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  1. Hospital Pharmacy, Albert Schweitzer Hospital, Dordrecht, The Netherlands
  2. Department of Elderly Care Medicine, Amsterdam Public Health Research Institute, Amsterdam UMC (location VUmc), Amsterdam, The Netherlands
  3. Corresponding author: Marieke M. Beex-Oosterhuis, PharmD, Albert Schweitzerplaats 25, 3318 AT Dordrecht, The Netherlands ([email protected]).
  4. Emergis, Institute for Mental Health Care, Goes, The Netherlands
  5. Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
  6. Department of Clinical Pharmacy, Utrecht University Medical Center, Utrecht, The Netherlands
  7. Research Group Innovation of Pharmaceutical Care, University of Applied Sciences Utrecht, Utrecht, The Netherlands
  8. Hospital Pharmacy, Albert Schweitzer Hospital, Dordrecht, The Netherlands
  9. Department of Elderly Care Medicine, Amsterdam Public Health Research Institute, Amsterdam UMC (location VUmc), Amsterdam, The Netherlands
  10. Geriatric and Clinical Pharmacology Department, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands
  1. Meltzer HY. An overview of the mechanism of action of clozapine. J Clin Psychiatry. 1994;55(suppl B):47–52. PubMed
  2. Stroup TS, Gerhard T, Crystal S, et al. Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia. Am J Psychiatry. 2016;173(2):166–173. PubMed CrossRef
  3. Remington G, Lee J, Agid O, et al. Clozapine’s critical role in treatment resistant schizophrenia: ensuring both safety and use. Expert Opin Drug Saf. 2016;15(9):1193–1203. PubMed CrossRef
  4. Clozapine Product Manufacturers Group. Clozapine risk evaluation and mitigation strategy (REMS). Clozapine REMS. Accessed April 29, 2021. https://www.clozapinerems.com
  5. Toh S, Li Q, Cheetham TC, et al. Prevalence and trends in the use of antipsychotic medications during pregnancy in the US, 2001–2007: a population-based study of 585,615 deliveries. Arch Women Ment Health. 2013;16(2):149–157. PubMed CrossRef
  6. Forrester T, Siskind D, Winckel K, et al. Increasing clozapine dispensing trends in Queensland, Australia 2004–2013. Pharmacopsychiatry. 2015;48(4-5):164–169. PubMed CrossRef
  7. Gören JL, Rose AJ, Smith EG, et al. The business case for expanded clozapine utilization. Psychiatr Serv. 2016;67(11):1197–1205. PubMed CrossRef
  8. Genees-en hulpmiddelen Informatie Project (GIP), Zorginstituut Nederland, The Netherlands. The drug information system of National Health Care Institute. GIPdatabank. Updated 2018. Accessed November 15, 2018. https://www.gipdatabank.nl/databank.asp
  9. Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Disease Primers. 2015. https://www.nature.com/articles/nrdp201567
  10. Cohen LS, Viguera AC, McInerney KA, et al. Reproductive safety of second-generation antipsychotics: current data from the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics. Am J Psychiatry. 2016;173(3):263–270. PubMed CrossRef
  11. Howard LML, Thornicroft G, Salmon M, et al. Predictors of parenting outcome in women with psychotic disorders discharged from mother and baby units. Acta Psychiatr Scand. 2004;110(5):347–355. PubMed CrossRef
  12. Gilbert H. “About Helen”: antipsychotic medication use during pregnancy. A case study. Aust Nurs J. 2009;16(7):20.
  13. Chisolm MS, Payne JL. Management of psychotropic drugs during pregnancy. BMJ. 2016;532:h5918. PubMed
  14. Huybrechts KF, Hernández-Díaz S, Patorno E, et al. Antipsychotic use in pregnancy and the risk for congenital malformations. JAMA Psychiatry. 2016;73(9):938–946. PubMed CrossRef
  15. Mehta TM, Van Lieshout RJ. A review of the safety of clozapine during pregnancy and lactation. Arch Women Ment Health. 2017;20(1):1–9. PubMed CrossRef
  16. Moher D, Liberati A, Tetzlaff J, et al; PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. PubMed CrossRef
  17. Westin AA, Brekke M, Molden E, et al. Treatment with antipsychotics in pregnancy: changes in drug disposition. Clin Pharmacol Ther. 2018;103(3):477–484. PubMed CrossRef
  18. Hatters Friedman S, Moller-Olsen C, Prakash C, et al. Atypical antipsychotic use and outcomes in an urban maternal mental health service. Int J Psychiatry Med. 2016;51(6):521–533. PubMed CrossRef
  19. Kulkarni J, Worsley R, Gilbert H, et al. A prospective cohort study of antipsychotic medications in pregnancy: the first 147 pregnancies and 100 one year old babies. PLoS One. 2014;9(5):e94788. PubMed CrossRef
  20. Bodén R, Lundgren M, Brandt L, et al. Antipsychotics during pregnancy: relation to fetal and maternal metabolic effects. Arch Gen Psychiatry. 2012;69(7):715–721. PubMed CrossRef
  21. Reis M, Källén B. Maternal use of antipsychotics in early pregnancy and delivery outcome. J Clin Psychopharmacol. 2008;28(3):279–288. PubMed CrossRef
  22. Beex-Oosterhuis MM, Samb A, Heerdink ER, et al. Safety of clozapine use during pregnancy: analysis of international pharmacovigilance data. Pharmacoepidemiol Drug Saf. 2020;29(6):725–735. PubMed CrossRef
  23. Montastruc F, Salvo F, Arnaud M, et al. Signal of gastrointestinal congenital malformations with antipsychotics after minimising competition bias: a disproportionality analysis using data from vigibase. Drug Saf. 2016;39(7):689–696. PubMed CrossRef
  24. Shao P, Ou J, Peng M, et al. Effects of clozapine and other atypical antipsychotics on infants development who were exposed to as fetus: a post-hoc analysis. PLoS One. 2015;10(4):e0123373. PubMed CrossRef
  25. Newham JJ, Thomas SH, MacRitchie K, et al. Birth weight of infants after maternal exposure to typical and atypical antipsychotics: prospective comparison study. Br J Psychiatry. 2008;192(5):333–337. PubMed CrossRef
  26. Oltulu C, Karadag CH. The effect of intrauterine antipsychotic drug exposure on learning and memory in adult rats. Klin Psikofarmakol Bul. 2016;26(4):364–373. CrossRef
  27. Donohoe DR, Weeks K, Aamodt EJ, et al. Antipsychotic drugs alter neuronal development including ALM neuroblast migration and PLM axonal outgrowth in Caenorhabditis elegans. Int J Dev Neurosci. 2008;26(3–4):371–380. PubMed CrossRef
  28. Wang JH, Yang JZ, Wilson FAW, et al. Differently lasting effects of prenatal and postnatal chronic clozapine/haloperidol on activity and memory in mouse offspring. Pharmacol Biochem Behav. 2006;84(3):468–478. PubMed CrossRef
  29. Nguyen T, Mordecai J, Watt F, et al. Obstetric and neonatal outcomes of clozapine exposure in pregnancy: a consecutive case series. Arch Women Ment Health. 2020;23(3):441–445. PubMed CrossRef
  30. Imaz ML, Oriolo G, Torra M, et al. Clozapine use during pregnancy and lactation: a case-series report. Front Pharmacol. 2018;9:264. PubMed CrossRef
  31. Molins C, Fortea A, Bioque M, et al. Clozapine and electroconvulsive therapy is an effective and safe treatment during pregnancy: a case report. J ECT. 2019;35(3):e30–e32. PubMed CrossRef
  32. Narayanaswamy P, Shaji KS, Sumesh TP. Meningomyelocele on exposure to clozapine during prenatal period. Indian J Psychiatry. 2018;60(5):71.
  33. Uygur ÖF, Uygur H. Neurodevelopmental and growth follow-up of the baby exposed to antipsychotics during pregnancy and lactation: a case report. Psychiatry Clin Psychopharmacol. 2019;29(4):744–747. CrossRef
  34. Hodge F, Amin P, Smith S. Case report: CTG abnormalities due to clozapine use. BJOG Int J Obstet Gynaecol. 2016;123:50.
  35. Köse Çınar R. Olanzapine and clozapine use in a woman with schizophrenia during consecutive pregnancies: a case report. Drugs Ther Perspect. 2016;32(9):403–405. CrossRef
  36. Sreeraj VS, Venkatasubramanian G. Safety of clozapine in a woman with triplet pregnancy: A case report. Asian J Psychiatr. 2016;22:67–68. PubMed CrossRef
  37. Guyon L, Auffret M, Coussemacq M, et al. Alteration of the fetal heart rate pattern induced by the use of clozapine during pregnancy. Therapie. 2015;70(3):301–303. PubMed CrossRef
  38. Coston A-L, Hoffmann P, Equy V, et al. Fetal heart rate variability and clozapine treatment. Gynécol Obstét Fertil. 2012;40(9):549–552. PubMed CrossRef
  39. Moreno-Bruna MD, de Montgolfier I, Chabaud M, et al. Case report: neonatal delayed peristalsis after in-utero exposure to clozapine. Arch Pediatr. 2012;19(9):913–916. PubMed CrossRef
  40. Novikova N, Chitnis M, Linder V, et al. Atypical antipsychotic (clozapine) self-poisoning in late pregnancy presenting with absent fetal heart rate variability without acidosis and delayed peristalsis in the newborn baby: a case report. Aust N Z J Obstet Gynaecol. 2009;49(4):442–444. PubMed CrossRef
  41. Duran A, Ugur MM, Turan S, et al. Clozapine use in two women with schizophrenia during pregnancy. J Psychopharmacol. 2008;22(1):111–113. PubMed CrossRef
  42. Kłys M, Rojek S, Rzepecka-Woźniak E. Neonatal death following clozapine self-poisoning in late pregnancy: an unusual case report. Forensic Sci Int. 2007;171(1):e5–e10. PubMed CrossRef
  43. Mendhekar DN. Possible delayed speech acquisition with clozapine therapy during pregnancy and lactation. J Neuropsychiatry Clin Neurosci. 2007;19(2):196–197. PubMed CrossRef
  44. Sethi S. Clozapine in pregnancy. Indian J Psychiatry. 2006;48(3):196–197. PubMed CrossRef
  45. Doherty J, Bell PF, King DJ. Implications for anaesthesia in a patient established on clozapine treatment. Int J Obstet Anesth. 2006;15(1):59–62. PubMed CrossRef
  46. Walch E, Blankenstein O, Bührer C. Conspicuous facies with microcephaly in intrauterine clozapine exposure. diagnosis: congenital hypothyroidism and trisomy 21, left middle-ear deafness. Monatsschr Kinderheilkd. 2005;153(11):1108–1110.
  47. Gupta N, Grover S. Safety of clozapine in 2 successive pregnancies. Can J Psychiatry. 2004;49(12):863. PubMed CrossRef
  48. Karakuła H, Szajer K, Spila B, et al. Clozapine and pregnancy: a case history. Pharmacopsychiatry. 2004;37(6):303–304. PubMed CrossRef
  49. Mendhekar DN, Sharma JB, Srivastava PK, et al. Clozapine and pregnancy. J Clin Psychiatry. 2003;64(7):850. PubMed CrossRef
  50. Nguyen HN, Lalonde P. Clozapine and pregnancy. Encephale. 2003;29(2):119–124. PubMed
  51. Yogev Y, Ben-Haroush A, Kaplan B. Maternal clozapine treatment and decreased fetal heart rate variability. Int J Gynaecol Obstet. 2002;79(3):259–260. PubMed CrossRef
  52. Dickson RA, Hogg L. Pregnancy of a patient treated with clozapine. Psychiatr Serv. 1998;49(8):1081–1083. PubMed CrossRef
  53. Tënyi TTM. Clozapine in the treatment of pregnant schizophrenic women. Psychiatr Danub. 1998;10(1):15–18.
  54. Stoner SC, Sommi RWJ Jr, Marken PA, et al. Clozapine use in two full-term pregnancies. J Clin Psychiatry. 1997;58(8):364–365. PubMed CrossRef
  55. Di Michele V, Ramenghi L, Sabatino G. Clozapine and lorazepam administration in pregnancy. Eur Psychiatry. 1996;11(4):214–219. PubMed CrossRef
  56. Dev VJ, Krupp P. Adverse event profile and safety of clozapine. Rev Contemp Pharmacother. 1995;6:197–208.
  57. Barnas C, Bergant A, Hummer M, et al. Clozapine concentrations in maternal and fetal plasma, amniotic fluid, and breast milk. Am J Psychiatry. 1994;151(6):945. PubMed CrossRef
  58. Waldman MDM, Safferman AZ. Pregnancy and clozapine. Am J Psychiatry. 1993;150(1):168–169. PubMed CrossRef
  59. Tracy TS, Venkataramanan R, Glover DD, et al; National Institute for Child Health and Human Development Network of Maternal-Fetal-Medicine Units. Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancy. Am J Obstet Gynecol. 2005;192(2):633–639. PubMed CrossRef
  60. Abernethy DR, Todd EL. Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives. Eur J Clin Pharmacol. 1985;28(4):425–428. PubMed CrossRef
  61. Schoretsanitis G, Kane JM, de Leon J. Adding oral contraceptives to clozapine may require halving the clozapine dose: a new case and a literature review. J Clin Psychopharmacol. 2020;40(3):308–310. PubMed CrossRef
  62. Newport DJ, Calamaras MR, DeVane CL, et al. Atypical antipsychotic administration during late pregnancy: placental passage and obstetrical outcomes. Am J Psychiatry. 2007;164(8):1214–1220. PubMed CrossRef
  63. Ke AB, Rostami-Hodjegan A, Zhao P, et al. Pharmacometrics in pregnancy: an unmet need. Annu Rev Pharmacol Toxicol. 2014;54(1):53–69. PubMed CrossRef
  64. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. 10th ed. Lippincott Williams & Wilkins; 2014.
  65. Schaber G, Stevens I, Gaertner HJ, et al. Pharmacokinetics of clozapine and its metabolites in psychiatric patients: plasma protein binding and renal clearance. Br J Clin Pharmacol. 1998;46(5):453–459. PubMed CrossRef
  66. Brunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill; 2011.
  67. Israili ZH, Dayton PG. Human alpha-1-glycoprotein and its interactions with drugs. Drug Metab Rev. 2001;33(2):161–235. PubMed CrossRef
  68. Notarianni LJ. Plasma protein binding of drugs in pregnancy and in neonates. Clin Pharmacokinet. 1990;18(1):20–36. PubMed CrossRef
  69. O’Hara K, Wright IM, Schneider JJ, et al. Pharmacokinetics in neonatal prescribing: evidence base, paradigms and the future. Br J Clin Pharmacol. 2015;80(6):1281–1288. PubMed CrossRef
  70. Jassen AK, Yang H, Miller GM, et al. Receptor regulation of gene expression of axon guidance molecules: implications for adaptation. Mol Pharmacol. 2006;70(1):71–77. PubMed CrossRef
  71. Spencer GEG, Klumperman J, Syed NI. Neurotransmitters and neurodevelopment: role of dopamine in neurite outgrowth, target selection and specific synapse formation. Perspect Dev Neurobiol. 1998;5(4):451–467. PubMed
  72. Fernandez E, Perez R, Hernandez A, et al. Factors and mechanisms for pharmacokinetic differences between pediatric population and adults. Pharmaceutics. 2011;3(1):53–72. PubMed CrossRef
  73. Grundmann M, Kacirova I, Urinovska R. Therapeutic drug monitoring of atypical antipsychotic drugs. Acta Pharm. 2014;64(4):387–401. PubMed CrossRef
  74. Myles N, Myles H, Xia S, et al. Meta-analysis examining the epidemiology of clozapine-associated neutropenia. Acta Psychiatr Scand. 2018;138(2):101–109. PubMed CrossRef
  75. Webb RT, Pickles AR, King-Hele SA, et al. Parental mental illness and fatal birth defects in a national birth cohort. Psychol Med. 2008;38(10):1495–1503. PubMed CrossRef
  76. Galbally M, Snellen M, Power J. Antipsychotic drugs in pregnancy: a review of their maternal and fetal effects. Ther Adv Drug Saf. 2014;5(2):100–109. PubMed CrossRef

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