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Exposure to Reactive Intermediate-Inducing Drugs During Pregnancy and the Incident Use of Psychotropic Medications Among Children

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Exposure to Reactive Intermediate-Inducing Drugs During Pregnancy and the Incident Use of Psychotropic Medications Among Children pharmacoepidemiology and drug safety 2017; 26: 265–273 Published online 18 January 2017 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.4161 ORIGINAL REPORT Exposure to reactive intermediate-inducing drugs during pregnancy and the incident use of psychotropic medications among children Yen-Hao Tran1* , Henk Groen2, Jorieke E.H. Bergman3, Eelko Hak1 and Bob Wilffert1,4 1Groningen Research Institute of Pharmacy, Unit of Pharmacotherapy, Epidemiology and Economics, University of Groningen, Groningen, The Netherlands 2Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 3Eurocat Registration Northern Netherlands, Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 4Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands ABSTRACT Purpose Our study aimed to investigate the association between prenatal exposure to reactive intermediate (RI)-inducing drugs and the initiation of psychotropic medications among children. Methods We designed a cohort study using a pharmacy prescription database. Pregnant women were considered exposed when they received a prescription of RI-inducing drugs. These drugs could be either used alone (RI+/FAAÀ) or combined with drugs exhibiting folic acid antagonism (FAA, RI+/FAA+). The reference group included pregnant women who did not receive any RI-inducing drugs or FAA drugs. Results We analyzed 4116 exposed and 30 422 reference pregnancies. The hazard ratio (HR) with 95% confidence interval (CI) was 1.27 (95%CI 1.15–1.41) for pregnancies exposed to RI-inducing drugs as a whole. Considering subgroups of RI-inducing drugs, prenatal exposure to both RI+/FAA+ and RI+/FAAÀ was associated with the children’s initiation of psychotropic medications, HRs being 1.35 (95%CI 1.10–1.66) and 1.26 (1.13–1.41), respectively. The HRs were increased with prolonged exposure to RI-inducing drugs, especially in the first and second trimesters. In a detailed examination of the psychotropics, the incidences of receiving antimigraine preparations and psychostimulants were significantly increased for the exposed children, compared with the reference children. The incidences of receiving antipsychotics and hypnotics were also higher for the exposed children; however, the HRs did not reach significance after adjustment. Conclusions We found a significantly increased incident use of psychotropic medications among children prenatally exposed to RI-inducing drugs, especially during the first and second trimesters. This suggests a detrimental effect during critical periods of brain development. Copyright © 2017 John Wiley & Sons, Ltd. key words—reactive intermediates; folic acid antagonism; pregnancy; drug exposure; psychotropic medications; pharmacoepidemiology Received 14 August 2016; Revised 7 December 2016; Accepted 11 December 2016 INTRODUCTION and the self-repair of oxidative damage.1 An imbal- ance towards increased RIs and ROS may adversely Drugs can exert their teratogenicity through a reactive affect the fetus. intermediate (RI)-mediated mechanism. This mecha- Experimental studies found widespread neuronal nism involves the bioactivation of a relatively non- death in the developing brain under ROS-induced toxic drug into electrophilic/free radical RIs and conditions (e.g., hypoxia and high glucose concentra- reactive oxygen species (ROS), which damage cellular tions).2,3 Additionally, the use of ionizing radiation macromolecules or alter signal transduction. However, as a source of RI and ROS generation in adult mice there are other counteracting pathways: the detoxifica- showed that the brain was the most vulnerable among tion of cellular antioxidants and detoxifying enzymes all other tissues.4 Besides, human studies have added the role of increased oxidative markers in various *Correspondence to: Y.-H. Tran, Groningen Research Institute of Pharmacy, nervous system disorders,5–7 whereby environmental Unit of Pharmacotherapy, Epidemiology and Economics, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. factors and genetic alterations in redox enzymes may Email: [email protected] share a role. Copyright © 2017 John Wiley & Sons, Ltd. 266 y.-h. tran et al. We therefore hypothesized that prenatal exposure to Exposure ’ RI-inducing drugs might have an effect on the child s Drug identification. Because RIs are not stable nervous system. We set out to examine the incident enough to be transported from the mother to the fetus, use of psychotropic medications (as a proxy for the they must be generated within the fetus to exert a effect on the nervous system) among the exposed teratogenic effect.1 Although a dose–response rela- and reference children. Because folates (folic acid tionship has been suggested for teratogens, a dose and its derivatives) may act as free radical scavengers threshold for the teratogenicity of most drugs has not or link to the metabolism of the cellular antioxidant 8,9 been determined. To identify RI-inducing drugs, we glutathione, folates may be associated with the first listed all drugs used by pregnant women in the fi detoxi cation process. We thereby explored the database. We cross-referenced these drugs against exposure to drugs exhibiting folic acid antagonism previously compiled lists of drugs that are known to (FAA) in addition to RI-inducing-drugs. be bioactivated into RIs and ROS (Supporting infor- mation). We selected 48 drugs with systemic absorp- METHODS tion and with a defined daily dose (DDD) ≥50 mg (based on http://www.whocc.no/atc_ddd_index/) as Design and setting RI-inducing drugs (Table S1). The cut-off value of Our cohort study used the pregnancy database, which 50 mg was chosen on the basis of the relationship is part of the pharmacy prescription database (IADB. between daily dose and idiosyncratic adverse drug nl) holding prescription records of approximately reactions (IADRs)12,13: (1) IADRs mainly resulted 600 000 patients in the Northern Netherlands. Because from conjugates of an electrophilic RI of a drug with of the high patient pharmacy loyalty in the cellular macromolecules; and (2) more than 90% of Netherlands, the prescription records for each patient drugs with black box warning for IADRs have a in the database are virtually complete, except for DDD ≥50 mg. Thus, we used the cut-off value of over-the-counter (OTC) drugs and drugs dispensed 50 mg to select drugs with a higher burden of RI and during hospitalization.10 ROS generation, making them more likely to be The pregnancy database was generated by linking associated with RI-mediated adverse effects. a mother to her child using an address code as previously described.11 Approximately 65% of the We identified FAA drugs using the list of van children in the main IADB database could be linked Gelder14 and the current Pubmed entries of “Folic to their mothers, and validation showed 99% Acid Antagonists” (Pharmacological Action). Addi- accuracy.11 tionally, we searched the whole PubMed database up Because we only used unidentifiable pre-existing to August 2015, using the terms “Folic Acid data, ethical approval was not needed. Antagonists”[Mesh] AND Review[ptyp]. This resulted in 608 citations from which one additional Study population FAA drug (proguanil) was found. In total, 14 FAA drugs were used in the pregnancy database. Eight We included pregnancies with children born between drugs have both RI-inducing and FAA properties 1994 and 2011. Pregnancies were excluded if they (sulfasalazine, trimethoprim, phenobarbital, resulted in twins/multiple births (i.e., more than one primidone, phenytoin, carbamazepine, valproic acid, child born on the same date and at the same address and lamotrigine) (Table S2). with one possible mother). Pregnancies were also excluded if they had less than 12 months of maternal data prior to the child’s birth or less than 36 months Exposure definitions. Because information on the of child data, or if they were exposed to FAA drugs conception date was unavailable, we used a standard- only (RIÀ/FAA+). When we compared the RI+/FAA ized period of 273 days to define pregnancy duration + exposure group with the reference group (see section (91 days for each trimester) as previously described.15 on Exposure definations and Figure 1), we excluded The exposed group included women who received a pregnancies that were not exposed to RI-inducing prescription of RI-inducing drugs at any time during drugs and FAA drugs in the same trimester. Figure 1 pregnancy or received a prescription of RI-inducing shows the flow diagram of the study population. drugs before pregnancy, but the duration of the treat- Depending on the sensitivity analyses, we considered ment lasted into pregnancy. The reference group in- other exclusion criteria (see section on Sensitivity cluded women who did not receive any RI-inducing analyses). drugs or FAA drugs during pregnancy. Copyright © 2017 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2017; 26: 265–273 DOI: 10.1002/pds prenatal exposure to ri-inducing drugs 267 Figure 1. Flow diagram of the study population We also investigated exposure to RI-inducing drugs +/FAA+ category included eight drugs with both in each trimester. Exposure in the second trimester RI-inducing and FAA properties, and/or an excluded women who had a prior exposure in the first RI-inducing drug only (RI+/FAAÀ) combined with trimester, and exposure in the third trimester excluded an FAA drug only (RIÀ/FAA+) in the same trimester. women who had a prior exposure in the first and Finally, we stratified the exposure into three second trimesters. standardized levels of DDDs of RI-inducing drugs: Similarly, we investigated two different FAA expo- ≤3DDDs, 3–14DDDs (this category does not include sure categories: exposure to the combination of 3DDDs) and >14DDDs. This categorization was RI-inducing and FAA drugs (RI+/FAA+) and expo- used to distinguish short-term use from prolonged sure to RI-inducing drugs only (RI+/FAA–). The RI use. Copyright © 2017 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2017; 26: 265–273 DOI: 10.1002/pds 268 y.-h.
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