A pilot study of newer antidepressant concentrations in cord and maternal serum and possible effects in the neonate

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1 International Journal of Neuropsychopharmacology (2004), 7, Copyright f 2004 CINP DOI: /S A pilot study of newer antidepressant concentrations in cord and maternal serum and possible effects in the neonate BRIEF REPORT Jonathan Rampono 1, Stephen Proud 1, L. Peter Hackett 2, Judith H. Kristensen 3 and Kenneth F. Ilett 2,4 1 Department of Psychological Medicine, Women s and Children s Health Service Subiaco, WA, Australia 2 Clinical Pharmacology & Toxicology, The Western Australian Centre for Pathology & Medical Research, Nedlands, WA, Australia 3 Department of Pharmacy, Women s and Children s Health Service Subiaco, WA, Australia 4 Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia Abstract Antidepressants are often used antenatally, and placental transfer may lead to adverse effects (toxicity) in the neonate. Pregnant women taking fluoxetine (n=4), sertraline (n=4), paroxetine (n=2) or venlafaxine (n=1) in the last trimester were studied. Maternal and cord sera were collected at delivery and infant serum on day 5 after birth for measurement of antidepressant concentrations. Neonatal Abstinence Scores (NAS) were measured in the infants on days 1 3 after birth. In maternal serum, median drug concentrations were: fluoxetine (96 mg/l), norfluoxetine (110 mg/l), sertraline (11 mg/l), desmethylsertraline (38 mg/l), paroxetine (mean 12 mg/l), venlafaxine (220 mg/l), and O-desmethylvenlafaxine (392 mg/l). Corresponding median values in cord serum were: fluoxetine (65 mg/l), norfluoxetine (81 mg/l), sertraline (10 mg/l), desmethylsertraline (27 mg/l), paroxetine (mean 6 mg/l), venlafaxine (232 mg/l), and O-desmethylvenlafaxine (406 mg/l). Corresponding median cord:maternal concentration ratios were 0.67 for fluoxetine and 0.72 for norfluoxetine, 0.67 for sertraline and 0.63 for desmethylsertraline, 0.52 (mean) for paroxetine, and 1.1 and 1.0 for venlafaxine and O-desmethylvenlafaxine respectively. The neonates of two patients taking fluoxetine had high NAS. Only fluoxetine and norfluoxetine were detected in infant serum. Our data show substantial placental transfer of antidepressants, but only fluoxetine persisted in the infant s serum. Neonatal toxicity may be associated with serotonin re-uptake blockade, and also be influenced by neonatal clearance. Received 5 May 2003; Reviewed 12 June 2003; Revised 12 November 2003; Accepted 16 November 2003 Key words: Antidepressants, neonatal intolerance, neonatal toxicity, neonate, pregnancy. Introduction Postnatal depression is a well-recognized entity (Cox et al., 1993). The use of antidepressants as part of the management of postnatal depression and the subsequent exposure of the breastfed infant to antidepressant medication has been well documented (Hale and Ilett, 2002). More recently, the prevalence of antenatal depression has been noted (Evans et al., 2001), and antidepressant medication may be part of the recommended management of a significant number of women suffering depression in the antenatal period. Address for correspondence: Dr J. Rampono, Department of Psychological Medicine, King Edward Memorial Hospital, Bagot Road, Subiaco, 6008, WA, Australia. Tel.: Fax: Jonathan.Rampono@health.wa.gov.au Many women in this situation are concerned about the possibility of the antidepressant medication crossing the placenta and about any short-term and long-term effects of that exposure on their children. In relation to the latter, in-utero exposure to either fluoxetine (Nulman et al., 1997, 2002) or dothiepin (Buist and Janson, 1995) showed no detectable effects on development in children aged up to 6 yr, although fluoxetine has been found to decrease weight gain between ages 2 and 6 months (Chambers et al., 1999) and is also associated with low birth weight (Hendrick et al., 2003a). The transfer of most drugs across the placenta is substantial (Mihaly and Morgan, 1983) but quantitative data for the newer antidepressants are sparse (Hendrick et al., 2003b; Hostetter et al., 2000). Various short-term adverse effects often describing symptoms of a neonatal withdrawal or intolerance syndrome

2 330 J. Rampono et al. have previously been reported for fluoxetine (Chambers et al., 1996; Lester et al., 1993; Mhanna et al., 1997; Mohan and Moore, 2000; Spencer and Escondido, 1993). More recently symptoms of a neonatal discontinuation syndrome have also been reported for paroxetine (Bhatt and Coombs, 2001; Costei et al., 2002; Dahl et al., 1997; Nijhuis et al., 2001) and paroxetine/ desipramine (Stiskal et al., 2001). It is interesting to note that the neonatal syndrome seen after maternal use of paroxetine, and presumably also after use of related selective serotonin reuptake inhibitors may be more appropriately classified as neonatal serotonin toxicity (Isbister et al., 2001). The present pilot study was aimed at investigating the possible relationship between the extent of neonatal antidepressant exposure in utero, and neonatal well-being in the first few days after birth. Measurement of antidepressants Fluoxetine, norfluoxetine, paroxetine, sertraline, desmethylsertraline, venlafaxine and O-desmethylvenlafaxine in serum were measured by validated high performance liquid chromatographic methods from our laboratory (Begg et al., 1999; Ilett et al., 1998; Kristensen et al., 1998, 1999). Using 1 ml of plasma (available for all maternal and cord samples), the limits of quantitation (LOQ) and detection (LOD) respectively for the assays were: fluoxetine (1.5 and 0.5 mg/l), norfluoxetine (2.3 and 0.5 mg/l), paroxetine (1.0 and 0.5 mg/l), sertraline (1.5 and 0.5 mg/l), N-desmethylsertraline (1.0 and 0.5 mg/l), venlafaxine (5 and 1.5 mg/l), O-desmethylvenlafaxine (2.5 and 1 mg/l). Effective LOQ or LOD values for the day-5 neonatal samples were derived by dividing the usual assay sensitivity by the volume of the infant sample. Methods Patients and procedures Thirteen women were recruited into the study. All were taking antidepressants in their third trimester for at least 4 wk before delivery and had clinically established steady-state concentrations prior to delivery. Inclusion criteria required only that informed consent be given. Exclusion criteria included pre-eclampsia, or diabetes or chronic use of other psychoactive drugs including methadone, and benzodiazepines other than temazepam. Patient age, weight, smoking status, and current medication history, as well as infant birth weight and gestational age were recorded. Maternal venous blood serum for antidepressant assay was obtained by the mid-wife in the delivery suite during the first stage of labour, while cord venous blood serum was obtained soon after delivery on day 1. Neonatal well-being was determined by measuring gestation age, birth weight and Apgar scores after birth (Apgar, 1953). The Neonatal Abstinence Score (Finnegan et al., 1975) (NAS; average of 3 4 daily scores; zero score indicates no adverse effects, while the maximum possible score is approximately 42) was also recorded for each neonate, on each of the first three days postpartum. Infant blood serum was collected by heel prick sampling on day 5 (at the same time as the Guthrie test sample was taken) to enable measurement of antidepressant concentration. The study was approved by the Ethics Committee of Princess Margaret and King Edward Memorial Hospitals and written informed consent was obtained from all patients and also from their partners where possible. Data analysis Data have been summarized as mean (range) or median (25th and 75th percentile range) as appropriate. Results Thirteen women were recruited into the study. However, in two cases, the neonate had to be admitted to the special care nursery immediately after birth (caesarian section for placenta praevia and low birth weight), and infant samples could not be obtained. These two were excluded from the study group, leaving 11 women with a mean age of 29 yr (range yr), and their 12 neonates. The mean gestational age of the neonates was 38 wk (range wk) and their mean birth weight was 2.88 kg (range kg). Antidepressant therapy included four women taking fluoxetine (median 20 mg/d, range mg/d), four taking sertraline (all 50 mg/d), two taking paroxetine (both 20 mg/d) and one taking venlafaxine (150 mg/d). Two of the women taking fluoxetine were smokers, while all of the others were non-smokers. Antidepressant concentrations in the maternal and cord sera at birth are summarized in Table 1. The median cord: maternal concentration ratios were 0.67 ( ; 25th and 75th percentile range) for fluoxetine, 0.72 ( ) for norfluoxetine, 0.67 ( ) for sertraline and 0.63 ( ) for desmethylsertraline. Cord: maternal concentration ratios for the two patients taking paroxetine were 0.5 and 0.54, and 1.1 and 1.0 for venlafaxine and O-desmethylvenlafaxine respectively in one patient.

3 Newer antidepressant effect in the neonate 331 Table 1. Antidepressant concentrations in maternal and cord serum and cord: maternal concentration ratio Table 2. Fluoxetine and norfluoxetine in cord venous serum at birth (day 1) and neonate venous serum (day 5) Patient no. Drug (metabolite) Maternal Cord Ratio 1 Fluoxetine (Norfluoxetine) Fluoxetine (Norfluoxetine) Fluoxetine (Norfluoxetine) Fluoxetine (Norfluoxetine) Sertraline (Desmethylsertraline) Sertraline (Desmethylsertraline) Sertraline (Desmethylsertraline) Sertraline (Desmethylsertraline) Paroxetine 13 a a n.d. b n.d. b 10 Paroxetine Venlafaxine (O-Desmethylvenlafaxine) a Non-identical twins. b n.d., Cord serum sample too small to enable paroxetine measurement. The 5-min Apgar scores were 9, 9, 9 and 10 respectively for neonates whose mothers were taking fluoxetine, 9, 9, 9 and 7 respectively for neonates whose mothers were taking sertraline, 9, 9 and 8 for respectively for neonates whose mothers were taking paroxetine, and 9 for the one neonate whose mother was taking venlafaxine. For the neonates of two of the four patients taking fluoxetine (patient nos. 2 and 4), NAS were 7 on day 1 and 8, 5 and 5 on days 1, 2 and 3 respectively. For one neonate whose mother was taking sertraline, a NAS of 1 was recorded on day 3, while for another neonate whose mother was taking paroxetine, NAS of 6, 3 and 2 were recorded on days 1, 2 and 3 respectively. However, in this latter neonate (one of twins), hypothermia and hypoglycaemia were also present on day 1. NAS values for the remaining seven infants were zero at all observation times. Concentrations of fluoxetine in the cord venous serum at birth and in serum collected on day 5 (available volumes: neonate 1, no data available; neonate 2, 0.75 ml; neonate 3, ml; neonate 4, ml) are summarized in Table 2. Day 5 serum sertraline and Neonate of patient number desmethylsertraline (available volumes: neonate 5, no data available; neonate 6, 0.05 ml; neonate 7, ml; neonate 8, 0.2 ml), paroxetine (available volumes: neonate 9, 0.2 ml; neonate 10, ml), venlafaxine (available volume: neonate 11, 0.1 ml) and O-desmethylvenlafaxine were below the respective assay LODs day 5. These volumes respectively translate to effective LODs of 1, 2 and 4 mg/l for both fluoxetine and norfluoxetine (neonates 2 4), 10, 2 and 2.5 mg/l for both sertraline and N-desmethylsertraline (neonates 6 8), 2.5 and 7 mg/l for paroxetine (infants 9 and 10), 15 mg/l for venlafaxine and 10 mg/l for O- desmethylvenlafaxine (infant 11). Discussion Serum fluoxetine Serum norfluoxetine Cord Day 5 Cord Day n.d. a 8 n.d. a a n.d., No data available. Our data show that there is very significant in-utero exposure to all drugs tested, with cord: maternal serum ratios being 0.52 (mean) for paroxetine, 0.67 (median) for sertraline, 0.63 (median) for N- desmethylsertraline, 0.67 (median) for fluoxetine, 0.72 (median) for norfluoxetine, 1.1 (single case) venlafaxine and 1 (single case) for O-desmethylvenlafaxine. One study has reported mean cord blood: maternal serum ratios for sertraline (0.77) and desmethylsertraline (0.47) but much higher ratios for venlafaxine (1.7) and O-desmethylvenlafaxine (3.24) (Hostetter et al., 2000), while another recently reported median values of 0.56 for paroxetine, 0.27 for sertraline, 0.25 for N- desmethylsertraline, 0.54 for fluoxetine, and 0.6 for norfluoxetine (Hendrick et al., 2003b). As in the two previous studies, we also noted considerable interindividual variability in cord: maternal drug concentration ratios. In our study only fluoxetine and its nor-metabolite were measurable in the infant s blood on day 5, some 96 h after birth. When considered in the light of high cord serum concentrations (232 mg/l for venlafaxine

4 332 J. Rampono et al. and 406 mg/l for O-desmethylvenlafaxine), the effective LODs of 15 mg/l for venlafaxine and 10 mg/l for O-desmethylvenlafaxine in the infant day-5 serum suggest that the neonate we studied had significant ability to clear both of these drugs. However, our ability to detect sertraline, N-desmethylsertraline and paroxetine was constrained by low cord drug concentrations, and also by the effective LOD that could be achieved for the day-5 infant serum sample (10, 2 and 2.5 mg/l for sertraline and N-desmethylsertraline, and 2.5 and 7 mg/l for paroxetine). Previous studies in older breastfed infants whose mothers took paroxetine or sertraline have not detected paroxetine (LOQs of 1 2 mg/l) (Begg et al., 1999; Mammen et al., 1997), or have reported low or undetectable concentrations of sertraline and/or N- desmethylsertraline (LOQs of 1 5 mg/l) (Kristensen et al., 1998; Misri et al., 2000; Stowe et al., 1997). Similarly, previously published data from 10 breastfed infants whose mothers took venlafaxine did not detect venlafaxine in infant plasma (LOD 1.5 mg/l), while O-desmethylvenlafaxine (range mg/l) was detected in seven of these infants (Ilett et al., 1998, 2002). Hence, in our present study, we cannot rule out a minor contribution to infant day-5 plasma drug concentrations from breastfeeding. Nevertheless, this is unlikely to be significant given the generally low infant exposure during breastfeeding, and the fact that the infant samples were taken on day 5, only 2 d after initiation of lactation and breastfeeding. There is often confusion over the attribution of adverse effects in very young infants to drugs acquired through placental transfer and that from transfer through breast milk (Anonymous, 2003). Data from our present study and other recent studies (Hendrick et al., 2003b; Hostetter et al., 2000) clearly demonstrate that placental transfer of antidepressants is at least an order of magnitude greater than that from breast milk (Begg et al., 1999; Ilett et al., 2002; Kristensen et al., 1998, 1999; Mammen et al., 1997; Misri et al., 2000; Stowe et al., 1997, 2000; Wisner et al., 1998), and is therefore most influential in adverse events occurring the first 1 2 wk after birth. Apgar scores in our study were generally good to excellent for all of the neonates. Mildly increased NAS were seen early after birth in 2 of the 4 neonates whose mothers were taking fluoxetine, in one of the twins of a mother who was taking paroxetine, but in none of the neonates whose mothers took sertraline or venlafaxine. Symptoms of neonatal serotonin toxicity were not obviously connected to the extent of drug exposure in cord serum or its persistence in the infant s serum on day 5. For example, fluoxetine and norfluoxetine were present in all four infants at day 5, while only two had symptoms. These findings appear to be different from the withdrawal symptoms seen in methadoneexposed neonates, where severity of the syndrome is greatest at higher maternal dose exposure (Malpas et al., 1995), and typically starts 2 or more days after birth (Zelson et al., 1973). Our findings with fluoxetine generally support previous case reports of short-term adverse effects (Lester et al., 1993; Mhanna et al., 1997; Mohan and Moore, 2000; Spencer and Escondido, 1993). In the three neonates (including one pair of twins) whose mothers took paroxetine an elevated NAS was seen only in one of the twins. Since the other twin was also exposed to the drug but had a zero NAS, other factors (hypothermia and hypoglycaemia) are presumed to have been causative. Thus for paroxetine, our two cases do not mirror the plethora of previous case reports of adverse effects (Bhatt and Coombs, 2001; Dahl et al., 1997; Nijhuis et al., 2001; Stiskal et al., 2001), or a recent study (n=55) (Costei et al., 2002) in which 22% of neonates had adverse effects. However, in considering our results, the small sample size is undoubtedly an important limiting factor. In summary, from our limited data-set we hypothesize that low clearance of antidepressants may predispose to short-term neonatal serotonin toxicity that has variously been described as neonatal intolerance or withdrawal syndrome, or neonatal discontinuation syndrome. Since treatment of maternal anxiety and depression during pregnancy is beneficial for the long-term behavioural and emotional development of the child (O Connor et al., 2002), our hypothesis is worthy of further study in a larger population. 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