increases the risk for cardiovascular morbidity and mortality in adulthood. Heart rate variability (HRV), which reflects the autonomic nervous system function, has been used for risk assessment in adults while its dysfunction has been linked to poor cardiovascular outcome. OBJECTIVE: We hypothesized that children who were born with fetal growth restriction (FGR) and antenatal blood flow redistribution have decreased HRV at early school age compared to their gestational age matched peers with normal intrauterine growth. STUDY DESIGN: A prospectively collected cohort of children born with FGR (birth weight <10th percentile and/or abnormal umbilical artery flow, n = 28) underwent a 24-hour Holter monitoring at the mean age of 9 years and gestational age matched children with birth weight appropriate for gestational age (AGA, n = 19) served as controls. Time- and frequency domain HRV indices were measured and their associations with antenatal hemodynamic changes were analyzed. RESULTS: Time- and frequency domain HRV parameters (standard deviation of R-R intervals, SDNN; low frequency, LF; high frequency, HF; LF/HF; very low frequency, VLF) did not differ significantly between FGR and AGA groups born between 24 and 40 weeks. Neither did they differ between children born with FGR and normal umbilical artery pulsatility or increased umbilical artery pulsatility. In total, 56% of the FGR children demonstrated blood flow redistribution (cerebroplacental ratio, CPR < -2 SD) during fetal life and their SDNN (p = .01), HF (p = .03) and VLF (p = .03) values were significantly lower than in FGR children with CPR ≥ -2SD. CONCLUSIONS: Early school age children born with FGR and intrauterine blood flow redistribution demonstrated altered heart rate variability. These prenatal and postnatal findings may be helpful in targeting preventive cardiovascular measures in FGR.

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.

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.

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.

Effects of nifedipine and sildenafil on placental hemodynamics and gas exchange during fetal hypoxemia in a chronic sheep model.

INTRODUCTION: We hypothesized that nifedipine and sildenafil would have no detrimental effects on placental hemodynamics and gas exchange under fetal hypoxemia. METHODS: In 33 chronically instrumented fetal sheep, placental volume blood flow (QPlac) and umbilical artery (UA) vascular impedance were measured by Doppler ultrasonography. Fetal carotid artery blood pressure and blood gas values were monitored. After baseline data collection, maternal and fetal hypoxemia were induced. Following hypoxemia phase data collection, 12 fetuses received sildenafil and 9 fetuses nifedipine infusion, and 12 fetuses served as controls receiving saline infusion. Data were collected 30 and 120 min after infusion was started. Then maternal oxygenation was normalized and normoxemia phase data were collected, while infusion was continued. RESULTS: Hypoxemia significantly decreased fetal pO2 and blood pressure. In the sildenafil group at 30- and 120-min hypoxemia + infusion phases, fetal blood pressure and QPlac were significantly lower and pCO2 higher than at baseline without returning to baseline level at normoxemia + infusion phase. In hypoxemia, nifedipine did not affect fetal blood pressure or placental hemodynamics. Both in the sildenafil and nifedipine groups, fetal pO2 remained significantly lower at normoxemia + infusion phase than in the control group. Umbilical artery vascular impedance did not change during the experiment. DISCUSSION: In fetal hypoxemia, sildenafil had detrimental effects on placental hemodynamics that disturbed placental gas exchange. Nifedipine did not alter placental hemodynamics in hypoxemia but disturbed placental gas exchange upon returning to normoxemia. Umbilical artery vascular impedance did not reflect alterations in placental hemodynamics.

Oxycodone concentrations in the central nervous system and cerebrospinal fluid after epidural administration to the pregnant ewe.

The main sites of the analgesic action of oxycodone are the brain and spinal cord. The present study describes the concentrations of oxycodone and its metabolites in the brain and spinal cord after epidural administration to the ewe. Twenty pregnant ewes undergoing laparotomy were randomized into two groups to receive epidural oxycodone: infusion group (n = 10, 0.1 mg·kg-1 bolus followed by continuous infusion of 0.05 mg·kg-1 ·h-1 for five days) or repeated boluses group (n = 10, 0.2 + 2x0.1 mg·kg-1 bolus followed by a 0.2 mg·kg-1 bolus every 12 hours for five days). After five days of oxycodone administration, arterial blood samples were collected, the sheep were killed, and a CSF sample and tissue samples from the cortex, thalamus, cerebellum and spinal cord were obtained for the quantification of oxycodone and its main metabolites. The median plasma and CSF concentrations of oxycodone were 9.0 and 14.2 ng·mL-1 after infusion and 0.4 and 1.1 ng·mL-1 after repeated boluses. In the infusion group, the cortex, thalamus and cerebellum oxycodone concentrations were 4-8 times higher and in the spinal cord 1310 times higher than in plasma. In the repeated boluses group, brain tissue concentrations were similar in the three areas, and in the spinal cord were 720 times higher than in plasma. Oxymorphone was the main metabolite detected, which accumulated in the brain and spinal cord tissue. In conclusion, first, accumulation of oxycodone and oxymorphone in the CNS was observed, and second, high spinal cord concentrations suggest that epidural oxycodone may provide segmental analgesia.

Fetal hemodynamics and language skills in primary school-aged children with fetal growth restriction: A longitudinal study.

AIM: Long-term follow-up studies on children born with fetal growth restriction (FGR) have revealed a specific profile of neurocognitive difficulties, including problems with speech, language and literacy skills. We hypothesized that problems with communication skills, including language use and literacy skills of FGR children at primary school age are associated with prenatal circulatory changes. METHODS: Ultrasonographic assessment of fetoplacental hemodynamics was performed prenatally in 77 fetuses. After a follow-up period of 8-10 years, assessment of reading and spelling skills using standardized tests and the Children's Communication Questionnaire (CCC-2) was performed to measure different language skills in 37 FGR children and 31 appropriately grown (AGA) controls, matched for gestational age. RESULTS: Increased blood flow resistance in the umbilical artery (UA PI >2 SD) during fetal life showed odds ratios of 3.5-19.1 for poor literacy and communication skills and need for speech and language therapy. Furthermore, FGR children with prenatal cerebral vasodilatation (cerebroplacental ratio (CPR) < -2 SD) had significantly poorer literacy and communication skills, at primary school age compared to the AGA controls. Abnormal CPR demonstrated odds ratios of 4.2-28.1 for poor literacy and communication skills and need for speech and language therapy. CONCLUSION: Increased blood flow resistance in the umbilical artery and cerebral vasodilatation are associated with poor communication, language, and literacy skills at early school age in children born with FGR. These findings indicate the need for continuous follow-up of this group and timely targeted support to ensure optimal academic outcomes.

Effect of Sildenafil on Pulmonary Circulation and Cardiovascular Function in Near-Term Fetal Sheep During Hypoxemia.

Sildenafil is a potential new treatment for placental insufficiency in human pregnancies as it reduces the breakdown of vasodilator nitric oxide. Pulmonary vasodilatation is observed in normoxemic fetuses following sildenafil administration. Placental insufficiency often leads to fetal hypoxemia that can cause pulmonary vasoconstriction and fetal cardiac dysfunction as evidenced by reduced isovolumic myocardial velocities. We tested the hypotheses that sildenafil, when given directly to the hypoxemic fetus, reverses reactive pulmonary vasoconstriction, increases left ventricular cardiac output by increasing pulmonary venous return, and ameliorates hypoxemic myocardial dysfunction. We used an instrumented sheep model. Fetuses were made hypoxemic over a mean (standard deviation) duration of 41.3 (9.5) minutes and then given intravenous sildenafil or saline infusion. Volume blood flow through ductus arteriosus was measured with an ultrasonic transit-time flow probe. Fetal left and right ventricular outputs and lung volume blood flow were calculated, and ventricular function was examined using echocardiography. Lung volume blood flow decreased and the ductus arteriosus volume blood flow increased with hypoxemia. There was a significant reduction in left ventricular and combined cardiac outputs during hypoxemia in both groups. Hypoxemia led to a reduction in myocardial isovolumic velocities, increased ductus venosus pulsatility, and reduced left ventricular myocardial deformation. Direct administration of sildenafil to hypoxemic fetus did not reverse the redistribution of cardiac output. Furthermore, fetal cardiac systolic and diastolic dysfunction was observed during hypoxemia, which was not improved by fetal sildenafil treatment. In conclusion, sildenafil did not improve pulmonary blood flow or cardiac function in hypoxemic sheep fetuses.

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.

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.

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.