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A review of the safety of clozapine during pregnancy and lactation

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Abstract

Clozapine is an antipsychotic used in the management of treatment-resistant schizophrenia. However, little is known about clozapine use during pregnancy and lactation, or its impact on the mother, foetus, and infant. This review aims to summarize the available literature on the safety of clozapine use during the perinatal period. EMBASE, PsycINFO, and MEDLINE were searched from their inceptions through June 2016. The review encompasses 21 studies that have examined clozapine use during pregnancy and lactation. The limited available data do not support an increased risk of congenital malformations in foetuses exposed to clozapine during pregnancy, though rates of gestational diabetes are twice as high in pregnant women using clozapine. Clozapine accumulation in foetal serum possibly contributes to increased rates of floppy infant syndrome at delivery, decreased foetal heart rate variability, and seizures in infancy. Clozapine crosses the placenta and also accumulates in breast milk, which may increase the risk of agranulocytosis in infants and may necessitate infant testing. The majority of these data come from case reports and case series, making it unclear if the published risks associated with clozapine are due to mental illness, lifestyle factors, or co-treatment with other psychotropic medications. While the available literature on clozapine use during the perinatal period is very limited, the risks of clozapine use during pregnancy and the postpartum period should be discussed with women and weighed against those associated with other treatments and partially or untreated schizophrenia.

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References

  • American Academy of Pediatrics. Committee on Drugs (2001) The transfer of drugs and other chemicals into human milk. Pediatrics 108(3):776–789

    Article  Google Scholar 

  • American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Pub

  • Armstrong C (2008) ACOG guidelines on psychiatric medication use during pregnancy and lactation. Obstet Gynecol 111(4):1001–1020

    Article  Google Scholar 

  • Barnas C, Bergant A, Hummer M, Saria A, Fleischhacker WW (1994) Clozapine concentrations in maternal and fetal plasma, amniotic fluid, and breast milk. Am J Psychiatry 151(6):945

    Article  CAS  PubMed  Google Scholar 

  • Bodén R, Lundgren M, Brandt L, Reutfors J, Andersen M, Kieler H (2012a) Risks of adverse pregnancy and birth outcomes in women treated or not treated with mood stabilisers for bipolar disorder: population based cohort study. BMJ 345(6):e7085–e7085

    Article  PubMed  PubMed Central  Google Scholar 

  • Bodén R, Lundgren M, Brandt L, Reutfors J, Kieler H (2012b) Antipsychotics during pregnancy: relation to fetal and maternal metabolic effects. Arch Gen Psychiat 69(7):715–721

    Article  PubMed  Google Scholar 

  • Canadian Psychiatric Association (2005) Clinical practice guidelines: treatment of schizophrenia. Can J Psychiatr 50(13):7S

    Google Scholar 

  • Dekker JM, Crow RS, Folsom AR, Hannan PJ, Liao D, Swenne CA, Schouten EG (2000) Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several causes: the ARIC study. Circulation 102(11):1239–1244

    Article  CAS  PubMed  Google Scholar 

  • Dev V, Krupp P (1995) The side effects and safety of clozapine. Rev Contemp Pharmacother 6:197–208

    CAS  Google Scholar 

  • Di Michele V, Ramenghi LA, Sabatino G (1996) Clozapine and lorazepam administration in pregnancy. Eur Psychiat 11(4):214

    Article  Google Scholar 

  • Dickson RA, Hogg L (1998) Pregnancy of a patient treated with clozapine. Psychiatr Serv 49(8):1081–1083

    Article  CAS  PubMed  Google Scholar 

  • Doherty J, Bell PF, King DJ (2006) Implications for anaesthesia in a patient established on clozapine treatment. Int J Obstet Anesth 15(1):59–62

    Article  CAS  PubMed  Google Scholar 

  • Duran A, Ugur MM, Turan S, Emul M (2008) Case report: clozapine use in two women with schizophrenia during pregnancy. J Psychopharmacol 22(1):111–113

    Article  CAS  PubMed  Google Scholar 

  • Ernst CL, Goldberg JF (2002) The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics. J Clin Psychiat 63(Suppl 4):42–55

    CAS  Google Scholar 

  • Gupta N, Grover S (2004) Safety of clozapine in 2 successive pregnancies. Can J Psychiatry 49(12):863

    PubMed  Google Scholar 

  • Guyon L, Auffret M, Coussemacq M, Béné J, Deruelle P, Gautier S (2015) Alteration of the fetal heart rate pattern induced by the use of clozapine during pregnancy. Therapie 70(3):301–303

    Article  PubMed  Google Scholar 

  • Hale T (2012) Medications and mothers’ milk. Hale Publishing, Amarilla

    Google Scholar 

  • Hennen J, Baldessarini RJ (2005) Suicidal risk during treatment with clozapine: a meta-analysis. Schizophr Res 73(2):139–145

    Article  PubMed  Google Scholar 

  • Howard LM, Kumar R, Thornicroft G (2001) Psychosocial characteristics and needs of mothers with psychotic disorders. Brit J Psychiat 178(5):427–432

    Article  CAS  PubMed  Google Scholar 

  • Igarashi M (2004) Floppy infant syndrome. J Clin Neuromuscul Dis 6(2):69–90

    Article  PubMed  Google Scholar 

  • Jablensky AV, Morgan V, Zubrick SR, Bower C, Yellachich LA (2005) Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major affective disorders. Am J Psychiat 162(1):79–91

    Article  PubMed  Google Scholar 

  • Karakuła H, Szajer K, Rpila B, Grzywa A, Chuchra M (2004) Clozapine and pregnancy--a case history. Pharmacopsychiatry 37(6):303–304

    Article  PubMed  Google Scholar 

  • Kilian JG, Kerr K, Lawrence C, Celermajer DS (1999) Myocarditis and cardiomyopathy associated with clozapine. Lancet 354(9193):1841–1845

    Article  CAS  PubMed  Google Scholar 

  • Kłys M, Rojek S, Rzepecka-Woźniak E (2007) Neonatal death following clozapine self-poisoning in late pregnancy: an unusual case report. Forensic Sci Int 171(1):e5–e10

    Article  PubMed  Google Scholar 

  • Kulkarni J, Worsley J, Gilbert H, Gavrilidis E, Van Rheenen TE, Wang W, McCauley K, Fitzgerald P (2014) A prospective cohort study of antipsychotic medications in pregnancy: the first 147 pregnancies and 100 one year old babies. PLoS One 9(5):e94788

    Article  PubMed  PubMed Central  Google Scholar 

  • Kulkarni J, Storch A, Baraniuk A, Gilbert H, Gavrilidis E, Worsley R (2015) Antipsychotic use in pregnancy. Expert Opin Pharmacotherapy 16(9):1335–1345

    Article  CAS  Google Scholar 

  • Larsen ER, Damkier P, Pedersen LH, Fenger‐Gron J, Mikkelsen RL, Nielsen RE et al (2015) Use of psychotropic drugs during pregnancy and breast‐feeding. Acta Psychiatr Scand 132(S445):1–28

    Article  CAS  Google Scholar 

  • Lin HC, Chen IJ, Chen YH, Lee HC, Wu FJ (2010) Maternal schizophrenia and pregnancy outcome: does the use of antipsychotics make a difference. Schizophr Res 116(1):55–60

    Article  PubMed  Google Scholar 

  • McKenna K, Koren G, Tetelbaum M, Wilton L, Shakir S, Diav-Citrin O, Levinson A, Zipursky R, Einarson A (2005) Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study. J Clin Psychiat 66(4):444–449

    Article  CAS  Google Scholar 

  • Mendhekar DN (2006) Possible delayed speech acquisition with clozapine therapy during pregnancy and lactation. J Neuropsych Clin C 19(2):196–197

    Article  Google Scholar 

  • Mendhekar DN, Sharma JB, War L (2003) Clozapine and pregnancy. J Clin Psychiat 64(7):1–478

    Article  Google Scholar 

  • Miller DD (2000) Review and management of clozapine side effects. J Clin Psychiat 61(suppl 8):14–17

    CAS  Google Scholar 

  • Nilsson E, Lichtenstein P, Cnattingius S, Murray RM, Hultman CM (2002) Women with schizophrenia: pregnancy outcome and infant death among their offspring. Schizophr Res 58(2):221–229

    Article  PubMed  Google Scholar 

  • Parikh T, Goyal D, Scarff JR, Lippmann S (2014) Antipsychotic drugs and safety concerns for breast-feeding infants. South Med J 107(11):686–688

    Article  CAS  PubMed  Google Scholar 

  • Rajagopal S (2005) Clozapine, agranulocytosis, and benign ethnic neutropenia. Postgrad Med J 81(959):545–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson GE (2012) Treatment of schizophrenia in pregnancy and postpartum. J Popul Ther Clin Pharmacol 19(3):e380–e386

    PubMed  Google Scholar 

  • Shao P, Ou J, Peng M, Zhao J, Chen J, Wu R (2015) Effects of clozapine and other atypical antipsychotics on infants development who were exposed to as fetus: a post-hoc analysis. PloS one 10(4):e0123373

    Article  PubMed  PubMed Central  Google Scholar 

  • Stahl SM (2013) Stahl’s essential psychopharmacology: neuroscientific basis and practical applications. Cambridge university press, Cambridge

    Google Scholar 

  • Stoner SC, Sommi RW, Marken PA, Anya I, Vaughn J (1997) Clozapine use in two full-term pregnancies. J Clin Psychiat 58(8):1–478

    Article  Google Scholar 

  • Tényi T, Trixler M (1998) Clozapine in the treatment of pregnant schizophrenic women. Psychiatr Danub 10:15–18

    Google Scholar 

  • Uguz F (2016) Second-generation antipsychotics during the lactation period: a comparative systematic review on infant safety. J Clin Psychopharm 36(3):244–252

    Article  CAS  Google Scholar 

  • Vavrusova L, Konikova M (1998) Clozapine administration during pregnancy. Ceska Slov Psychiatr 94:282–285

    Google Scholar 

  • Waldman MD, Safferman AZ (1993) Pregnancy and clozapine. Am J Psychiat

  • Wong J, Delva N (2007) Clozapine-induced seizures: recognition and treatment. Can J Psychiat 52(7):457–463

    Article  Google Scholar 

  • Yogev Y, Ben-Haroush A, Kaplan B (2002) Maternal clozapine treatment and decreased fetal heart rate variability. Int J Gynecol Obstet 79(3):259–260

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Duncan Maccrimmon, Mr. John Krzeczkowski, and Ms. Eliza Pope for their helpful comments on an earlier version of this manuscript. Dr. Van Lieshout is supported by the Albert Einstein/Irving Zucker Chair in Neuroscience.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada

    Taylor M. Mehta & Ryan J. Van Lieshout

  2. Women’s Health Concerns Clinic, St. Joseph’s Hospital, 100 West 5th Street, Hamilton, ON, L8N 3K7, Canada

    Ryan J. Van Lieshout

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  1. Taylor M. Mehta
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  2. Ryan J. Van Lieshout
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Correspondence to Taylor M. Mehta.

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Mehta, T.M., Van Lieshout, R.J. A review of the safety of clozapine during pregnancy and lactation. Arch Womens Ment Health 20, 1–9 (2017). https://doi.org/10.1007/s00737-016-0670-0

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