- Email: [email protected]
Sertraline in pregnancy – Therapeutic drug monitoring in maternal blood, amniotic fluid and cord blood
Author’s Accepted Manuscript Sertraline in Pregnancy – Therapeutic Drug Monitoring in Maternal Blood, Amniotic Fluid and Cord Blood Michael Paulzen, Tamme W. Goecke, Elmar Stickeler, Gerhard Gründer, Georgios Schoretsanitis www.elsevier.com/locate/jad
PII: DOI: Reference:
S0165-0327(16)31935-8 http://dx.doi.org/10.1016/j.jad.2017.01.019 JAD8739
To appear in: Journal of Affective Disorders Received date: 18 October 2016 Revised date: 16 January 2017 Accepted date: 19 January 2017 Cite this article as: Michael Paulzen, Tamme W. Goecke, Elmar Stickeler, Gerhard Gründer and Georgios Schoretsanitis, Sertraline in Pregnancy – Therapeutic Drug Monitoring in Maternal Blood, Amniotic Fluid and Cord B l o o d , Journal of Affective Disorders, http://dx.doi.org/10.1016/j.jad.2017.01.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Sertraline in Pregnancy – Therapeutic Drug Monitoring in Maternal Blood, Amniotic Fluid and Cord Blood
Michael Paulzen, MD; Tamme W. Goecke, MD; Elmar Stickeler, MD; Gerhard Gründer, MD; and Georgios Schoretsanitis, MD.
Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany, and JARA – Translational Brain Medicine: MP, GG, GS
University Hospital of Psychiatry, Bern, Switzerland: GS
Department of Gynecology and Obstetrics, RWTH Aachen University: TWG, ES
Corresponding author: Michael Paulzen, MD Department of Psychiatry, Psychotherapy and Psychosomatics and JARA – Translational Brain Medicine RWTH Aachen University Pauwelsstr. 30 52074 Aachen, Germany Phone: +49-241-80-89508 Fax: +49-241-80-82401 Email: [email protected]
a) Running title page sertraline in pregnancy
b) The number of text pages, number of tables, figures, and references, and the number of words in the Abstract, Introduction, and Discussion number of text pages: 11 (double-spaced) number of tables: 1 number of figures: 1 number of references: 44 number of words in the abstract: 278 number of words in the introduction: 928 (including references); number of words in the materials and methods section: 592 (including references); number of words in the results section: 434 (including references); number of words in the discussion: 1,038 (including references and limitations); number of words in the manuscript: 2,992 (including headings and references)
Declaration of interests Gerhard Gründer has served as a consultant for Boehringer Ingelheim (Ingelheim, Germany), Cheplapharm (Greifswald, Germany), Eli Lilly (Indianapolis, Ind, USA), Lundbeck (Copenhagen, Denmark), Ono Pharmaceuticals (Osaka, Japan), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Eli Lilly, Gedeon Richter (Budapest, Hungary), Janssen Cilag (Neuss, Germany), Lundbeck, Roche, Servier, and Trommsdorf (Aachen, Germany). He has received grant support from Boehringer Ingelheim and Roche. He
II
is co-founder of Pharma Image GmbH (Düsseldorf, Germany) and Brainfoods UG (Selfkant, Germany). He reports no conflict of interest with this publication. Georgios Schoretsanitis received a grant from the bequest "in memory of Maria Zaoussi”, State Scholarships Foundation, Greece for clinical research in Psychiatry for the academic year 2015-2016. All other authors declare no conflicts of interest as well. The research study did not receive funds or support from any source.
III
Abstract Rationale: This study is the first to measure and correlate sertraline concentrations in maternal blood, amniotic fluid and umbilical cord blood and account for distribution of the drug between these three compartments. Methods: Concentrations of sertraline were measured in six mother infant pairs at the time of delivery. Data are provided as median values, first and third quartiles as well as ranges. To account for the penetration ratio into amniotic fluid and cord blood, the concentration of sertraline in both environments was divided by the concentration in maternal serum. Daily doses were correlated with maternal serum- and umbilical cord blood-concentrations, and serum levels were correlated with levels in amniotic fluid. Results: The median daily dose of sertraline was 75 mg (Q1: 43.75 mg, Q3: 100 mg; range 25100 mg). Amniotic fluid concentrations of sertraline strongly correlated with the daily dose (r=0.833, p=0.039) while neither maternal serum concentrations nor cord blood concentrations correlated with the daily dose (p>0.05). The median penetration ratio for sertraline into amniotic fluid was 0.57 (Q1: 0.28, Q3: 0.75; range: 0.22-0.88). The median penetration ratio into the fetal circulation, calculated on the basis of umbilical cord bloodconcentrations, was found to be 0.36 (Q1: 0.28, Q3: 0.49; range: 0.17-0.65). Conclusions: Sertraline concentrations in amniotic fluid gave evidence that maternally administered sertraline is constantly accessible to the fetus via amniotic fluid in a manner not previously appreciated. A relatively low penetration into fetal circulation may contribute to a sufficient safety profile of sertraline during pregnancy although in our study APGAR Scores were relatively low in three infants. Our data support the important role of
IV
therapeutic drug monitoring in maintaining the safety of pregnant women and exposed infants. Keywords:
pregnancy;
depression;
antidepressants;
sertraline;
therapeutic drug monitoring; amniotic fluid; cord blood; placental transfer
V
pharmacokinetics;
Paulzen et al.
Sertraline in Pregnancy
Introduction Extensive data regarding the safety of selective serotonin reuptake inhibitors (SSRI) provide minimal absolute risk rates, so that SSRIs are suggested as a first line medication for antenatal depression (Ram and Gandotra, 2015). A recent bayesian analysis of an enormous sample reassured the safety of the prescription of SSRIs in pregnancy with the exceptions of paroxetine and fluoxetine (Reefhuis et al., 2015). Despite a high prevalence of depressive disorders during pregnancy and the increasing use of antidepressant drugs during pregnancy over the last years (Jimenez-Solem, 2014; Kallen et al., 2013; Thomas and Yates, 2012), there is still a lack of clinical data regarding safety of these drugs for both, pregnant women and unborn children. Furthermore, evidence supporting prescription strategies of psychotropic agents during pregnancy remains inconclusive (Schaefer, 2011). Accordingly, to enhance both, safety and efficacy of antidepressant drug treatment during pregnancy there is a need for more comprehensive data on the short- and log-term effects of antidepressant exposure during pregnancy. Apart from possible drug-associated effects on pregnant women and their infants, pregnancy outcomes and clinical decision-making processes are also affected by the natural course of the untreated psychiatric diseases. Due to methodological limitations of relevant studies, data investigating the risks of untreated depression on both, the expectant mothers and their infants remain sparse and rather unclear. However, adverse perinatal effects such as intrauterine growth retardation (Grote et al., 2010; Henrichs et al., 2010; Uguz et al., 2011), increased preterm delivery (Dayan et al., 2006; Diego et al., 2009) or low birth weight (Diego et al., 2009) have been reported. Furthermore, children of mothers with untreated or inadequately treated psychiatric diseases such as depression or psychosis might be at risk of future psychopathology (Nulman et al., 2012) or even at risk for maternal suicidal behaviour 1
Paulzen et al.
Sertraline in Pregnancy
due to uncontrolled symptomatology (Paulzen et al., 2015a). Hence, a major challenge for clinicians is to balance between a minimal fetal drug exposure and a maximum maternal stability, i.e. relapse prevention or improvement of psychopathology. Although limiting the exchange of xenobiotics between mother and infant, the placenta is not able to provide a fully protected environment for the fetus (Eshkoli et al., 2011) and a plethora of drugs has shown teratogenic effects in the past. However, the placenta constitutes the sole structural barrier at the maternal-fetal interface (Ganapathy et al., 2000) and separates the maternal and fetal circulations. It performs many functions that support the maintenance of pregnancy and the normal development of the fetus but various factors can influence placental transfer, including the physicochemical properties of a drug (Hutson et al., 2011). Additional factors include pharmacokinetic parameters and physiological conditions such as protein binding, volume of distribution, renal plasma flow and glomerular filtration rate. Moreover the placenta expresses a multitude of transporters such as pglycoprotein, multi-drug-resistance proteins and others facilitating or preventing the passage of xenobiotics (Giaginis et al., 2012). Through enzyme activity such as cytochromes (CYP) or UDP-glucuronosyltransferase (UGT), the human placenta is able to metabolize a large diversity of pharmacologically active molecules eliciting or inhibiting fetotoxic effects (Giaginis et al., 2012; Reimers et al., 2011). All available antidepressant drugs are able to cross the placenta to a varying degree (Hendrick et al., 2003; Newport et al., 2001). Quantifying the extent of transplacental passage or knowledge about the accumulation of a drug in amniotic fluid as an important route of fetal exposure (Loughhead et al., 2006) can facilitate drug selection and ultimately provide insight into whether or not neonatal complications are directly related to drug exposure with measurable drug concentrations in amniotic fluid or fetal circulation. 2
Paulzen et al.
Sertraline in Pregnancy
Sertraline (SERT) is a naphthalenamine derivative, acting as SSRI. It belongs to the most commonly prescribed antidepressants and has been shown to provide various comparative advantages in terms of efficacy comparing to other antidepressants (Cipriani et al., 2009; Kaplan and Zhang, 2012). Recent data support a sufficient reproductive safety profile (Gadzhanova and Roughead, 2015; Reefhuis et al., 2015) with daily dosages below 150mg suggested as a safe treatment option during pregnancy (Roca et al., 2011). Sertraline is primarily metabolized through the liver by N-desmethylation, catalysed via CYP2B6 and to a lesser extent via CYP2C19, CYP2C9, CYP3A4, and CYP2D6 (Kobayashi et al., 1999; Xu et al., 1999) with a terminal half-life time of 26 hours. In vitro data suggest a high affinity of sertraline for the efflux transporter P-glycoprotein (P-gp) (Wang et al., 2008). This might explain a lower fetal access of sertraline compared to other antidepressants (Hendrick et al., 2003), since P-gp comprises a major efflux transporter on the maternal side of the placenta limiting the passage of various xenobiotics (Mason et al., 2011). An increase of P-gp activity during ongoing pregnancy may essentially contribute to this function (Hebert et al., 2008) but sertraline may above that inhibit a P-gp activity with undetermined maternal and fetal consequences (Feghali et al., 2015). Umbilical cord serum samples support a lower extent of placental transfer of sertraline and thereby lower infant exposure for sertraline compared with other antidepressants (Hendrick et al., 2003; Rampono et al., 2004; Rampono et al., 2009). The low infant exposure may contribute to the sufficient reproductive safety profile eventually
lacking
infant
serotonergic
overstimulation
outcomes
such
as
neurodevelopmental symptoms as reported for other SSRIs (Laine et al., 2003). Aim of our study was to analyse the distribution pattern of sertraline in maternal serum, amniotic fluid and umbilical cord blood, to account for the relation between the applied daily doses of sertraline and the serum- as well as the umbilical cord blood concentrations 3
Paulzen et al.
Sertraline in Pregnancy
and concentrations in amniotic fluid at the time of delivery under naturalistic/clinical conditions.
Materials and methods Patients This investigation is part of an observational study examining the distribution pattern of different psychotropic drugs in maternal blood, amniotic fluid and umbilical cord blood in pregnant women at the time of delivery (Paulzen et al., 2015b). It was carried out as a collaboration between the Department of Psychiatry, Psychotherapy, and Psychosomatics, and the Department of Gynecology and Obstetrics, at the University hospital of RWTH Aachen University, Germany, since November 2012. The study protocol was approved by the local Ethics Committee. Data of six pregnant women, age ranging from 23 to 37 years (mean age = 31.66 ± 5.2; median = 32.5), and 6 newborns are presented. Women were treated throughout their pregnancies with sertraline in daily doses of between 25 and 100 mg. The last dose adaptions were done more than 2 weeks before delivery so steady state conditions were available at time of delivery. One patient was under stable co-medication with 900mg quetiapine per day at the time of delivery. Five of the patients were diagnosed with a depressive episode in stable remission, one with schizoaffective disorder. All six motherinfant pairs provided maternal serum concentrations, amniotic fluid concentrations and umbilical cord concentrations at delivery (see table 1). Methods The present study is a naturalistic prospective investigation of sertraline concentrations in maternal serum and amniotic fluid in six women and umbilical cord blood of their six 4
Paulzen et al.
Sertraline in Pregnancy
newborns. Blood was taken at the same time as delivery at steady-state conditions with regard to the ingested drug but due to clinical circumstances not as trough levels. As indicator for drug levels in blood we used serum concentrations. Serum was prepared by centrifugation of blood samples at 14,171 g for 15 minutes. Sertraline concentrations in maternal serum, amniotic fluid and umbilical cord blood were determined with an isocratic HPLC system with UV detector. Chromatographic separation was conducted with a Waters Acquity® UPLC system with gradient elution on a Waters Acquity® UPLC BEH-C18 column (2.1 mm × 50 mm, 1.7-μm particle size). For quantification, a Waters Acquity® TQ detector was used. The method is linear from the designated limit of quantification of 1.0 ng/mL up to the upper limit of 392 ng/mL for sertraline. Intra- and inter-assay precision across four quality control levels were ≤5.7% and ≤7.6%, respectively Statistical Analysis To account for the placental penetration, the correlation between maternal serum concentrations of sertraline and the cord blood concentration was calculated. Furthermore, the correlation between maternal serum and amniotic fluid was computed to account for the impact of drug accumulation in amniotic fluid as one way of fetal exposure. A concentration-by-dose- (C/D) ratio [in (ng/ml)/(mg/day)] for sertraline in maternal serum (MS), amniotic fluid (AF) and cord blood (CB), was calculated by dividing the serum-, amniotic fluid- and cord blood-concentrations of sertraline by the applied dose of sertraline. Additionally, the penetration ratio into the amniotic fluid and cord blood of sertraline was calculated. For this purpose the concentration of sertraline in AF as well as in CB were divided by their counterpart values in MS, reflecting the penetration-ratio into amniotic fluid and cord blood, respectively. Data are provided as median values, first (25th percentile, Q1) and third quartiles (75th percentile, Q3) as well as ranges between min and max values. 5
Paulzen et al.
Sertraline in Pregnancy
Correlations were computed to assess the relation between the drug concentrations in maternal serum, amniotic fluid and cord blood, as well as the relation of these concentrations with the daily dose of sertraline. Due to small sample size, non-parametric tests were used. Statistical analyses were conducted with SPSS (version 21, IBM, Armonk, NY, USA). Results Obstetrical outcome data, data on daily doses, serum-, amniotic fluid- and cord bloodconcentrations of sertraline are displayed in Table 1. Obstetrical outcome data are available for all six infants. One of six was classified as a preterm delivery (i.e., <37 weeks gestational age). One infant was postnatally karyotyped as a trisomy 21. Three infants showed initially low APGAR scores (≤7) and were therefore temporarily admitted to the intensive care unit. In one of these cases the mother had previously reported vaginal bleeding and birth arrest four days before the expected delivery date, due to which she was admitted to Department of Gynecology and Obstetrics. Regarding the body weight only one infant had a low birth weight (i.e., <2.5 kg, 5.5 lbs) and the other five were within a range between the 5th and the 95th percentile. The median daily dose of sertraline was 75 mg (Q1: 43.75 mg, Q3: 100 mg; range 25-100 mg). The median maternal serum concentration of sertraline was 15.4 ng/mL (Q1: 11.88 mg/mL, Q3: 20.88 mg/mL; range 9.7-30.1 ng/mL) recommended therapeutic reference range for the drug concentration 10-150 ng/mL). Serum concentrations given in mass units can be converted to molar units by multiplication with the conversion factor (CF) nmol/L = ng/mL x CF that is 3.27 in case of sertraline (Hiemke et al., 2011)). In amniotic fluid, the median sertraline concentration was 8.9 ng/mL (Q1: 4.38ng/mL, Q3: 11.0 ng/mL; range 4-14 ng/mL) and in the cord blood the median drug-concentration was 5.7 ng/mL (Q1: 4.52 ng/mL, Q3: 7.05 ng/mL; range: 3.1-9.3 ng/mL). The concentration-by-dose-ratio (C/D) was 6
Paulzen et al.
Sertraline in Pregnancy
calculated as concentration of sertraline (in ng/mL) divided by the daily dose of sertraline dose (in mg/day) according to [(ng/mL)/mg/day)] (Reis et al., 2004). In maternal serum it was 0.28 (Q1: 0.16, Q3: 0.37; range: 0.15-0.39 (ng/mL)/(mg/day)), for amniotic fluid 0.12 (Q1: 0.09, Q3: 0.18; range: 0.08-0.0.18 (ng/mL)/(mg/day)) and for cord blood 0.08 (Q1: 0.06, Q3: 0.15; range: 0.05-0.25 (ng/mL)/(mg/day)). The relation between the daily dosage of sertraline and its concentrations in maternal serum and cord blood failed to reach significance levels (p>0.05). However, daily dosage of sertraline was positively correlated amniotic fluid concentrations (r=0.833, p=0.039). Correlations were detected neither between values for serum and cord blood concentrations, nor for serum and amniotic fluid concentrations nor for amniotic fluid and cord blood concentrations of sertraline (p>0.05). The median penetration ratio for sertraline into amniotic fluid was 0.57 (Q1: 0.28, Q3: 0.75; range: 0.22-0.88). The median penetration ratio into the fetal circulation, calculated on the basis of umbilical cord blood-concentrations, was found to be 0.36 (Q1: 0.28, Q3: 0.49; range: 0.17-0.65), see fig. 1. “place fig. 1 about here” Discussion Wilson’s six principles of teratology have guided research in developmental toxicology to this day (Wilson, 1973). His sixth and final principle "Manifestations of Deviant Development Increase in Frequency and Degree as Dosage Increases, from No-effect to the Totally Lethal Level" among others describes the range of toxicity from no effect to completely lethal (Aston, 2014). This means that the outcome depends on dose, threshold and duration of xenobiotic influence and the lack of a correlation between maternal serum concentrations
7
Paulzen et al.
Sertraline in Pregnancy
and concentrations in fetal circulation suggests low drug concentrations in the unborn child and hence missing negative effects on the infant’s structural outcome. Aim of our study was to measure drug concentrations rather than evaluating obstetrical and/or structural outcome and we found relatively low concentrations of sertraline in amniotic fluid as well as in cord blood. Associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects remain controversial but the absolute risk of teratogenesis associated with SSRIs seems to be small (Jordan et al., 2016). However, differences in teratogenicity within the group of SSRIs makes it important to consider which antidepressant drug to recommend during pregnancy, and data suggest that paroxetine and perhaps fluoxetine should be avoided if possible. Data on the distribution pattern of sertraline between maternal blood, amniotic fluid and umbilical cord blood may help to assess the risk of in-utero exposition but are lacking so far, despite its worldwide prescription during pregnancy. Our ongoing prospective study aims to characterize the placental transfer and accumulation properties of different psychotropic drugs in amniotic fluid using serum concentrations as an indicator for drug concentrations in blood. Therapeutic drug monitoring (TDM) has proven a valuable clinical tool aiming patientmatched and safe psychopharmacotherapy, even during pregnancy (Hiemke et al., 2011) and data from epidemiological and cohort studies consistently support a sufficient reproductive safety profile for sertraline (Gadzhanova and Roughead, 2015; Reefhuis et al., 2015). Regardless of the contribution of maternal and fetal hepatic elimination of sertraline, our data suggest that fetal development occurs in a continuous environment of a pharmacologically active drug when pregnant women are treated with sertraline. With regard to the fetal exposure during pregnancy, it is important that the impact of measurable antidepressants’ concentrations in amniotic fluid, consistently ingested by swallowing 8
Paulzen et al.
Sertraline in Pregnancy
amniotic fluid in late pregnancy or due to respiratory exposure, should be systematically investigated (Hostetter et al., 2000; Loughhead et al., 2006). Fetal exposure can be more clearly defined by an improved understanding of the routes of fetal exposure and the factors that influence such pathways. Hence, measuring the concentration of sertraline in amniotic fluid and umbilical cord blood facilitates the understanding of intrauterine drug exposure during pregnancy. Knowledge about the penetration properties of different drugs into amniotic fluid or fetal circulation and knowledge about the correlation between the concentrations in the different compartments could stimulate the development of novel pharmaceutical agents that less easily enter amniotic fluid or fetal circulation, hence preventing the unborn child from potentially negative effects. Taken together, measuring sertraline concentrations in maternal blood during pregnancy is a valuable tool for predicting the in-utero exposition of the unborn child. As the daily dosage of sertraline significantly correlates with drug concentrations in amniotic fluid but not umbilical cord-blood it can be stated that sertraline rather selectively crosses the placenta. Additionally, it must be appreciated that maternal drug concentrations failed to show a correlation with drug concentrations in amniotic fluid or umbilical cord blood as it has been shown e.g. for lamotrigine (Paulzen et al., 2015b). It remains important to note that three of the six infants showed low initial APGAR scores necessitating a temporary observation in an ICU unit while the structural abnormality in one of the infants (trisomy 21) obviously cannot be attributed to the psychopharmacological treatment with sertraline. In this context, Gentile defined a prenatal antidepressant exposure syndrome in order to increase clinicians' awareness about the spectrum of risks which may concern the mother-infant pair when antidepressant treatment is deemed indispensable during late pregnancy (Gentile, 2010). 9
Paulzen et al.
Sertraline in Pregnancy
Therapeutic efforts should be driven by an orientation towards the lowest therapeutically effective serum concentrations of sertraline in maternal blood for an improvement in psychopathology or to prevent relapse of depressive episodes to reduce the threat of potentially negative effects on the fetus. The data presented here underscore the need to apply lowest doses for efficacy and to use multiple times of administration (b.i.d.) to avoid an overload of the placental barrier in the course of very high plasma or serum levels of a drug. From a clinical point of view, it might be helpful to target effective plasma or serum concentrations of sertraline that were considered to be effective before becoming pregnant. To ensure safety and efficacy of antidepressant treatment strategies during pregnancy, clinicians should be aware of both possible changes in serum concentration of the antidepressant drug as well as of changes in the psychopathology (Freeman et al., 2008). The first is controlled by therapeutic drug monitoring and a close cooperation between gynecologists and psychiatrists is recommended. The need for further research in order to warrant drug safety and efficacy during pregnancy remains as before. There is a considerable lack of data, although some assumptions of considerable interpatient variability regarding amniotic fluid and umbilical cord-blood drug concentrations can be made; e.g. in a sample of four pregnant patients the median cord-maternal concentration ratio for sertraline was 0.67 (Rampono et al., 2004). In our sample, the highest value reported was 0.65. Therefore, larger samples would be helpful to validate clinical observations. Limitations The small number of patients is obviously the main limitation of the study. Hence, our findings do not allow for drawing general conclusions on concentrations that can be expected within the investigated environments and corresponding effects. Further 10
Paulzen et al.
Sertraline in Pregnancy
information about the long-term effects of antidepressant drugs during pregnancy on others issues than birth defects (e.g. neurodevelopmental behavior) are mandatory for assessing the risk profile of psychotropic drugs that are prescribed during pregnancy (Gentile, 2010; Gentile and Galbally, 2011). Finally, information about the metabolizer status of the polymorphic cytochrome P450 enzymes (CYP2C19 and CYP2D6) in both, mother and infant, would be of high interest for better assessing the pharmacokinetic patterns and hence the exposition of both.
11
Paulzen et al.
Sertraline in Pregnancy
Authorship Contributions Participated in research design: MP, GG. Conducted experiments: MP, TWG, ES. Performed data analysis: MP, GS. Wrote or contributed to the writing of the manuscript: MP, TWG, ES, GG, GS
XII
Paulzen et al.
Sertraline in Pregnancy
Acknowledgments The authors wish to thank Mr. Geer Janssen from the Medical Care Center, Dr. Stein and colleagues, Moenchengladbach, Germany, for determination of sertraline for this investigation and for the fruitful collaboration. Furthermore, the authors wish to express their gratitude to the number of people from the Department of Gynecology and Obstetrics, RWTH Aachen University who support the ongoing study by identifying pregnant women that are medicated with psychotropic drugs. So special thanks goes to the whole wonderful team of midwifes and to Dr. Cordula Franz, Dr. Helena Sassmannshausen, Dr. Rebecca Caspers,
MUDr.
Tomáš
Kupec
XIII
and
Bartlomiej
Berger.
Paulzen et al.
Sertraline in Pregnancy
Declaration of interests Gerhard Gründer has served as a consultant for Boehringer Ingelheim (Ingelheim, Germany), Cheplapharm (Greifswald, Germany), Eli Lilly (Indianapolis, Ind, USA), Lundbeck (Copenhagen, Denmark), Ono Pharmaceuticals (Osaka, Japan), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Eli Lilly, Gedeon Richter (Budapest, Hungary), Janssen Cilag (Neuss, Germany), Lundbeck, Roche, Servier, and Trommsdorf (Aachen, Germany). He has received grant support from Boehringer Ingelheim and Roche. He is co-founder of Pharma Image GmbH (Düsseldorf, Germany) and Brainfoods UG (Selfkant, Germany). He reports no conflict of interest with this publication. Georgios Schoretsanitis received a grant from the bequest "in memory of Maria Zaoussi”, State Scholarships Foundation, Greece for clinical research in Psychiatry for the academic year 2015-2016. All other authors declare no conflicts of interest as well. The research study did not receive funds or support from any source.
XIV
Paulzen et al.
Sertraline in Pregnancy
Table / Figure legends Table 1: Patients' characteristics and clinical characteristics of six mothers taking sertraline during pregnancy and their infants. Figure 1: A – Boxplot of the penetration ratios into amniotic fluid (left), median 0.57, Q1: 0.28, Q3: 0.75; range: 0.22-0.88, and into the fetal circulation (right), median 0.36, Q1: 0.28, Q3: 0.49; range: 0.17-0.65. B-D – Correlations were detected neither between values for serum and cord blood concentrations (B) of sertraline, nor between amniotic fluid and cord blood levels (C) or between cord blood concentrations and amniotic fluid concentrations of sertraline (D) (p>0.05).
XV
Sertraline in Pregnancy
34
23
31
37
36
2
3
4
5
6
37+6
39+4
39+6
37+0
36+4
40+3
delivery (weeks)
Section
Section
Spontaneous
Section
Spontaneous
Section
Mode of delivery
2,560
4,125
3,635
3,370
2,180
3,760
weight (g)
Body sex
♂
♂
♂
♂
♂
♂
50th
3rd
73rd
53rd
90th
5th
Infant
Percentile
Weight
6/8/10
6/8/8
9/10/10
7/7/7
9/10/10
9/10/10
APGAR
25
100
100
50
50
100
(mg)
9.7
30.1
14.8
17.8
12.6
16.0
(ng/mL)
*
DD sertraline sertraline MS
0.39
0.30
0.15
0.36
0.25
0.16
C/D MS
4.5
9.0
10.0
4.0
8.8
14.0
(ng/mL)
sertraline AF
0.18
0.09
0.1
0.08
0.18
0.14
C/D AF
0.46
0.30
0.68
0.22
0.70
0.88
AF/MS
Ratio
6.3
9.3
5.9
3.1
5.5
5.0
(ng/mL)
sertraline CB
0.25
0.09
0.06
0.06
0.11
0.05
C/D CB
0.65
0.31
0.40
0.17
0.44
0.31
CB/MS
Ratio
-
quetiapine
-
-
-
-
medication
Concomitant
maternal anaemia
low APGAR, postnatal
maternal anaemia
low APGAR, postnatal
ng/mL x CF that is 3.27 in case of sertraline. DD – daily dose; MS – maternal serum; C/D – concentration to dose ratio in [(ng/mL)/[mg/day)]; AF –
XV
amniotic fluid; CB – Cord blood; PROM – premature rupture of membranes
anaemia
postnatal maternal
arrest
low APGAR, birth
trisomy 21
postnatally karyotyped
preterm birth,
PROM
Outcome / birth defect
Legend: *Plasma concentrations given in mass units can be converted to molar units by multiplication with the conversion factor (CF) nmol/L =
29
age
Maternal Gestational age at
1
Patient
table 1: Patients' characteristics and clinical characteristics of six mothers taking sertraline during pregnancy and their infants
Paulzen et al.
Paulzen et al.
Sertraline in Pregnancy
References Aston, S.A., 2014. James G. Wilson's Six Principles of Teratology, Embryo Project Encyclopedia ed. Embryo Project Encyclopedia. Cipriani, A., Furukawa, T.A., Salanti, G., Geddes, J.R., Higgins, J.P., Churchill, R., Watanabe, N., Nakagawa, A., Omori, I.M., McGuire, H., Tansella, M., Barbui, C., 2009. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multipletreatments meta-analysis. Lancet 373(9665), 746-758. Dayan, J., Creveuil, C., Marks, M.N., Conroy, S., Herlicoviez, M., Dreyfus, M., Tordjman, S., 2006. Prenatal depression, prenatal anxiety, and spontaneous preterm birth: a prospective cohort study among women with early and regular care. Psychosomatic medicine 68(6), 938946. Diego, M.A., Field, T., Hernandez-Reif, M., Schanberg, S., Kuhn, C., Gonzalez-Quintero, V.H., 2009. Prenatal depression restricts fetal growth. Early human development 85(1), 6570. Eshkoli, T., Sheiner, E., Ben-Zvi, Z., Feinstein, V., Holcberg, G., 2011. Drug transport across the placenta. Current pharmaceutical biotechnology 12(5), 707-714. Feghali, M., Venkataramanan, R., Caritis, S., 2015. Pharmacokinetics of drugs in pregnancy. Seminars in perinatology 39(7), 512-519. Freeman, M.P., Nolan, P.E., Jr., Davis, M.F., Anthony, M., Fried, K., Fankhauser, M., Woosley, R.L., Moreno, F., 2008. Pharmacokinetics of sertraline across pregnancy and postpartum. Journal of clinical psychopharmacology 28(6), 646-653. Gadzhanova, S., Roughead, E., 2015. Use of prescription medicines in Australian women of child-bearing age. BMC pharmacology & toxicology 16(1), 33. Ganapathy, V., Prasad, P.D., Ganapathy, M.E., Leibach, F.H., 2000. Placental transporters relevant to drug distribution across the maternal-fetal interface. Journal of Pharmacology and Experimental Therapeutics 294(2), 413-420. Gentile, S., 2010. On Categorizing Gestational, Birth, and Neonatal Complications Following Late Pregnancy Exposure to Antidepressants: The Prenatal Antidepressant Exposure Syndrome. CNS Spectrums 15(3), 167-185. Gentile, S., Galbally, M., 2011. Prenatal exposure to antidepressant medications and neurodevelopmental outcomes: a systematic review. Journal of affective disorders 128(1-2), 1-9. Giaginis, C., Theocharis, S., Tsantili-Kakoulidou, A., 2012. Current toxicological aspects on drug and chemical transport and metabolism across the human placental barrier. Expert opinion on drug metabolism & toxicology 8(10), 1263-1275. Grote, N.K., Bridge, J.A., Gavin, A.R., Melville, J.L., Iyengar, S., Katon, W.J., 2010. A metaanalysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Archives of general psychiatry 67(10), 1012-1024. Hebert, M.F., Easterling, T.R., Kirby, B., Carr, D.B., Buchanan, M.L., Rutherford, T., Thummel, K.E., Fishbein, D.P., Unadkat, J.D., 2008. Effects of pregnancy on CYP3A and Pglycoprotein activities as measured by disposition of midazolam and digoxin: a University of Washington specialized center of research study. Clinical pharmacology and therapeutics 84(2), 248-253. Hendrick, V., Stowe, Z.N., Altshuler, L.L., Hwang, S., Lee, E., Haynes, D., 2003. Placental passage of antidepressant medications. The American journal of psychiatry 160(5), 993-996.
I
Paulzen et al.
Sertraline in Pregnancy
Henrichs, J., Schenk, J.J., Roza, S.J., van den Berg, M.P., Schmidt, H.G., Steegers, E.A., Hofman, A., Jaddoe, V.W., Verhulst, F.C., Tiemeier, H., 2010. Maternal psychological distress and fetal growth trajectories: the Generation R Study. Psychological medicine 40(4), 633-643. Hiemke, C., Baumann, P., Bergemann, N., Conca, A., Dietmaier, O., Egberts, K., Fric, M., Gerlach, M., Greiner, C., Gründer, G., Haen, E., Havemann-Reinecke, U., Jaquenoud Sirot, E., Kirchherr, H., Laux, G., Lutz, U.C., Messer, T., Müller, M.J., Pfuhlmann, B., Rambeck, B., Riederer, P., Schoppek, B., Stingl, J., Uhr, M., Ulrich, S., Waschgler, R., Zernig, G., 2011. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011. Pharmacopsychiatry 44(6), 195-235. Hostetter, A., Ritchie, J.C., Stowe, Z.N., 2000. Amniotic fluid and umbilical cord blood concentrations of antidepressants in three women. Biol Psychiatry. 2000 Nov 15;48(10):1032-4. Hutson, J.R., Garcia-Bournissen, F., Davis, A., Koren, G., 2011. The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs. Clinical Pharmacology & Therapeutics 90(1), 67-76. Jimenez-Solem, E., 2014. Exposure to antidepressants during pregnancy--prevalences and outcomes. Danish medical journal 61(9), B4916. Jordan, S., Morris, J.K., Davies, G.I., Tucker, D., Thayer, D.S., Luteijn, J.M., Morgan, M., Garne, E., Hansen, A.V., Klungsoyr, K., Engeland, A., Boyle, B., Dolk, H., 2016. Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark. PloS one 11(12), e0165122. Kallen, B., Borg, N., Reis, M., 2013. The use of central nervous system active drugs during pregnancy. Pharmaceuticals (Basel). 2013 Oct 10;6(10):1221-86. doi: 10.3390/ph6101221. Kaplan, C., Zhang, Y., 2012. Assessing the comparative-effectiveness of antidepressants commonly prescribed for depression in the US Medicare population. The journal of mental health policy and economics 15(4), 171-178. Kobayashi, K., Ishizuka, T., Shimada, N., Yoshimura, Y., Kamijima, K., Chiba, K., 1999. Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. Drug metabolism and disposition: the biological fate of chemicals 27(7), 763-766. Laine, K., Heikkinen, T., Ekblad, U., Kero, P., 2003. Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry 60(7), 720-726. Loughhead, A.M., Fisher, A.D., Newport, D.J., Ritchie, J.C., Owens, M.J., DeVane, C.L., Stowe, Z.N., 2006. Antidepressants in amniotic fluid: another route of fetal exposure. American Journal of Psychiatry 163(1), 145-147. Mason, C.W., Buhimschi, I.A., Buhimschi, C.S., Dong, Y., Weiner, C.P., Swaan, P.W., 2011. ATP-binding cassette transporter expression in human placenta as a function of pregnancy condition. Drug metabolism and disposition: the biological fate of chemicals 39(6), 10001007. Newport, D.J., Wilcox, M.M., Stowe, Z.N., 2001. Antidepressants during pregnancy and lactation: defining exposure and treatment issues. Seminars in perinatology 25(3), 177-190. Nulman, I., Koren, G., Rovet, J., Barrera, M., Pulver, A., Streiner, D., Feldman, B., 2012. Neurodevelopment of children following prenatal exposure to venlafaxine, selective serotonin reuptake inhibitors, or untreated maternal depression. Am J Psychiatry. 2012 Nov 1;169(11):1165-74. doi: 10.1176/appi.ajp.2012.11111721.
II
Paulzen et al.
Sertraline in Pregnancy
Paulzen, M., Gründer, G., Orlikowsky, T., Graf, C.M., Hoeltzenbein, M., Veselinovic, T., 2015a. Suicide attempt during late pregnancy with quetiapine: nonfatal outcome despite severe intoxication. Journal of clinical psychopharmacology 35(3), 343-344. Paulzen, M., Lammertz, S.E., Veselinovic, T., Goecke, T.W., Hiemke, C., Gründer, G., 2015b. Lamotrigine in pregnancy - therapeutic drug monitoring in maternal blood, amniotic fluid, and cord blood. International clinical psychopharmacology 30(5), 249-254. Ram, D., Gandotra, S., 2015. Antidepressants, anxiolytics, and hypnotics in pregnancy and lactation. Indian journal of psychiatry 57(Suppl 2), S354-371. Rampono, J., Proud, S., Hackett, L.P., Kristensen, J.H., Ilett, K.F., 2004. A pilot study of newer antidepressant concentrations in cord and maternal serum and possible effects in the neonate. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum 7(3), 329-334. Rampono, J., Simmer, K., Ilett, K.F., Hackett, L.P., Doherty, D.A., Elliot, R., Kok, C.H., Coenen, A., Forman, T., 2009. Placental transfer of SSRI and SNRI antidepressants and effects on the neonate. Pharmacopsychiatry 42(3), 95-100. Reefhuis, J., Devine, O., Friedman, J.M., Louik, C., Honein, M.A., National Birth Defects Prevention, S., 2015. Specific SSRIs and birth defects: Bayesian analysis to interpret new data in the context of previous reports. Bmj 351, h3190. Reimers, A., Ostby, L., Stuen, I., Sundby, E., 2011. Expression of UDPglucuronosyltransferase 1A4 in human placenta at term. Eur J Drug Metab Pharmacokinet. 2011 Jan;35(3-4):79-82. doi: 10.1007/s13318-010-0021-x. Epub 2010 Dec 30. Reis, M., Aberg-Wistedt, A., Agren, H., Hoglund, P., Akerblad, A.C., Bengtsson, F., 2004. Serum disposition of sertraline, N-desmethylsertraline and paroxetine: a pharmacokinetic evaluation of repeated drug concentration measurements during 6 months of treatment for major depression. Human psychopharmacology 19(5), 283-291. Roca, A., Garcia-Esteve, L., Imaz, M.L., Torres, A., Hernandez, S., Botet, F., Gelabert, E., Subira, S., Plaza, A., Valdes, M., Martin-Santos, R., 2011. Obstetrical and neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitors: the relevance of dose. Journal of affective disorders 135(1-3), 208-215. Schaefer, C., 2011. Drug safety in pregnancy: utopia or achievable prospect? Risk information, risk research and advocacy in Teratology Information Services. Congenital anomalies 51(1), 6-11. Thomas, S.H.L., Yates, L.M., 2012. Prescribing without evidence - pregnancy. British journal of clinical pharmacology 74(4), 691-697. Uguz, F., Gezginc, K., Yazici, F., 2011. Are major depression and generalized anxiety disorder associated with intrauterine growth restriction in pregnant women? A case-control study. Gen Hosp Psychiatry. 2011 Nov-Dec;33(6):640.e7-9. doi: 10.1016/j.genhosppsych.2011.05.007. Epub 2011 Jun 21. Wang, J.S., Zhu, H.J., Gibson, B.B., Markowitz, J.S., Donovan, J.L., DeVane, C.L., 2008. Sertraline and its metabolite desmethylsertraline, but not bupropion or its three major metabolites, have high affinity for P-glycoprotein. Biological & pharmaceutical bulletin 31(2), 231-234. Wilson, J.G., 1973. Environment and Birth Defects. Academic Press, New York. Xu, Z.H., Wang, W., Zhao, X.J., Huang, S.L., Zhu, B., He, N., Shu, Y., Liu, Z.Q., Zhou, H.H., 1999. Evidence for involvement of polymorphic CYP2C19 and 2C9 in the N-demethylation of sertraline in human liver microsomes. Br J Clin Pharmacol 48(3), 416-423.
III
Paulzen et al.
Sertraline in Pregnancy
Key points / highlights
·
Therapeutic drug monitoring in maternal serum, amniotic fluid and cord-blood allows for calculation of in-utero exposition during antidepressant therapy.
·
Sertraline concentrations in amniotic fluid give evidence that maternally administered sertraline is constantly accessible to the fetus.
·
A relatively low penetration into fetal circulation may contribute to the sufficient reproductive safety profile of sertraline.
IV
Paulzen et al.
Sertraline in Pregnancy
V
PII: DOI: Reference:
S0165-0327(16)31935-8 http://dx.doi.org/10.1016/j.jad.2017.01.019 JAD8739
To appear in: Journal of Affective Disorders Received date: 18 October 2016 Revised date: 16 January 2017 Accepted date: 19 January 2017 Cite this article as: Michael Paulzen, Tamme W. Goecke, Elmar Stickeler, Gerhard Gründer and Georgios Schoretsanitis, Sertraline in Pregnancy – Therapeutic Drug Monitoring in Maternal Blood, Amniotic Fluid and Cord B l o o d , Journal of Affective Disorders, http://dx.doi.org/10.1016/j.jad.2017.01.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Sertraline in Pregnancy – Therapeutic Drug Monitoring in Maternal Blood, Amniotic Fluid and Cord Blood
Michael Paulzen, MD; Tamme W. Goecke, MD; Elmar Stickeler, MD; Gerhard Gründer, MD; and Georgios Schoretsanitis, MD.
Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany, and JARA – Translational Brain Medicine: MP, GG, GS
University Hospital of Psychiatry, Bern, Switzerland: GS
Department of Gynecology and Obstetrics, RWTH Aachen University: TWG, ES
Corresponding author: Michael Paulzen, MD Department of Psychiatry, Psychotherapy and Psychosomatics and JARA – Translational Brain Medicine RWTH Aachen University Pauwelsstr. 30 52074 Aachen, Germany Phone: +49-241-80-89508 Fax: +49-241-80-82401 Email: [email protected]
a) Running title page sertraline in pregnancy
b) The number of text pages, number of tables, figures, and references, and the number of words in the Abstract, Introduction, and Discussion number of text pages: 11 (double-spaced) number of tables: 1 number of figures: 1 number of references: 44 number of words in the abstract: 278 number of words in the introduction: 928 (including references); number of words in the materials and methods section: 592 (including references); number of words in the results section: 434 (including references); number of words in the discussion: 1,038 (including references and limitations); number of words in the manuscript: 2,992 (including headings and references)
Declaration of interests Gerhard Gründer has served as a consultant for Boehringer Ingelheim (Ingelheim, Germany), Cheplapharm (Greifswald, Germany), Eli Lilly (Indianapolis, Ind, USA), Lundbeck (Copenhagen, Denmark), Ono Pharmaceuticals (Osaka, Japan), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Eli Lilly, Gedeon Richter (Budapest, Hungary), Janssen Cilag (Neuss, Germany), Lundbeck, Roche, Servier, and Trommsdorf (Aachen, Germany). He has received grant support from Boehringer Ingelheim and Roche. He
II
is co-founder of Pharma Image GmbH (Düsseldorf, Germany) and Brainfoods UG (Selfkant, Germany). He reports no conflict of interest with this publication. Georgios Schoretsanitis received a grant from the bequest "in memory of Maria Zaoussi”, State Scholarships Foundation, Greece for clinical research in Psychiatry for the academic year 2015-2016. All other authors declare no conflicts of interest as well. The research study did not receive funds or support from any source.
III
Abstract Rationale: This study is the first to measure and correlate sertraline concentrations in maternal blood, amniotic fluid and umbilical cord blood and account for distribution of the drug between these three compartments. Methods: Concentrations of sertraline were measured in six mother infant pairs at the time of delivery. Data are provided as median values, first and third quartiles as well as ranges. To account for the penetration ratio into amniotic fluid and cord blood, the concentration of sertraline in both environments was divided by the concentration in maternal serum. Daily doses were correlated with maternal serum- and umbilical cord blood-concentrations, and serum levels were correlated with levels in amniotic fluid. Results: The median daily dose of sertraline was 75 mg (Q1: 43.75 mg, Q3: 100 mg; range 25100 mg). Amniotic fluid concentrations of sertraline strongly correlated with the daily dose (r=0.833, p=0.039) while neither maternal serum concentrations nor cord blood concentrations correlated with the daily dose (p>0.05). The median penetration ratio for sertraline into amniotic fluid was 0.57 (Q1: 0.28, Q3: 0.75; range: 0.22-0.88). The median penetration ratio into the fetal circulation, calculated on the basis of umbilical cord bloodconcentrations, was found to be 0.36 (Q1: 0.28, Q3: 0.49; range: 0.17-0.65). Conclusions: Sertraline concentrations in amniotic fluid gave evidence that maternally administered sertraline is constantly accessible to the fetus via amniotic fluid in a manner not previously appreciated. A relatively low penetration into fetal circulation may contribute to a sufficient safety profile of sertraline during pregnancy although in our study APGAR Scores were relatively low in three infants. Our data support the important role of
IV
therapeutic drug monitoring in maintaining the safety of pregnant women and exposed infants. Keywords:
pregnancy;
depression;
antidepressants;
sertraline;
therapeutic drug monitoring; amniotic fluid; cord blood; placental transfer
V
pharmacokinetics;
Paulzen et al.
Sertraline in Pregnancy
Introduction Extensive data regarding the safety of selective serotonin reuptake inhibitors (SSRI) provide minimal absolute risk rates, so that SSRIs are suggested as a first line medication for antenatal depression (Ram and Gandotra, 2015). A recent bayesian analysis of an enormous sample reassured the safety of the prescription of SSRIs in pregnancy with the exceptions of paroxetine and fluoxetine (Reefhuis et al., 2015). Despite a high prevalence of depressive disorders during pregnancy and the increasing use of antidepressant drugs during pregnancy over the last years (Jimenez-Solem, 2014; Kallen et al., 2013; Thomas and Yates, 2012), there is still a lack of clinical data regarding safety of these drugs for both, pregnant women and unborn children. Furthermore, evidence supporting prescription strategies of psychotropic agents during pregnancy remains inconclusive (Schaefer, 2011). Accordingly, to enhance both, safety and efficacy of antidepressant drug treatment during pregnancy there is a need for more comprehensive data on the short- and log-term effects of antidepressant exposure during pregnancy. Apart from possible drug-associated effects on pregnant women and their infants, pregnancy outcomes and clinical decision-making processes are also affected by the natural course of the untreated psychiatric diseases. Due to methodological limitations of relevant studies, data investigating the risks of untreated depression on both, the expectant mothers and their infants remain sparse and rather unclear. However, adverse perinatal effects such as intrauterine growth retardation (Grote et al., 2010; Henrichs et al., 2010; Uguz et al., 2011), increased preterm delivery (Dayan et al., 2006; Diego et al., 2009) or low birth weight (Diego et al., 2009) have been reported. Furthermore, children of mothers with untreated or inadequately treated psychiatric diseases such as depression or psychosis might be at risk of future psychopathology (Nulman et al., 2012) or even at risk for maternal suicidal behaviour 1
Paulzen et al.
Sertraline in Pregnancy
due to uncontrolled symptomatology (Paulzen et al., 2015a). Hence, a major challenge for clinicians is to balance between a minimal fetal drug exposure and a maximum maternal stability, i.e. relapse prevention or improvement of psychopathology. Although limiting the exchange of xenobiotics between mother and infant, the placenta is not able to provide a fully protected environment for the fetus (Eshkoli et al., 2011) and a plethora of drugs has shown teratogenic effects in the past. However, the placenta constitutes the sole structural barrier at the maternal-fetal interface (Ganapathy et al., 2000) and separates the maternal and fetal circulations. It performs many functions that support the maintenance of pregnancy and the normal development of the fetus but various factors can influence placental transfer, including the physicochemical properties of a drug (Hutson et al., 2011). Additional factors include pharmacokinetic parameters and physiological conditions such as protein binding, volume of distribution, renal plasma flow and glomerular filtration rate. Moreover the placenta expresses a multitude of transporters such as pglycoprotein, multi-drug-resistance proteins and others facilitating or preventing the passage of xenobiotics (Giaginis et al., 2012). Through enzyme activity such as cytochromes (CYP) or UDP-glucuronosyltransferase (UGT), the human placenta is able to metabolize a large diversity of pharmacologically active molecules eliciting or inhibiting fetotoxic effects (Giaginis et al., 2012; Reimers et al., 2011). All available antidepressant drugs are able to cross the placenta to a varying degree (Hendrick et al., 2003; Newport et al., 2001). Quantifying the extent of transplacental passage or knowledge about the accumulation of a drug in amniotic fluid as an important route of fetal exposure (Loughhead et al., 2006) can facilitate drug selection and ultimately provide insight into whether or not neonatal complications are directly related to drug exposure with measurable drug concentrations in amniotic fluid or fetal circulation. 2
Paulzen et al.
Sertraline in Pregnancy
Sertraline (SERT) is a naphthalenamine derivative, acting as SSRI. It belongs to the most commonly prescribed antidepressants and has been shown to provide various comparative advantages in terms of efficacy comparing to other antidepressants (Cipriani et al., 2009; Kaplan and Zhang, 2012). Recent data support a sufficient reproductive safety profile (Gadzhanova and Roughead, 2015; Reefhuis et al., 2015) with daily dosages below 150mg suggested as a safe treatment option during pregnancy (Roca et al., 2011). Sertraline is primarily metabolized through the liver by N-desmethylation, catalysed via CYP2B6 and to a lesser extent via CYP2C19, CYP2C9, CYP3A4, and CYP2D6 (Kobayashi et al., 1999; Xu et al., 1999) with a terminal half-life time of 26 hours. In vitro data suggest a high affinity of sertraline for the efflux transporter P-glycoprotein (P-gp) (Wang et al., 2008). This might explain a lower fetal access of sertraline compared to other antidepressants (Hendrick et al., 2003), since P-gp comprises a major efflux transporter on the maternal side of the placenta limiting the passage of various xenobiotics (Mason et al., 2011). An increase of P-gp activity during ongoing pregnancy may essentially contribute to this function (Hebert et al., 2008) but sertraline may above that inhibit a P-gp activity with undetermined maternal and fetal consequences (Feghali et al., 2015). Umbilical cord serum samples support a lower extent of placental transfer of sertraline and thereby lower infant exposure for sertraline compared with other antidepressants (Hendrick et al., 2003; Rampono et al., 2004; Rampono et al., 2009). The low infant exposure may contribute to the sufficient reproductive safety profile eventually
lacking
infant
serotonergic
overstimulation
outcomes
such
as
neurodevelopmental symptoms as reported for other SSRIs (Laine et al., 2003). Aim of our study was to analyse the distribution pattern of sertraline in maternal serum, amniotic fluid and umbilical cord blood, to account for the relation between the applied daily doses of sertraline and the serum- as well as the umbilical cord blood concentrations 3
Paulzen et al.
Sertraline in Pregnancy
and concentrations in amniotic fluid at the time of delivery under naturalistic/clinical conditions.
Materials and methods Patients This investigation is part of an observational study examining the distribution pattern of different psychotropic drugs in maternal blood, amniotic fluid and umbilical cord blood in pregnant women at the time of delivery (Paulzen et al., 2015b). It was carried out as a collaboration between the Department of Psychiatry, Psychotherapy, and Psychosomatics, and the Department of Gynecology and Obstetrics, at the University hospital of RWTH Aachen University, Germany, since November 2012. The study protocol was approved by the local Ethics Committee. Data of six pregnant women, age ranging from 23 to 37 years (mean age = 31.66 ± 5.2; median = 32.5), and 6 newborns are presented. Women were treated throughout their pregnancies with sertraline in daily doses of between 25 and 100 mg. The last dose adaptions were done more than 2 weeks before delivery so steady state conditions were available at time of delivery. One patient was under stable co-medication with 900mg quetiapine per day at the time of delivery. Five of the patients were diagnosed with a depressive episode in stable remission, one with schizoaffective disorder. All six motherinfant pairs provided maternal serum concentrations, amniotic fluid concentrations and umbilical cord concentrations at delivery (see table 1). Methods The present study is a naturalistic prospective investigation of sertraline concentrations in maternal serum and amniotic fluid in six women and umbilical cord blood of their six 4
Paulzen et al.
Sertraline in Pregnancy
newborns. Blood was taken at the same time as delivery at steady-state conditions with regard to the ingested drug but due to clinical circumstances not as trough levels. As indicator for drug levels in blood we used serum concentrations. Serum was prepared by centrifugation of blood samples at 14,171 g for 15 minutes. Sertraline concentrations in maternal serum, amniotic fluid and umbilical cord blood were determined with an isocratic HPLC system with UV detector. Chromatographic separation was conducted with a Waters Acquity® UPLC system with gradient elution on a Waters Acquity® UPLC BEH-C18 column (2.1 mm × 50 mm, 1.7-μm particle size). For quantification, a Waters Acquity® TQ detector was used. The method is linear from the designated limit of quantification of 1.0 ng/mL up to the upper limit of 392 ng/mL for sertraline. Intra- and inter-assay precision across four quality control levels were ≤5.7% and ≤7.6%, respectively Statistical Analysis To account for the placental penetration, the correlation between maternal serum concentrations of sertraline and the cord blood concentration was calculated. Furthermore, the correlation between maternal serum and amniotic fluid was computed to account for the impact of drug accumulation in amniotic fluid as one way of fetal exposure. A concentration-by-dose- (C/D) ratio [in (ng/ml)/(mg/day)] for sertraline in maternal serum (MS), amniotic fluid (AF) and cord blood (CB), was calculated by dividing the serum-, amniotic fluid- and cord blood-concentrations of sertraline by the applied dose of sertraline. Additionally, the penetration ratio into the amniotic fluid and cord blood of sertraline was calculated. For this purpose the concentration of sertraline in AF as well as in CB were divided by their counterpart values in MS, reflecting the penetration-ratio into amniotic fluid and cord blood, respectively. Data are provided as median values, first (25th percentile, Q1) and third quartiles (75th percentile, Q3) as well as ranges between min and max values. 5
Paulzen et al.
Sertraline in Pregnancy
Correlations were computed to assess the relation between the drug concentrations in maternal serum, amniotic fluid and cord blood, as well as the relation of these concentrations with the daily dose of sertraline. Due to small sample size, non-parametric tests were used. Statistical analyses were conducted with SPSS (version 21, IBM, Armonk, NY, USA). Results Obstetrical outcome data, data on daily doses, serum-, amniotic fluid- and cord bloodconcentrations of sertraline are displayed in Table 1. Obstetrical outcome data are available for all six infants. One of six was classified as a preterm delivery (i.e., <37 weeks gestational age). One infant was postnatally karyotyped as a trisomy 21. Three infants showed initially low APGAR scores (≤7) and were therefore temporarily admitted to the intensive care unit. In one of these cases the mother had previously reported vaginal bleeding and birth arrest four days before the expected delivery date, due to which she was admitted to Department of Gynecology and Obstetrics. Regarding the body weight only one infant had a low birth weight (i.e., <2.5 kg, 5.5 lbs) and the other five were within a range between the 5th and the 95th percentile. The median daily dose of sertraline was 75 mg (Q1: 43.75 mg, Q3: 100 mg; range 25-100 mg). The median maternal serum concentration of sertraline was 15.4 ng/mL (Q1: 11.88 mg/mL, Q3: 20.88 mg/mL; range 9.7-30.1 ng/mL) recommended therapeutic reference range for the drug concentration 10-150 ng/mL). Serum concentrations given in mass units can be converted to molar units by multiplication with the conversion factor (CF) nmol/L = ng/mL x CF that is 3.27 in case of sertraline (Hiemke et al., 2011)). In amniotic fluid, the median sertraline concentration was 8.9 ng/mL (Q1: 4.38ng/mL, Q3: 11.0 ng/mL; range 4-14 ng/mL) and in the cord blood the median drug-concentration was 5.7 ng/mL (Q1: 4.52 ng/mL, Q3: 7.05 ng/mL; range: 3.1-9.3 ng/mL). The concentration-by-dose-ratio (C/D) was 6
Paulzen et al.
Sertraline in Pregnancy
calculated as concentration of sertraline (in ng/mL) divided by the daily dose of sertraline dose (in mg/day) according to [(ng/mL)/mg/day)] (Reis et al., 2004). In maternal serum it was 0.28 (Q1: 0.16, Q3: 0.37; range: 0.15-0.39 (ng/mL)/(mg/day)), for amniotic fluid 0.12 (Q1: 0.09, Q3: 0.18; range: 0.08-0.0.18 (ng/mL)/(mg/day)) and for cord blood 0.08 (Q1: 0.06, Q3: 0.15; range: 0.05-0.25 (ng/mL)/(mg/day)). The relation between the daily dosage of sertraline and its concentrations in maternal serum and cord blood failed to reach significance levels (p>0.05). However, daily dosage of sertraline was positively correlated amniotic fluid concentrations (r=0.833, p=0.039). Correlations were detected neither between values for serum and cord blood concentrations, nor for serum and amniotic fluid concentrations nor for amniotic fluid and cord blood concentrations of sertraline (p>0.05). The median penetration ratio for sertraline into amniotic fluid was 0.57 (Q1: 0.28, Q3: 0.75; range: 0.22-0.88). The median penetration ratio into the fetal circulation, calculated on the basis of umbilical cord blood-concentrations, was found to be 0.36 (Q1: 0.28, Q3: 0.49; range: 0.17-0.65), see fig. 1. “place fig. 1 about here” Discussion Wilson’s six principles of teratology have guided research in developmental toxicology to this day (Wilson, 1973). His sixth and final principle "Manifestations of Deviant Development Increase in Frequency and Degree as Dosage Increases, from No-effect to the Totally Lethal Level" among others describes the range of toxicity from no effect to completely lethal (Aston, 2014). This means that the outcome depends on dose, threshold and duration of xenobiotic influence and the lack of a correlation between maternal serum concentrations
7
Paulzen et al.
Sertraline in Pregnancy
and concentrations in fetal circulation suggests low drug concentrations in the unborn child and hence missing negative effects on the infant’s structural outcome. Aim of our study was to measure drug concentrations rather than evaluating obstetrical and/or structural outcome and we found relatively low concentrations of sertraline in amniotic fluid as well as in cord blood. Associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects remain controversial but the absolute risk of teratogenesis associated with SSRIs seems to be small (Jordan et al., 2016). However, differences in teratogenicity within the group of SSRIs makes it important to consider which antidepressant drug to recommend during pregnancy, and data suggest that paroxetine and perhaps fluoxetine should be avoided if possible. Data on the distribution pattern of sertraline between maternal blood, amniotic fluid and umbilical cord blood may help to assess the risk of in-utero exposition but are lacking so far, despite its worldwide prescription during pregnancy. Our ongoing prospective study aims to characterize the placental transfer and accumulation properties of different psychotropic drugs in amniotic fluid using serum concentrations as an indicator for drug concentrations in blood. Therapeutic drug monitoring (TDM) has proven a valuable clinical tool aiming patientmatched and safe psychopharmacotherapy, even during pregnancy (Hiemke et al., 2011) and data from epidemiological and cohort studies consistently support a sufficient reproductive safety profile for sertraline (Gadzhanova and Roughead, 2015; Reefhuis et al., 2015). Regardless of the contribution of maternal and fetal hepatic elimination of sertraline, our data suggest that fetal development occurs in a continuous environment of a pharmacologically active drug when pregnant women are treated with sertraline. With regard to the fetal exposure during pregnancy, it is important that the impact of measurable antidepressants’ concentrations in amniotic fluid, consistently ingested by swallowing 8
Paulzen et al.
Sertraline in Pregnancy
amniotic fluid in late pregnancy or due to respiratory exposure, should be systematically investigated (Hostetter et al., 2000; Loughhead et al., 2006). Fetal exposure can be more clearly defined by an improved understanding of the routes of fetal exposure and the factors that influence such pathways. Hence, measuring the concentration of sertraline in amniotic fluid and umbilical cord blood facilitates the understanding of intrauterine drug exposure during pregnancy. Knowledge about the penetration properties of different drugs into amniotic fluid or fetal circulation and knowledge about the correlation between the concentrations in the different compartments could stimulate the development of novel pharmaceutical agents that less easily enter amniotic fluid or fetal circulation, hence preventing the unborn child from potentially negative effects. Taken together, measuring sertraline concentrations in maternal blood during pregnancy is a valuable tool for predicting the in-utero exposition of the unborn child. As the daily dosage of sertraline significantly correlates with drug concentrations in amniotic fluid but not umbilical cord-blood it can be stated that sertraline rather selectively crosses the placenta. Additionally, it must be appreciated that maternal drug concentrations failed to show a correlation with drug concentrations in amniotic fluid or umbilical cord blood as it has been shown e.g. for lamotrigine (Paulzen et al., 2015b). It remains important to note that three of the six infants showed low initial APGAR scores necessitating a temporary observation in an ICU unit while the structural abnormality in one of the infants (trisomy 21) obviously cannot be attributed to the psychopharmacological treatment with sertraline. In this context, Gentile defined a prenatal antidepressant exposure syndrome in order to increase clinicians' awareness about the spectrum of risks which may concern the mother-infant pair when antidepressant treatment is deemed indispensable during late pregnancy (Gentile, 2010). 9
Paulzen et al.
Sertraline in Pregnancy
Therapeutic efforts should be driven by an orientation towards the lowest therapeutically effective serum concentrations of sertraline in maternal blood for an improvement in psychopathology or to prevent relapse of depressive episodes to reduce the threat of potentially negative effects on the fetus. The data presented here underscore the need to apply lowest doses for efficacy and to use multiple times of administration (b.i.d.) to avoid an overload of the placental barrier in the course of very high plasma or serum levels of a drug. From a clinical point of view, it might be helpful to target effective plasma or serum concentrations of sertraline that were considered to be effective before becoming pregnant. To ensure safety and efficacy of antidepressant treatment strategies during pregnancy, clinicians should be aware of both possible changes in serum concentration of the antidepressant drug as well as of changes in the psychopathology (Freeman et al., 2008). The first is controlled by therapeutic drug monitoring and a close cooperation between gynecologists and psychiatrists is recommended. The need for further research in order to warrant drug safety and efficacy during pregnancy remains as before. There is a considerable lack of data, although some assumptions of considerable interpatient variability regarding amniotic fluid and umbilical cord-blood drug concentrations can be made; e.g. in a sample of four pregnant patients the median cord-maternal concentration ratio for sertraline was 0.67 (Rampono et al., 2004). In our sample, the highest value reported was 0.65. Therefore, larger samples would be helpful to validate clinical observations. Limitations The small number of patients is obviously the main limitation of the study. Hence, our findings do not allow for drawing general conclusions on concentrations that can be expected within the investigated environments and corresponding effects. Further 10
Paulzen et al.
Sertraline in Pregnancy
information about the long-term effects of antidepressant drugs during pregnancy on others issues than birth defects (e.g. neurodevelopmental behavior) are mandatory for assessing the risk profile of psychotropic drugs that are prescribed during pregnancy (Gentile, 2010; Gentile and Galbally, 2011). Finally, information about the metabolizer status of the polymorphic cytochrome P450 enzymes (CYP2C19 and CYP2D6) in both, mother and infant, would be of high interest for better assessing the pharmacokinetic patterns and hence the exposition of both.
11
Paulzen et al.
Sertraline in Pregnancy
Authorship Contributions Participated in research design: MP, GG. Conducted experiments: MP, TWG, ES. Performed data analysis: MP, GS. Wrote or contributed to the writing of the manuscript: MP, TWG, ES, GG, GS
XII
Paulzen et al.
Sertraline in Pregnancy
Acknowledgments The authors wish to thank Mr. Geer Janssen from the Medical Care Center, Dr. Stein and colleagues, Moenchengladbach, Germany, for determination of sertraline for this investigation and for the fruitful collaboration. Furthermore, the authors wish to express their gratitude to the number of people from the Department of Gynecology and Obstetrics, RWTH Aachen University who support the ongoing study by identifying pregnant women that are medicated with psychotropic drugs. So special thanks goes to the whole wonderful team of midwifes and to Dr. Cordula Franz, Dr. Helena Sassmannshausen, Dr. Rebecca Caspers,
MUDr.
Tomáš
Kupec
XIII
and
Bartlomiej
Berger.
Paulzen et al.
Sertraline in Pregnancy
Declaration of interests Gerhard Gründer has served as a consultant for Boehringer Ingelheim (Ingelheim, Germany), Cheplapharm (Greifswald, Germany), Eli Lilly (Indianapolis, Ind, USA), Lundbeck (Copenhagen, Denmark), Ono Pharmaceuticals (Osaka, Japan), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Eli Lilly, Gedeon Richter (Budapest, Hungary), Janssen Cilag (Neuss, Germany), Lundbeck, Roche, Servier, and Trommsdorf (Aachen, Germany). He has received grant support from Boehringer Ingelheim and Roche. He is co-founder of Pharma Image GmbH (Düsseldorf, Germany) and Brainfoods UG (Selfkant, Germany). He reports no conflict of interest with this publication. Georgios Schoretsanitis received a grant from the bequest "in memory of Maria Zaoussi”, State Scholarships Foundation, Greece for clinical research in Psychiatry for the academic year 2015-2016. All other authors declare no conflicts of interest as well. The research study did not receive funds or support from any source.
XIV
Paulzen et al.
Sertraline in Pregnancy
Table / Figure legends Table 1: Patients' characteristics and clinical characteristics of six mothers taking sertraline during pregnancy and their infants. Figure 1: A – Boxplot of the penetration ratios into amniotic fluid (left), median 0.57, Q1: 0.28, Q3: 0.75; range: 0.22-0.88, and into the fetal circulation (right), median 0.36, Q1: 0.28, Q3: 0.49; range: 0.17-0.65. B-D – Correlations were detected neither between values for serum and cord blood concentrations (B) of sertraline, nor between amniotic fluid and cord blood levels (C) or between cord blood concentrations and amniotic fluid concentrations of sertraline (D) (p>0.05).
XV
Sertraline in Pregnancy
34
23
31
37
36
2
3
4
5
6
37+6
39+4
39+6
37+0
36+4
40+3
delivery (weeks)
Section
Section
Spontaneous
Section
Spontaneous
Section
Mode of delivery
2,560
4,125
3,635
3,370
2,180
3,760
weight (g)
Body sex
♂
♂
♂
♂
♂
♂
50th
3rd
73rd
53rd
90th
5th
Infant
Percentile
Weight
6/8/10
6/8/8
9/10/10
7/7/7
9/10/10
9/10/10
APGAR
25
100
100
50
50
100
(mg)
9.7
30.1
14.8
17.8
12.6
16.0
(ng/mL)
*
DD sertraline sertraline MS
0.39
0.30
0.15
0.36
0.25
0.16
C/D MS
4.5
9.0
10.0
4.0
8.8
14.0
(ng/mL)
sertraline AF
0.18
0.09
0.1
0.08
0.18
0.14
C/D AF
0.46
0.30
0.68
0.22
0.70
0.88
AF/MS
Ratio
6.3
9.3
5.9
3.1
5.5
5.0
(ng/mL)
sertraline CB
0.25
0.09
0.06
0.06
0.11
0.05
C/D CB
0.65
0.31
0.40
0.17
0.44
0.31
CB/MS
Ratio
-
quetiapine
-
-
-
-
medication
Concomitant
maternal anaemia
low APGAR, postnatal
maternal anaemia
low APGAR, postnatal
ng/mL x CF that is 3.27 in case of sertraline. DD – daily dose; MS – maternal serum; C/D – concentration to dose ratio in [(ng/mL)/[mg/day)]; AF –
XV
amniotic fluid; CB – Cord blood; PROM – premature rupture of membranes
anaemia
postnatal maternal
arrest
low APGAR, birth
trisomy 21
postnatally karyotyped
preterm birth,
PROM
Outcome / birth defect
Legend: *Plasma concentrations given in mass units can be converted to molar units by multiplication with the conversion factor (CF) nmol/L =
29
age
Maternal Gestational age at
1
Patient
table 1: Patients' characteristics and clinical characteristics of six mothers taking sertraline during pregnancy and their infants
Paulzen et al.
Paulzen et al.
Sertraline in Pregnancy
References Aston, S.A., 2014. James G. Wilson's Six Principles of Teratology, Embryo Project Encyclopedia ed. Embryo Project Encyclopedia. Cipriani, A., Furukawa, T.A., Salanti, G., Geddes, J.R., Higgins, J.P., Churchill, R., Watanabe, N., Nakagawa, A., Omori, I.M., McGuire, H., Tansella, M., Barbui, C., 2009. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multipletreatments meta-analysis. Lancet 373(9665), 746-758. Dayan, J., Creveuil, C., Marks, M.N., Conroy, S., Herlicoviez, M., Dreyfus, M., Tordjman, S., 2006. Prenatal depression, prenatal anxiety, and spontaneous preterm birth: a prospective cohort study among women with early and regular care. Psychosomatic medicine 68(6), 938946. Diego, M.A., Field, T., Hernandez-Reif, M., Schanberg, S., Kuhn, C., Gonzalez-Quintero, V.H., 2009. Prenatal depression restricts fetal growth. Early human development 85(1), 6570. Eshkoli, T., Sheiner, E., Ben-Zvi, Z., Feinstein, V., Holcberg, G., 2011. Drug transport across the placenta. Current pharmaceutical biotechnology 12(5), 707-714. Feghali, M., Venkataramanan, R., Caritis, S., 2015. Pharmacokinetics of drugs in pregnancy. Seminars in perinatology 39(7), 512-519. Freeman, M.P., Nolan, P.E., Jr., Davis, M.F., Anthony, M., Fried, K., Fankhauser, M., Woosley, R.L., Moreno, F., 2008. Pharmacokinetics of sertraline across pregnancy and postpartum. Journal of clinical psychopharmacology 28(6), 646-653. Gadzhanova, S., Roughead, E., 2015. Use of prescription medicines in Australian women of child-bearing age. BMC pharmacology & toxicology 16(1), 33. Ganapathy, V., Prasad, P.D., Ganapathy, M.E., Leibach, F.H., 2000. Placental transporters relevant to drug distribution across the maternal-fetal interface. Journal of Pharmacology and Experimental Therapeutics 294(2), 413-420. Gentile, S., 2010. On Categorizing Gestational, Birth, and Neonatal Complications Following Late Pregnancy Exposure to Antidepressants: The Prenatal Antidepressant Exposure Syndrome. CNS Spectrums 15(3), 167-185. Gentile, S., Galbally, M., 2011. Prenatal exposure to antidepressant medications and neurodevelopmental outcomes: a systematic review. Journal of affective disorders 128(1-2), 1-9. Giaginis, C., Theocharis, S., Tsantili-Kakoulidou, A., 2012. Current toxicological aspects on drug and chemical transport and metabolism across the human placental barrier. Expert opinion on drug metabolism & toxicology 8(10), 1263-1275. Grote, N.K., Bridge, J.A., Gavin, A.R., Melville, J.L., Iyengar, S., Katon, W.J., 2010. A metaanalysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Archives of general psychiatry 67(10), 1012-1024. Hebert, M.F., Easterling, T.R., Kirby, B., Carr, D.B., Buchanan, M.L., Rutherford, T., Thummel, K.E., Fishbein, D.P., Unadkat, J.D., 2008. Effects of pregnancy on CYP3A and Pglycoprotein activities as measured by disposition of midazolam and digoxin: a University of Washington specialized center of research study. Clinical pharmacology and therapeutics 84(2), 248-253. Hendrick, V., Stowe, Z.N., Altshuler, L.L., Hwang, S., Lee, E., Haynes, D., 2003. Placental passage of antidepressant medications. The American journal of psychiatry 160(5), 993-996.
I
Paulzen et al.
Sertraline in Pregnancy
Henrichs, J., Schenk, J.J., Roza, S.J., van den Berg, M.P., Schmidt, H.G., Steegers, E.A., Hofman, A., Jaddoe, V.W., Verhulst, F.C., Tiemeier, H., 2010. Maternal psychological distress and fetal growth trajectories: the Generation R Study. Psychological medicine 40(4), 633-643. Hiemke, C., Baumann, P., Bergemann, N., Conca, A., Dietmaier, O., Egberts, K., Fric, M., Gerlach, M., Greiner, C., Gründer, G., Haen, E., Havemann-Reinecke, U., Jaquenoud Sirot, E., Kirchherr, H., Laux, G., Lutz, U.C., Messer, T., Müller, M.J., Pfuhlmann, B., Rambeck, B., Riederer, P., Schoppek, B., Stingl, J., Uhr, M., Ulrich, S., Waschgler, R., Zernig, G., 2011. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011. Pharmacopsychiatry 44(6), 195-235. Hostetter, A., Ritchie, J.C., Stowe, Z.N., 2000. Amniotic fluid and umbilical cord blood concentrations of antidepressants in three women. Biol Psychiatry. 2000 Nov 15;48(10):1032-4. Hutson, J.R., Garcia-Bournissen, F., Davis, A., Koren, G., 2011. The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs. Clinical Pharmacology & Therapeutics 90(1), 67-76. Jimenez-Solem, E., 2014. Exposure to antidepressants during pregnancy--prevalences and outcomes. Danish medical journal 61(9), B4916. Jordan, S., Morris, J.K., Davies, G.I., Tucker, D., Thayer, D.S., Luteijn, J.M., Morgan, M., Garne, E., Hansen, A.V., Klungsoyr, K., Engeland, A., Boyle, B., Dolk, H., 2016. Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark. PloS one 11(12), e0165122. Kallen, B., Borg, N., Reis, M., 2013. The use of central nervous system active drugs during pregnancy. Pharmaceuticals (Basel). 2013 Oct 10;6(10):1221-86. doi: 10.3390/ph6101221. Kaplan, C., Zhang, Y., 2012. Assessing the comparative-effectiveness of antidepressants commonly prescribed for depression in the US Medicare population. The journal of mental health policy and economics 15(4), 171-178. Kobayashi, K., Ishizuka, T., Shimada, N., Yoshimura, Y., Kamijima, K., Chiba, K., 1999. Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. Drug metabolism and disposition: the biological fate of chemicals 27(7), 763-766. Laine, K., Heikkinen, T., Ekblad, U., Kero, P., 2003. Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry 60(7), 720-726. Loughhead, A.M., Fisher, A.D., Newport, D.J., Ritchie, J.C., Owens, M.J., DeVane, C.L., Stowe, Z.N., 2006. Antidepressants in amniotic fluid: another route of fetal exposure. American Journal of Psychiatry 163(1), 145-147. Mason, C.W., Buhimschi, I.A., Buhimschi, C.S., Dong, Y., Weiner, C.P., Swaan, P.W., 2011. ATP-binding cassette transporter expression in human placenta as a function of pregnancy condition. Drug metabolism and disposition: the biological fate of chemicals 39(6), 10001007. Newport, D.J., Wilcox, M.M., Stowe, Z.N., 2001. Antidepressants during pregnancy and lactation: defining exposure and treatment issues. Seminars in perinatology 25(3), 177-190. Nulman, I., Koren, G., Rovet, J., Barrera, M., Pulver, A., Streiner, D., Feldman, B., 2012. Neurodevelopment of children following prenatal exposure to venlafaxine, selective serotonin reuptake inhibitors, or untreated maternal depression. Am J Psychiatry. 2012 Nov 1;169(11):1165-74. doi: 10.1176/appi.ajp.2012.11111721.
II
Paulzen et al.
Sertraline in Pregnancy
Paulzen, M., Gründer, G., Orlikowsky, T., Graf, C.M., Hoeltzenbein, M., Veselinovic, T., 2015a. Suicide attempt during late pregnancy with quetiapine: nonfatal outcome despite severe intoxication. Journal of clinical psychopharmacology 35(3), 343-344. Paulzen, M., Lammertz, S.E., Veselinovic, T., Goecke, T.W., Hiemke, C., Gründer, G., 2015b. Lamotrigine in pregnancy - therapeutic drug monitoring in maternal blood, amniotic fluid, and cord blood. International clinical psychopharmacology 30(5), 249-254. Ram, D., Gandotra, S., 2015. Antidepressants, anxiolytics, and hypnotics in pregnancy and lactation. Indian journal of psychiatry 57(Suppl 2), S354-371. Rampono, J., Proud, S., Hackett, L.P., Kristensen, J.H., Ilett, K.F., 2004. A pilot study of newer antidepressant concentrations in cord and maternal serum and possible effects in the neonate. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum 7(3), 329-334. Rampono, J., Simmer, K., Ilett, K.F., Hackett, L.P., Doherty, D.A., Elliot, R., Kok, C.H., Coenen, A., Forman, T., 2009. Placental transfer of SSRI and SNRI antidepressants and effects on the neonate. Pharmacopsychiatry 42(3), 95-100. Reefhuis, J., Devine, O., Friedman, J.M., Louik, C., Honein, M.A., National Birth Defects Prevention, S., 2015. Specific SSRIs and birth defects: Bayesian analysis to interpret new data in the context of previous reports. Bmj 351, h3190. Reimers, A., Ostby, L., Stuen, I., Sundby, E., 2011. Expression of UDPglucuronosyltransferase 1A4 in human placenta at term. Eur J Drug Metab Pharmacokinet. 2011 Jan;35(3-4):79-82. doi: 10.1007/s13318-010-0021-x. Epub 2010 Dec 30. Reis, M., Aberg-Wistedt, A., Agren, H., Hoglund, P., Akerblad, A.C., Bengtsson, F., 2004. Serum disposition of sertraline, N-desmethylsertraline and paroxetine: a pharmacokinetic evaluation of repeated drug concentration measurements during 6 months of treatment for major depression. Human psychopharmacology 19(5), 283-291. Roca, A., Garcia-Esteve, L., Imaz, M.L., Torres, A., Hernandez, S., Botet, F., Gelabert, E., Subira, S., Plaza, A., Valdes, M., Martin-Santos, R., 2011. Obstetrical and neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitors: the relevance of dose. Journal of affective disorders 135(1-3), 208-215. Schaefer, C., 2011. Drug safety in pregnancy: utopia or achievable prospect? Risk information, risk research and advocacy in Teratology Information Services. Congenital anomalies 51(1), 6-11. Thomas, S.H.L., Yates, L.M., 2012. Prescribing without evidence - pregnancy. British journal of clinical pharmacology 74(4), 691-697. Uguz, F., Gezginc, K., Yazici, F., 2011. Are major depression and generalized anxiety disorder associated with intrauterine growth restriction in pregnant women? A case-control study. Gen Hosp Psychiatry. 2011 Nov-Dec;33(6):640.e7-9. doi: 10.1016/j.genhosppsych.2011.05.007. Epub 2011 Jun 21. Wang, J.S., Zhu, H.J., Gibson, B.B., Markowitz, J.S., Donovan, J.L., DeVane, C.L., 2008. Sertraline and its metabolite desmethylsertraline, but not bupropion or its three major metabolites, have high affinity for P-glycoprotein. Biological & pharmaceutical bulletin 31(2), 231-234. Wilson, J.G., 1973. Environment and Birth Defects. Academic Press, New York. Xu, Z.H., Wang, W., Zhao, X.J., Huang, S.L., Zhu, B., He, N., Shu, Y., Liu, Z.Q., Zhou, H.H., 1999. Evidence for involvement of polymorphic CYP2C19 and 2C9 in the N-demethylation of sertraline in human liver microsomes. Br J Clin Pharmacol 48(3), 416-423.
III
Paulzen et al.
Sertraline in Pregnancy
Key points / highlights
·
Therapeutic drug monitoring in maternal serum, amniotic fluid and cord-blood allows for calculation of in-utero exposition during antidepressant therapy.
·
Sertraline concentrations in amniotic fluid give evidence that maternally administered sertraline is constantly accessible to the fetus.
·
A relatively low penetration into fetal circulation may contribute to the sufficient reproductive safety profile of sertraline.
IV
Paulzen et al.
Sertraline in Pregnancy
V