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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. 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. 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. 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.

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, Po2, pH, O2saturation, and O2content fell significantly, while Pco2and hemoglobin concentration increased. Blood glucose and lactate concentrations were unchanged, although the lactate level increased with decreasing Po2, particularly when below ∼13 mmHg. Multiple linear regression indicated that increasing fetal number was associated with decreased Po2and glucose level and increased pH, HCO3−, 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.

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.

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.To examine HPA basal levels and stress responsiveness in 3-month olds with prenatal exposure to SSRIs.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.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.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.

Aims To compare the disposition of fluoxetine and norfluoxetine enanantiomers in the mother, foetus and infant. Methods Blood from pregnant women taking fluoxetine (n = 9), during pregnancy was sampled in the third trimester and at delivery (maternal and cord venous blood), and from the infants 48 h after delivery. The subset of these women who were breastfeeding, plus additional subjects recruited in the postpartum period, were studied further, and maternal and infant blood, and breast milk was sampled between 6 days and 11 months (n = 23). Drug and metabolite concentrations were measured using gas chromatography/mass spectrometry or liquid chromatography, tandem mass spectrometry. Results There was a high correlation between maternal and foetal (cord blood) fluoxetine and norfluoxetine enantiomers (r2−0.9), the mean foetal/maternal ratios (95% confidence intervals) being 0.91 (0.61, 1.02) and 1.04 (0.93, 1.05), for fluoxetine and norfluoxetine, respectively. In 2 day old infants exposed to the drug in utero, the fluoxetine and norfluoxetine plasma concentrations were the same as in cord blood at delivery. Over the next 2 months, the plasma concentrations in the infants fell progressively. Stereoselective disposition of both the drug and metabolite in the mother, foetus, infant and breast milk was observed. The S : R ratios in the foetus and newborn (∼3) were significantly higher than in the serum (∼2) or breast milk (∼1.9) of the mothers, resulting in greater exposure of the foetus and infants to the biologically active enantiomers, particularly S-norfluoxetine. Conclusions Foetal and infant exposure to fluoxetine and norfluoxetine is enhanced by their stereoselective disposition in the mother, foetus, breast milk and infant. Increased exposure may also result from decreased metabolism of the drug in the foetus and neonate.

Depression during pregnancy is frequently treated with the selective serotonin reuptake inhibitor, fluoxetine (FX). FX increases serotonergic neurotransmission and serotonin plays a role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. We have therefore investigated the effect of chronic administration of FX to the pregnant ewe on the maternal and fetal HPA axes. Nineteen late-gestation sheep were surgically prepared for chronic study of the fetus. FX (n = 7, 98.5 microg/kg/d) or sterile water (control, n = 8) was administered to the ewe for 8 d by constant rate i.v. infusion with an initial FX bolus dose of 70 mg. Maternal and fetal plasma ACTH and cortisol concentrations were determined at 0700 h each day. Maternal plasma ACTH concentrations fell on infusion d 2, but no changes were observed in maternal plasma cortisol concentrations. Fetal plasma ACTH concentrations increased on infusion d 7, and fetal plasma cortisol concentrations increased on infusion d 6, 7, and 8 in the FX group. In addition, the regression coefficient for the relationship between fetal ACTH and cortisol levels was significantly greater in the FX group compared with the control group. Thus, maternal FX treatment increased fetal plasma cortisol concentration. These results are of particular interest in the context that exposure of the fetus to excess glucocorticoids at critical windows during development has been shown to increase the risk of poor health outcomes in later life.

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) μg 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 ∼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 μL 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.

Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines are frequently used to treat maternal depression during pregnancy, however the effect of increased serotonin (5HT) and gamma-amino-butyric acid (GABA) agonists in the fetal human brain remains unknown. 5HT and GABA are active during fetal neurologic growth and play early roles in pain modulation, therefore, if prolonged prenatal exposure alters neurodevelopment this may become evident in altered neonatal pain responses. To examine biologic and behavioral effects of prenatal exposure, neonatal responses to acute pain (phenylketonuria heel lance) in infants with prolonged prenatal exposure were examined. Facial action (Neonatal Facial Coding System) and cardiac autonomic reactivity derived from the relationship between respiratory activity and short term variations of heart rate (HRV) were compared between 22 infants with SSRI exposure (SE) [fluoxetine (n = 7), paroxetine (n = 11), sertraline (n = 4)]; 16 infants exposed to SSRIs and clonazepam (SE+) [paroxetine (n = 14), fluoxetine (n = 2)]; and 23 nonexposed infants during baseline, lance, and recovery periods of a heel lance. Length of maternal SSRI use did not vary significantly between exposure groups-[mean (range)] SE:SE+ 183 (31-281):141 (54-282) d (p > 0.05). Infants exposed to SE and SE+ displayed significantly less facial activity to heel lance than control infants. Mean HR increased with lance, but was significantly lower in SE infants during recovery. Using measures of HRV and the transfer relationship between heart rate and respiration, SSRI infants had a greater return of parasympathetic cardiac modulation in the recovery period, whereas a sustained sympathetic response continued in the control group. Prolonged prenatal SSRI exposure appears to be associated with reduced behavioral pain responses and increased parasympathetic cardiac modulation in recovery following an acute neonatal noxious event. Possible 5HT-mediated pain inhibition, pharmacologic factors and the developmental course remain to be studied.

Term and preterm labor are associated with increased fetal hypothalamic-pituitary-adrenal (HPA) activation and synthesis of prostaglandins (PGs) generated through the increased expression of prostaglandin H synthase-II (PGHS-II) in the placenta. Inhibition of PGHS-II has been advocated as a means of producing uterine tocolysis, but the effects of such treatment on fetal endocrine functions have not been thoroughly examined. Because PGE 2 is known to activate the fetal HPA axis, we hypothesized that administration of meloxicam, a PGHS-II inhibitor, to sheep in induced labor would suppress fetal HPA function. Chronically catheterized pregnant ewes were treated with RU486, a progesterone receptor antagonist, to produce active labor, and then treated with either high-maintenance-dose meloxicam, graded-maintenance-dose meloxicam, or a saline infusion. Maternal uterine contraction frequency increased 24 h after the RU486 injection and the animals were in active labor by 48 6 4 h. RU486 injection led to increased concentrations of PGE 2, ACTH, and cortisol in the fetal circulation, and increased concentrations of 13,14 dihydro 15-ketoprostaglandin F2a (PGFM) in the maternal circulation. Uterine activity was inhibited within 12 h of beginning meloxicam infusion at both infusion regimes. During meloxicam infusion there were significant decreases in fetal plasma PGE 2, ACTH, and cortisol concentrations, and PGFM concentrations in maternal plasma. In control animals, frequency of uterine contractions, maternal plasma PGFM, fetal plasma PGE 2, ACTH, and cortisol concentrations increased after RU486 administration, and continued to rise during saline infusion until delivery occurred. We conclude that RU486-provoked labor in sheep is associated with activation of fetal HPA function, and that this is attenuated during meloxicam treatment to a level considered compatible with pregnancy maintenance. ACTH, cortisol, parturition

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.

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.

Clinical depression, diagnosed in 5–15% of women during pregnancy, increases the risk of negative pregnancy outcomes including an increased incidence of low birth weight newborns and preterm delivery. Fluoxetine, a selective serotonin reuptake inhibitor, is often prescribed to treat depression due to its efficacy, high margin of safety, and mild side effects. However, fluoxetine initially increases plasma serotonin concentration, and serotonin causes uterine vasoconstriction in sheep, which could result in fetal hypoxemia. To assess fetal fluoxetine effects, late-gestation pregnant sheep were surgically prepared for the measurement of blood gases, heart rate, blood pressure, and uterine artery blood flow (n = 29). Ewes received a 70-mg bolus i.v. infusion of fluoxetine over 2 min in 10 mL of sterile water followed by continuous infusion at a rate of 100 μg/min for 8 d (n = 14), or continuous infusion of sterile water (n = 15). Transient decreases in uterine artery blood flow, fetal Po2, and oxygen saturation were observed within the first 15 min after fluoxetine exposure, which did not return to normal values by 24 h. Fetal pH decreased and Pco2 increased over the first 4 h with a return to normal by 24 h. However, there were no differences in uterine artery blood flow, blood gas status, or cardiovascular measures between the control and fluoxetine group over the rest of the 8-d infusion period. Thus, fluoxetine exposure during pregnancy has transient effects on fetal status that may be of developmental consequence if they occur repetitively.

The kinetics of metoclopramide and the effects of haemodialysis on metoclopramide kinetics were examined in eight uraemic subjects 1 h and 24 h prior to the onset of dialysis. In spite of the relatively minor contribution of renal clearance to total body clearance in normals, metoclopramide kinetics were substantially altered in uraemia. The total body clearance was decreased by 2-4 fold, terminal elimination half-life proportionately increased, while the volume of distribution appeared to be unaffected compared with that previously demonstrated in normal healthy subjects. Haemodialysis does not appear to be effective in removing metoclopramide from the body and metoclopramide clearance subsequent to dialysis is unaltered. The kinetic parameters in the uraemic subjects are not significantly different between drug administrations 1 or 24 h prior to the time of onset of haemodialysis. Following kidney transplantation, in one subject, there appeared to be a rapid return to apparently normal kinetics from the uraemic state.

The disposition of metoclopramide was studied on a four-way crossover basis in six healthy non-smoking volunteers. The linearity of kinetic parameters and absolute bioavailability of metoclopramide were examined. In contrast to previous reports, metoclopramide obeyed linear kinetics over oral doses ranging from 5 to 20 mg. The absolute bioavailability of metoclopramide was 0.76 +/- 0.38 (mean +/- s.d.) from the oral dosage forms examined in this study.

Twenty-three patients undergoing general anaesthesia for Caesarian section for healthy term pregnancies were entered into a double blind study using metoclopramide (MCP) and a normal saline placebo. Of these patients, eight received intravenous metoclopramide, 12 a normal saline placebo and three were lost to clinical follow-up. The maternal gastric volumes were measured and maternal and foetal MCP plasma concentrations were determined by gas-liquid chromatography. The Neurological and Adaptive Capacity Score tests of Amiel, Barrier and Schnider (NACS) were used to attempt evaluation of neonatal responses to MCP. Maternal gastric volume was significantly lower (p less than 0.05) in the treated patients. There were no marked differences in Apgar scores, cardiovascular parameters or neurobehavioural scores between the treated and untreated groups of neonates. At no time were the foetal metoclopramide plasma concentrations observed to exceed maternal values.