Postnatal outcomes in lambs exposed antenatally and acutely postnatally to fluoxetine.

BACKGROUND: Approximately 1/3 of newborns exposed antenatally to selective serotonin reuptake inhibitors (SSRIs) exhibit poor neonatal adaptation. Although several potential mechanisms have been proposed, the actual mechanism has not been elucidated. METHODS: We investigated outcomes in neonatal lambs exposed prenatally or postnatally to fluoxetine (FX). Daily FX injections (50 mg) were given intravenously (i.v.) to five pregnant ewes via implanted catheters beginning at 131-132 days gestation (term = 147 days) for 2 weeks. In another group, lambs with implanted vascular catheters had sterile water (n = 9) or FX (1 mg/kg, n = 12) injected i.v. on ~postnatal day (PND) 4. RESULTS: Prenatal FX-exposed lambs (n = 7) were hyperactive during PND 4 to 14 and their heart rate variability (HRV) was significantly lower than in control lambs (n = 7) on PND 2. In contrast, arterial pressure, heart rate, electrocardiogram, arterial blood gases, pH, glucose, lactate, cortisol, and sleep-activity cycles were not altered following postnatal FX injection. CONCLUSION: This abnormal postnatal hyperactivity with antenatal FX exposure may reflect increased maturity in terms of locomotory activity. The results suggest that altered brain development may be involved in the poor neonatal adaptation in human infants exposed to FX in utero.

An in vivo evaluation of the ontogeny of stereoselective fluoxetine metabolism and disposition in lambs from birth to one year of age.

1. The objective was to determine the ontogeny of stereoselective fluoxetine (FX) disposition in postnatal sheep from newborn to adulthood. 2. Catheters were implanted in a carotid artery and jugular vein. FX was administered intravenously, followed by serial arterial blood and cumulative urine collection. The concentrations of R,S-FX and R,S-norfluoxetine (R,S-NFX) in samples were measured using a validated enantioselective LC/MS/MS analytical method. 3. The metabolism of FX at 4.2 ± 0.4 days was limited compared to adults, but had developed compared to the fetus. Total body clearance (ClTB) did not significantly increase up to 33.6 ± 0.9 days, but significantly increased at 98.5 ± 2.0 days, with no further changes up to 397.3 ± 8.5 days. Up to 13.4 ± 0.8 days, the disposition of FX included Phase I metabolism to NFX and trifluoromethylphenol (TFMP), and renal elimination. At 32.9 ± 0.9 days, metabolism included Phase II conjugates of FX and NFX. Renal elimination of these compounds was low. 4. The elimination of FX increased in a non-linear manner during the first year in sheep. The metabolism and disposition of FX and NFX in plasma and urine were stereoselective and this appeared due to both stereoselective protein binding and metabolism.

Variations from morning to afternoon of middle cerebral and umbilical artery blood flow, and fetal heart rate variability, and fetal characteristics in the normally developing fetus.

OBJECTIVE: To determine if there are changes in maternal uterine blood flow, fetal brain blood flow, fetal heart rate variability, and umbilical blood flow between morning (AM) and afternoon (PM) in healthy, uncomplicated pregnancies. STUDY DESIGN: In this prospective study, 68 uncomplicated singleton pregnancies (mean 35 + 0.7 weeks gestation) underwent a standard observational protocol at both 08:00 (AM) and 13:30 (PM) of the same day. This protocol included Doppler measurements of uterine, umbilical, and fetal middle cerebral artery (MCA) volume flow parameters (flow, HR, peak systolic velocity [PSV], PI, and RI) followed by computerized cardiotocography. Standard descriptive statistics, χ2 and t tests were used where appropriate. P < .05 was considered significant. RESULTS: A significant increase in MCA flow and MCA PSV was observed in the PM compared to the AM. This was accompanied by a fall in MCA resistance. Higher umbilical artery resistance indices were also observed in the PM compared to AM. In contrast, fetal heart rate characteristics, maternal uterine artery Doppler flow and resistance indices did not vary significantly between the AM and PM. CONCLUSION: In normal pregnancies, variations in fetal cerebral and umbilical blood flow parameters were observed between AM and PM independent of other fetal movements or baseline fetal heart rate. In contrast, uterine flow parameters remained stable across the day. These findings may have implications for the use of serial Doppler parameters used to guide clinical management in high-risk pregnancies.

A validated assay to quantitate serotonin in lamb plasma using ultrahigh-performance liquid chromatography-tandem mass spectrometry: applications with LC/MS3.

An ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC/MS/MS) method was developed and validated for the quantification of serotonin (5-HT) in lamb plasma using [(2)d(4)]-serotonin ([(2)d(4)]-5-HT) as an internal standard. Charcoal-stripped human plasma was used as the blank matrix during validation, and 5-HT was quantitated using selected reaction monitoring. The UHPLC/MS/MS system consisted of an Agilent 1290 Infinity ultrahigh-performance liquid chromatograph coupled with an AB SCIEX QTRAP(®) 5500 hybrid linear ion trap triple quadrupole mass spectrometer. The method was validated for accuracy, precision, linearity, lower limit of quantification (LLOQ), selectivity, and other parameters. The LLOQ was 1.0 ng/mL, requiring 100 µL of sample. The method was applied to monitor the 5-HT levels in lamb plasma after the administration of fluoxetine. Tandem mass spectrometry cubed (MS(3)) experiments were also performed to investigate the fragmentation pattern of 5-HT and [(2)d(4)]-5-HT. A liquid chromatography-MS(3) (LC/MS(3)) method was developed, and the UHPLC/MS/MS and the LC/MS(3) methods were compared for performance.

Changes in fetal lamb arterial blood gas and acid-base status with advancing gestation.

To determine whether there are changes in blood gas and acid-base status with advancing gestation in the fetal lamb, similar to that reported in the human fetus, blood gas, acid-base, and blood metabolite values were measured in 447 control, arterial blood samples from 108 chronically instrumented fetal lambs between 103 and 146 days gestation. With advancing gestation, Po(2), pH, O(2) saturation, and O(2) content fell significantly, while Pco(2) and hemoglobin concentration increased. Blood glucose and lactate concentrations were unchanged, although the lactate level increased with decreasing Po(2), particularly when below ~13 mmHg. Multiple linear regression indicated that increasing fetal number was associated with decreased Po(2) and glucose level and increased pH, HCO(3)(-), base excess, and lactate concentration. Hemoglobin concentration was higher in female than male lambs. Overall, there was a linear relationship between glucose concentration and birth weight. It is concluded that in fetal lambs as in the human fetus, there are changes in blood gas and acid-base status with advancing gestation. This may be due to the decrease in fetal weight-normalized uterine and umbilical blood flows than occurs in these and other species as gestation proceeds. In addition, the reduced birth weight in twin and triplet lambs may be due to hypoglycemia rather than hypoxemia.

Ontogenesis of phase I hepatic drug metabolic enzymes in sheep.

Cytochrome P450 (CYP) enzymes are important for the metabolism of many drugs. While there is information on their identity and ontogeny in humans and rodents, similar data in sheep are lacking. In the present study, cDNA sequences of several CYP enzymes (CYP2A6, CYP2C19, CYP2D6) were cloned by rapid amplification of cDNA ends. In adult, newborn and fetal sheep the mRNA and protein levels of these CYPs and the regulatory factor, hepatic nuclear factor 4α (HNF4α) were determined in liver samples using real-time PCR and western blotting. The effect of antenatal glucocorticoid on these enzymes was also studied by i.v. infusion of cortisol (0.45 mgh(-1); 80 h) to another group of fetuses. The mRNA and protein levels of the CYPs and HNF4α were low or absent in the fetus, followed by increasing levels in the newborn and adult. Fetal cortisol administration significantly increased the mRNA and protein levels of CYP2D6. Moreover, the correlation observed between the CYP and HNF4α mRNA levels suggests a possible regulatory role for this transcription factor. The findings suggest that fetal and newborn lambs have a low ability to metabolise drugs that are substrates of these enzymes, and that this ability increases with advancing postnatal age, similar to the situation in humans.

Fetal serotonin reuptake inhibitor antidepressant exposure: maternal and fetal factors.

Prenatal serotonin reuptake inhibitor exposure is common and neonatal outcomes vary greatly, often leading to confusion about whether to use or even continue antenatal use of these antidepressants. Importantly, some but not all infants are affected, which raises questions about how maternal drug metabolism contributes to fetal drug exposure. To address this key question, our paper reviews the role of key maternal, fetal, and placental pharmacokinetic, metabolic, and genetic factors that affect the extent of fetal drug exposure. Considering the role of these factors may further our understanding of variables that may assist in optimizing maternal psychopharmacotherapy during pregnancy and neonatal outcomes.

Third trimester fetal heart rate and Doppler middle cerebral artery blood flow velocity characteristics during prenatal selective serotonin reuptake inhibitor exposure.

Prenatal selective serotonin reuptake inhibitor (SSRI) exposure increases the risk for adverse neonatal behavioral outcomes; although it is unknown whether altered brain function is present before birth. We investigated fetal vascular and heart rate changes at 36-wk gestation in SSRI-treated women with mood disorders (n = 29) [exposed (EXP)] and controls (n = 45) [non-EXP (NEXP)]. Fetal middle cerebral artery (MCA) flow parameters and heart rate characteristics were obtained during pre-SSRI dose morning and postdose afternoon sessions. Maternal mood and cord Hb and hematocrit were measured. Basal fetal heart rate (fHR) did not differ between groups or across the day. The fHR short- and long-term variations, accelerations, and duration of high variability episodes remained lower and did not change across the day in EXP, whereas all increased significantly in NEXP. In both groups, MCA flow velocity and volume flow increased significantly across the day. EXP MCA pulsatility index was significantly lower, as was MCA cross-sectional area. EXP cord Hb and hematocrit were significantly increased. Prenatal SSRI exposure reduced fetal MCA flow resistance and fHR variability, before and after an SSRI dose, controlling for maternal mood. These changes and the SSRI-related increased red cell indices suggest possible fetal hypoxia.

Ontogenesis of UDP-glucuronosyltransferase enzymes in sheep.

UDP glucuronosyltransferases (UGTs) are important for the metabolism of many drugs. To understand the ontogeny of these enzymes in sheep (Ovis aries), knowledge of their expression levels at different developmental stages is important. cDNA sequences of six UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A6 and UGT1A9) were cloned in sheep liver by rapid amplification of cDNA ends. The mRNA and protein levels of the enzymes in sheep liver (adult n=4; newborn n=3; fetus n=3) were determined using PCR and Western blots. mRNA levels in adult were very high followed by newborn and then fetus. However, no protein bands were detected on the Western blots of sheep hepatic microsomal proteins using several different antibodies against human UGTs. The effect of antenatal glucocorticoid administration was also studied by infusion of cortisol (0.45mg/h; 80h) to another group of fetuses (n=5). This did not result in any significant changes in fetal mRNA levels. However, the correlation observed between the UGT enzymes and hepatocyte nuclear factor 4α (HNF4α) suggests a possible regulatory role for this transcription factor in sheep. We postulate that fetal and newborn lambs may have a reduced ability to metabolize drugs that are substrates of these enzymes.

Maternal Serotonin Reuptake Inhibitor Antidepressants Have Acute Effects on Fetal Heart Rate Variability in Late Gestation.

Background: Prenatal exposure to serotonin reuptake inhibitor (SRI) antidepressants increases risk for adverse neurodevelopmental outcomes, yet little is known about whether effects are present before birth. In relation to maternal SRI pharmacokinetics, this study investigated chronic and acute effects of prenatal SRI exposure on third-trimester fetal heart rate variability (HRV), while evaluating confounding effects of maternal depressed mood. Methods: At 36-weeks' gestation, cardiotocograph measures of fetal HR and HRV were obtained from 148 pregnant women [four groups: SRI-Depressed (n = 31), SRI-Non-Depressed (n = 18), Depressed (unmedicated; n = 42), and Control (n = 57)] before, and ~5-h after, typical SRI dose. Maternal plasma drug concentrations were quantified at baseline (pre-dose) and four time-points post-dose. Mixed effects modeling investigated group differences between baseline/pre-dose and post-dose fetal HR outcomes. Post hoc analyses investigated sex differences and dose-dependent SRI effects. Results: Maternal SRI plasma concentrations were lowest during the baseline/pre-dose fetal assessment (trough) and increased to a peak at the post-dose assessment; concentration-time curves varied widely between individuals. No group differences in fetal HR or HRV were observed at baseline/pre-dose; however, following maternal SRI dose, short-term HRV decreased in both SRI-exposed fetal groups. In the SRI-Depressed group, these post-dose decreases were displayed by male fetuses, but not females. Further, episodes of high HRV decreased post-dose relative to baseline, but only among SRI-Non-Depressed group fetuses. Higher maternal SRI doses also predicted a greater number of fetal HR decelerations. Fetuses exposed to unmedicated maternal depressed mood did not differ from Controls. Conclusions: Prenatal SRI exposure had acute post-dose effects on fetal HRV in late gestation, which differed depending on maternal mood response to SRI pharmacotherapy. Importantly, fetal SRI effects were sex-specific among mothers with persistent depressive symptoms, as only male fetuses displayed acute HRV decreases. At trough (pre-dose), chronic fetal SRI effects were not identified; however, concurrent changes in maternal SRI plasma levels suggest that fetal drug exposure is inconsistent. Acute SRI-related changes in fetal HRV may reflect a pharmacologic mechanism, a transient impairment in autonomic functioning, or an early adaption to altered serotonergic signaling, which may differ between males and females. Replication is needed to determine significance with postnatal development.

Chronic fetal and maternal instrumentation in pregnant sheep: effect on gestation length and birthweight.

The objective was to compare gestation length in chronically instrumented (laboratory) pregnant sheep (n = 131) and in the breeding flock (n = 476) that provided the experimental sheep. In the breeding flock, gestation length was normally distributed and varied between 141 and 151 days (mean = 147 +/- 0.1 days). In the laboratory sheep, gestation length varied between 128 and 151 days (mean = 142 +/- 1 day), and was bimodal, with 35.9% delivering preterm (<141 days). To examine potential factors that contributed to the preterm birth, a severity score was used, which comprised surgery characteristics, number of experiments and maternal or fetal complications. There was a significant inverse linear relationship (P < 0.001) between the total severity score and gestation length. The median values for the surgical (15 v. 12), overall complication (6 v. 2), maternal complication (2 v. 0) and fetal complication (2 v. 2) components were significantly greater in the preterm compared with the term groups. There was no relationship between fetal number and gestation length in either group. It is concluded that in chronic pregnant sheep preparations, there is a significant incidence of preterm birth and that this is associated with the severity of the surgical intervention and with several maternal and fetal complications.

Hypothalamic-pituitary-adrenal (HPA) axis function in 3-month old infants with prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure.

BACKGROUND: Prenatal exposure to stress and selective serotonin reuptake inhibitors (SSRIs) alter hypothalamic-pituitary-adrenal (HPA) stress reactivity in offspring, however, the effects of combined exposure to HPA activity in human infants is unknown. OBJECTIVE: To examine HPA basal levels and stress responsiveness in 3-month olds with prenatal exposure to SSRIs. METHODS: Salivary cortisol levels in infants of SSRI treated mothers (n=31, mean exposure 230.2+/-72.2 days) were compared with non-SSRI exposed (n=45) infants in response to a challenge (infant-controlled habituation task) and under basal conditions in the late afternoon/early evening. Mode of feeding, to account for possible postnatal drug exposure via breast milk, as well as measures of pre and postnatal maternal mood, were included as covariates. RESULTS: Lower post-stress cortisol levels were observed in non-SSRI exposed/non-breastfed infants compared with non-SSRI exposed infants who were breastfed at 3 months of age. Stress reactivity patterns among SSRI exposed infants did not differ with mode of feeding. The cortisol reactivity slope (CRS) was significantly lower among non-SSRI exposed non-breastfed infants compared with non-SSRI exposed breastfed infants. Early evening basal cortisol levels were lower in SSRI exposed infants than in non-SSRI exposed infants, controlling for maternal mood and mode of feeding. Postnatal SSRI exposure (infant SSRI drug levels) via breast milk was not associated with stress or basal cortisol levels. Total cortisol, reflected by the AUC measure, did not differ significantly between exposure groups. CONCLUSIONS: Prenatal SSRI exposure altered HPA stress response patterns and reduced early evening basal cortisol levels. Stress challenge HPA response differences only became apparent when the moderating effect of method of feeding was accounted for. These findings suggest an early "programming" effect of antenatal maternal mood, prenatal SSRI exposure and postnatal maternal care giving on the HPA system.

Meloxicam effectively inhibits preterm labor uterine contractions in a chronically catheterized pregnant sheep model: impact on fetal blood flow and fetal-maternal physiologic parameters.

OBJECTIVE: Preterm birth occurs in 5% to 10% of all pregnancies and is associated with considerable neonatal mortality and morbidity. Effective and safe drugs to prevent preterm labor are not currently available. We have hypothesized that the nonsteroidal anti-inflammatory drug meloxicam, a more selective cyclooxygenase-2 inhibitor will successfully inhibit labor but avoid the complications associated with inhibition of cyclooxygenase-1. STUDY DESIGN: Preterm labor was induced in chronically catheterized sheep by RU486 administration. Animals were then randomized to receive maternal infusions of saline (n = 5) or meloxicam (n = 4) for 48 hours or until delivery when the animals were killed and tissues and blood samples collected. RESULTS: Maternal infusion of meloxicam inhibited uterine contractions, increasing contraction duration, and attenuating frequency and amplitude. Saline-treated animals progressed to delivery. Administration of meloxicam was not associated with any change in fetal or maternal blood gas status, osmolality, arterial pressure, heart rate, or fetal blood flows. CONCLUSION: Meloxicam may represent a potentially safe and effective tocolytic agent.

Fluoxetine during pregnancy: impact on fetal development.

Women are at greatest risk of suffering from depression during the childbearing years and thus may either become pregnant while taking an antidepressant or may require a prescription for one during pregnancy. The antidepressant fluoxetine (FX) is a selective serotonin reuptake inhibitor (SSRI), which increases serotonin neurotransmission. Serotonin is involved in the regulation of a variety of physiological systems, including the sleep-wake cycle, circadian rhythms and the hypothalamic-pituitary-adrenal axis. Each of these systems also plays an important role in fetal development. Compared with other antidepressant drugs, the SSRIs, such as FX, have fewer side effects. Because of this, they are now frequently prescribed, especially during pregnancy. Clinical studies suggest poor neonatal outcome after exposure to FX in utero. Recent studies in the sheep fetus describe the physiological effects of in utero exposure to FX with an 8 day infusion during late gestation in the sheep. This is a useful model for determining the effects of FX on fetal physiology. The fetus can be studied for weeks in its normal intrauterine environment with serial sampling of blood, thus permitting detailed studies of drug disposition in both mother and fetus combined with monitoring of fetal behavioural state and cardiovascular function. Fluoxetine causes an acute increase in plasma serotonin levels, leading to a transient reduction in uterine blood flow. This, in turn, reduces the delivery of oxygen and nutrients to the fetus, thereby presenting a mechanism for reducing growth and/or eliciting preterm delivery. Moreover, because FX crosses the placenta, the fetus is exposed directly to FX, as well as to the effects of the drug on the mother. Fluoxetine increases high-voltage/non-rapid eye movement behavioural state in the fetus after both acute and chronic exposure and, thus, may interfere with normal fetal neurodevelopment. Fluoxetine also alters hypothalamic function in the adult and increases the magnitude of the prepartum rise in fetal cortisol concentrations in sheep. Fetal FX exposure does not alter fetal circadian rhythms in melatonin or prolactin. Studies of the effects of FX exposure on fetal development in the sheep are important in defining possible physiological mechanisms that explain human clinical studies of birth outcomes after FX exposure. To date, there have been insufficient longer-term follow-up studies in any precocial species of offspring exposed to SSRIs in utero. Thus, further investigation of the long-term consequences of in utero exposure to FX and other SSRIs, as well as the mechanisms involved, are required for a complete understanding of the impact of these agents on development. This should involve studies in both humans and appropriate animal models.

Pharmacologic factors associated with transient neonatal symptoms following prenatal psychotropic medication exposure.

BACKGROUND: Selective serotonin reuptake inhibitor antidepressants (SSRIs) and benzodiazepines are frequently used to treat maternal depression and anxiety disorders during pregnancy. Recent reports suggest that prenatal SSRI exposure is associated with a neonatal discontinuation syndrome. It remains unclear whether these symptoms are directly related to SSRI exposure alone or are due to concurrent pharmacologic factors. Also, this study explores relationships between neonatal outcomes and medication levels during pregnancy, at delivery, and in the newborn period. METHOD: This study sought to compare newborn behavior following second and third trimester exposure to either single-agent SSRIs (group 1) or SSRIs combined with clonazepam (group 2). A prospective cohort of mothers and their infants (N = 46) who had received SSRI medication alone or in combination with clonazepam were studied from June 1996 through June 2000 and compared with a nonexposed control group (N = 23). Infants were assessed in the newborn period for signs suggestive of a "discontinuation syndrome." Maternal drug levels were measured during the pregnancy and at delivery. Infant drug levels from cord blood and at day 2 of life were also obtained. RESULTS: Overall, 30% of the exposed infants (groups 1 and 2, N = 14) showed symptoms of transient poor neonatal adaptation compared with 9% (N = 2) of control infants. In group 1, 25% had symptoms (fluoxetine N = 3; paroxetine N = 3; sertraline N = 1) and in group 2, 39% of infants had symptoms (paroxetine with clonazepam, N = 7). Symptoms were typically mild respiratory distress and, less commonly, hypotonia. Symptoms were self limited and not associated with other neonatal conditions. When paroxetine was combined with clonazepam, infants with symptoms had significantly elevated paroxetine levels when compared with similarly exposed infants without symptoms (p <.05). Among single-agent paroxetine-exposed infants, drug levels did not differ significantly between those with and without symptoms. Maternal dose of clonazepam was significantly higher (p <.05) during pregnancy and at delivery among symptomatic infants compared with nonsymptomatic infants. Developmental outcomes at 2 and 8 months of age did not differ between symptomatic and nonsymptomatic infants. CONCLUSION: While transient neonatal symptoms were found in infants after single-agent prenatal exposure to SSRIs and when paroxetine was combined with clonazepam, the addition of clonazepam appeared to alter paroxetine metabolism, leading to increased drug levels and risk for transient neonatal symptoms. These data highlight the importance of accounting for a variety of pharmacologic factors beyond single-agent SSRI exposure that may lead to poor neonatal adaptation. Further studies are needed with a larger sample of infants to determine the role of clonazepam and whether similar outcomes occur when exposure includes other SSRIs in combination with clonazepam.

Clearance and disposition of indometacin in chronically instrumented fetal lambs following a 3-day continuous intravenous infusion.

Indometacin is used in pregnancy for the treatment of premature labour, but there are limited data on the disposition of the drug in the fetus. In order to elucidate fetal indometacin pharmacokinetics at plasma levels and duration comparable with those occurring with use of the drug for tocolysis in humans, indometacin was administered at doses of 1.9 (low dose, LD; n = 5) or 7.5 (high dose, HD; n = 9) microg min(-1) to steady state over a 3-day period in chronically instrumented fetal lambs. Indometacin concentrations in biological fluid samples were analysed by a sensitive capillary gas chromatography-electron capture detection method. The mean steady-state fetal arterial plasma indometacin concentrations were 68.6+/-16.5 ng mL(-1) in the LD infusion and 230.3+/-28.8 ng mL(-1) in the HD infusion. Indometacin concentrations in amniotic fluid were approximately 10% of those in fetal plasma, and below assay detection limits in tracheal fluid. Total body clearance (TBC) in the LD and HD infusions were not different and the overall mean was 11.3+/-1.2 mL min(-1) kg(-1). In the 11 experiments where paired fetal arterial and umbilical venous samples were collected, the extraction of indometacin across the placenta averaged only 5.2+/-1.1%, indicating low placental permeability to the drug in sheep. However, fetal placental clearance (CLpl) of indometacin (10.0+/-2.5 mL min(-1) kg(-1), n = 10) averaged 115.1+/-41.2% of TBC in these animals and the calculated value for fetal non-placental clearance (0.6+/-2.8 mL min(-1) kg(-1)) was not significantly different from zero. Fetal renal clearance of intact indometacin (3.8+/-1.1 microL min(-1) kg(-1); n = 12) was also very low. However, treatment of fetal urine with glucuronidase indicated the presence of glucuronide conjugates and these comprised 69.9+/-8.2% of the total drug concentration (i.e. intact+conjugated) in urine. Thus, the fetal lamb appears to be able to glucuronidate indometacin, but the contribution of this and other non-placental routes to overall fetal elimination of the drug appear minimal. CLpl of the drug is also low owing to the physicochemical properties of indometacin (high polarity) and the permeability characteristics of the sheep placenta.

Effects of acute moderate hypoxemia on kinetics of metoclopramide and its metabolites in chronically instrumented sheep.

Hypoxemia is known to induce various physiological changes which can result in alteration in drug pharmacokinetics. To examine the effect of acute moderate hypoxemia on metoclopramide (MCP) pharmacokinetics, a continuous 14-hour infusion of MCP during a normoxemic, hypoxemic and subsequent normoxemic period was conducted in eight adult sheep. Arterial blood and urine samples were collected to examine the effects on the pharmacokinetics of MCP and its deethylated metabolites. MCP and its mono- and di-deethylated metabolites were quantitated using a GC/MS method. Steady-state concentrations of MCP were achieved in each of the three periods. During hypoxemia, MCP plasma steady-state concentration increased significantly from 50.72 +/- 1.06 to 63.62 +/- 1.79 ng/mL, and later decreased to 55.83 +/- 1.15 ng/mL during the post-hypoxemic recovery period. Total body clearance (CL(TB)) of MCP was significantly decreased from 274.2 +/- 48.0 L/h to 205.40 +/- 28.2 L/h during hypoxemia, and later restored to 245.8 +/- 44.2 L/h during the post-hypoxemic period. Plasma mono-deethylated MCP concentration (32.78 +/- 1.73 ng/mL) also increased, compared to the control group (21.20 +/- 1.39 ng/mL), during hypoxemia and subsequent normoxemic period. Renal excretion of MCP and its metabolites was also decreased during hypoxemia, while urine flow was increased with a concomitant decrease in urine osmolality. Thus, the results indicate that acute moderate hypoxemia affects MCP pharmacokinetics.

The impact of maternal positive and negative affect on fetal physiology and diurnal patterns.

BACKGROUND: While research has shown that maternal mood (depression and/or anxiety) can have effects on the fetus, little is known about whether maternal positive and negative affect influences the fetus. METHOD: We examined fetal vascular and heart rate changes at 36 weeks gestation in 53 euthymic mothers according to their Positive and Negative Affect Scale (PANAS) scores. RESULTS: Mothers who reported high levels of negative affect showed reduced uterine artery flow, decreased fetal heart rate (fHR) variability, an altered diurnal pattern, and decreased uterine artery cross-sectional area compared to mothers who reported low levels of negative affect. Mothers with low positive affect had a steeper diurnal pattern in fHR accelerations and decreased uterine artery mean velocity flow than mothers with high positive affect. LIMITATIONS: Our observational study suffers from a small sample size. CONCLUSION: Even in the absence of an Axis I Major Depressive Disorder (MDD), variations in maternal affect appear to be associated with variations in fetal and uterine physiology.

Real-time ultrasound assessment of body and breathing movements and abdominal diameter in fetal lambs from 55 days of gestation to term.

We used real-time ultrasound to measure motility and abdominal diameter in fetal lambs at weekly intervals for 30 minutes from 55 days to term (n = 8). Fetal body movement counts/min were relatively constant between 55 and ~90 days and declined progressively thereafter, a relationship best described by piecewise linear regression with 2 elements. The break point in the regression curves averaged 91.9 ± 5.2 days. The relationship between gestational age and abdominal diameter was also best described by piecewise linear regression. The break point of 113.1 ± 3.9 days was significantly greater than the movement break point. There was a significant linear relationship between the movement and abdominal break points, with the latter occurring 21.6 ± 6.6 days later. These results suggest that both fetal motility and growth may decrease in order to lower fetal O2 demands to match the progressive decline in fetal O2 delivery with advancing gestation.

Third trimester fetal pulmonary artery Doppler blood flow velocity characteristics following prenatal selective serotonin reuptake inhibitor (SSRI) exposure.

BACKGROUND: There have been contradictory reports on the risks of persistent pulmonary hypertension (PPHN) in infants exposed to SSRIs in utero. However, there has been no assessment of fetal pulmonary arterial dynamics in such pregnancies. AIMS AND SUBJECTS: To measure fetal right pulmonary artery (RPA) variables using Doppler ultrasound at 36 weeks gestation in fetuses of mothers taking SSRI antidepressants (n=23) and in a control, normal pregnancy group (n=35). OUTCOME MEASURES: At 36 weeks gestation, Doppler ultrasound estimates of Pulsatility Index (PI), Resistance Index (RI), vessel diameter, peak systolic velocity, mean velocity and volume flow were obtained from the fetal right pulmonary artery in a morning session (~0830), before the SSRI mothers took their daily drug dose and in an afternoon session (~1300). Venous blood was drawn at 5 time points across the day (~08:30AM, ~10:30AM, ~13:00PM, ~13:45PM, and ~15:00PM) from the SSRI treated mothers for measurement of plasma SSRI concentration using high performance liquid chromatography tandem mass spectrometry. RESULTS: There were no differences in the RPA Doppler measures between the control and SSRI-exposed fetuses. However 8 of the 23 latter fetuses experience transient respiratory difficulties at birth and, in these RPA flow was significantly higher than in the SSR-exposed fetuses without respiratory problems. There were, however, no differences in RPA PI and RI between the 2 groups. CONCLUSIONS: In SSRI-exposed infants with transient postnatal respiratory difficulties, fetal RPA flow in increased, likely due to partial constriction of the ductus arteriosus. However, this was not associated with PPHN.