pharmacoepidemiology and drug safety (2015) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.3749
Exposure to aripiprazole during embryogenesis: a prospective multicenter cohort study† Florelle Bellet1*, Marie-Noëlle Beyens1, Nathalie Bernard2, Delphine Beghin3, Elisabeth Elefant3 and Thierry Vial2 1
Centre Régional de Pharmacovigilance, Centre Hospitalo-Universitaire, Saint-Etienne, France Centre Régional de Pharmacovigilance, Hospices Civils de Lyon, Lyon, France 3 Centre de Référence sur les Agents Tératogènes, Hôpital Trousseau, Paris, France 2
ABSTRACT Purpose The main purpose of this study was to evaluate the risk of major malformations after aripiprazole exposure during the embryonic period. The secondary purposes were to assess the risk of miscarriage, prematurity, fetal growth retardation and maternal complications and to describe possible neonatal adverse effects. Methods We conducted a cohort study using data prospectively collected by the French Pharmacovigilance Centres participating to the Terappel program and the Centre de Référence sur les Agents Tératogènes between 2004 and 2011. The exposed group consisted of pregnant women exposed to aripiprazole during embryogenesis, and the unexposed group consisted of pregnant women without exposure or exposed to non-teratogenic agents. Two unexposed patients, matched for age and gestational age at call, were randomly selected for each exposed patient. Results Eighty-six patients were included in the exposed group and 172 in the unexposed group. Exposure to aripiprazole was not significantly associated with an increased rate of major malformations (OR 2.30, 95%CI 0.32–16.7) or miscarriage (1.66, 0.63–4.38) or gestational diabetes (1.15, 0.33–4.04) compared to non-exposure. The study revealed signiﬁcantly increased rates of prematurity (OR 2.57, 95%CI 1.06–6.27) and fetal growth retardation (2.97, 1.23–7.16) in exposed newborns, difﬁcult to interpret because of the short duration of maternal exposure. Two cases of neonatal complications were reported among the 19 newborns exposed to aripiprazole near delivery. Conclusion This study failed to demonstrate a signiﬁcant association between aripiprazole exposure during the embryonic period and major malformations. More powerful prospective studies are required to clarify the reproductive safety proﬁle of aripiprazole. Copyright © 2015 John Wiley & Sons, Ltd. key words—aripiprazole; cohort study; embryogenesis; malformation; pregnancy; pharmacoepidemiology Received 11 June 2014; Revised 16 September 2014; Accepted 10 December 2014
INTRODUCTION Pregnancy is a vulnerable period for women affected by psychiatric diseases. The risk of adverse maternal and neonatal outcomes associated with untreated psychiatric disorders has to be weighed against the possible negative effects of psychotropic drugs used during pregnancy. *Correspondence to: F. Bellet, Centre Régional de Pharmacovigilance, Centre Hospitalo-Universitaire de Saint-Etienne, Hôpital Nord, 42055 Saint-Etienne Cedex 2, France. E-mail: ﬂ[email protected]
th † This study has been presented as an oral communication at the 8 Meeting of Physiology, Pharmacology and Therapeutics (P2T) (Angers, France, April 22– th 24, 2013) and as a poster at the 13 International Society of Pharmacovigilance (ISOP) Annual Meeting (Pisa, Italy, October 1–4, 2013).
Copyright © 2015 John Wiley & Sons, Ltd.
Aripiprazole is an atypical antipsychotic with a unique action mechanism. It is a partial agonist of dopamine D2 and serotonin 5-HT1A receptors, and an antagonist of 5-HT2A receptors. It is marketed in France since 2004 and approved for schizophrenia and bipolar disorder. Its use is growing, including in women of childbearing age, while its reproductive safety proﬁle is relatively unknown. Preclinical studies have suggested a potential teratogenic effect, with an increased rate of diaphragmatic hernia in rats at high doses.1,2 Currently, clinical data are based on very sparse studies3–6 and isolated case reports7–18 that do not suggest a speciﬁc pattern of malformations that may be related to aripiprazole. It was conﬁrmed that this antipsychotic cross the placenta11,17 and isolated fetal or neonatal
f. bellet et al.
complications after exposure near delivery were reported.7,11,17 Accordingly, because of insufﬁcient clinical data and concerns raised by animal reproductive studies, aripiprazole is not recommended during pregnancy unless the expected beneﬁt clearly outweighs the potential risk to the fetus. The main objective of this study was to assess the association between exposure to aripiprazole during the embryonic period and major malformations. Secondary objectives were to assess the risk of miscarriage, prematurity, fetal growth retardation (FGR) and maternal complications and to describe possible neonatal adverse effects. METHODS Study design and data sources We conducted an observational prospective cohort study using two French databases speciﬁcally designed for collecting drug-exposed pregnancies: Terappel, a database shared by 20 pharmacovigilance centres, and the Paris TIS (Centre de Référence sur les Agents Tératogènes) database. Participants This study enrolled pregnant women who had contacted, directly or via their health care provider, a pharmacovigilance centre participating to the Terappel program or the Paris TIS, seeking counselling about the reproductive safety of drugs or other exposures, between July 2004 and December 2011. Patients included in the exposed group were women exposed to aripiprazole during embryogenesis, i.e. 4 to 10 gestational weeks (GW, i.e. weeks after the last menstrual period), whatever the duration of treatment during this period. The period of exposure included the duration of treatment and the duration of excretion of aripiprazole and its active metabolite after drug discontinuation, i.e. at least 28 days. Patients included in the unexposed group were women without exposure or exposed to agents known to be non-teratogenic (e.g. paracetamol, penicillins, oral contraceptive stopped before 6 GW, non-live vaccines, topical preparations with negligible systemic absorption, cosmetics, X-ray and MRI examinations, except examinations of the lower abdomen and pelvis…). Patients excluded from the study were: (i) duplicates, (ii) women not pregnant at the time of ﬁrst contact (preventive and retrospective cases), (iii) whose fetus had been identiﬁed as carrying a developmental anomaly before ﬁrst contact (retrospective cases), (iv) with ongoing pregnancy at 31 December 2011 and (5) lost to follow-up. Patients were also excluded from the Copyright © 2015 John Wiley & Sons, Ltd.
exposed group if they were co-exposed to known teratogen(s) during embryogenesis (e.g. carbamazepine, carbimazole, cyclophosphamide, lithium, methotrexate, misoprostol, mycophenolate, phenobarbital, retinoids, thalidomide, valproic acid and vitamin K antagonists). Two unexposed patients, matched for age (± 2 years) and gestational age at ﬁrst call (± 2 weeks), were randomly selected for each exposed patient. Documentation and follow-up All centres used similar documentation and follow-up methodology. Data ascertainment was performed using standardised questions at initial telephone contact and structured questionnaires after birth. At initial contact, data recorded were: maternal demographic characteristics, personal and familial medical history, previous and current obstetrical history, smoking, alcohol consumption and detailed exposures since the beginning of pregnancy, including concomitant prescription and non-prescription drugs (exact timing of exposure, dose and indication) and drugs of abuse. Prospective follow-up was conducted within 2 months of the expected date of delivery and focused on the course of pregnancy, gestational age at delivery, birth weight, congenital malformations and neonatal complications. Data processing Data were checked and validated before analysis. In case of incoherence, clariﬁcation was requested to the responsible centre. Primary endpoints The primary endpoint of the study was the presence of a major congenital malformation not related to a chromosomal defect or clinical genetic syndrome. Major malformations were deﬁned as malformations resulting in serious medical, surgical or cosmetic consequences.19 Congenital malformations were classiﬁed as either major or minor independently by two experts according to the European Surveillance of Congenital Anomalies (EUROCAT) guide.20 Only examinable babies and fetuses with anatomopathological examination were considered for malformation rate calculation. Secondary endpoints The secondary endpoints included (i) pregnancy course: miscarriage (spontaneous abortion before 22 GW), voluntary or therapeutic abortion, stillbirth (intrauterine death of the fetus after 22 GW) or live birth, (ii) preterm birth (birth occurring before 37 GW, Pharmacoepidemiology and Drug Safety, (2015) DOI: 10.1002/pds
exposure to aripiprazole during pregnancy: a prospective cohort study
excluding multiple births), (iii) FGR (birth weight