1. Kamelia Mirdamadi BSc. Pina Bozzo BSc. Gideon Koren MD, FRCPC The Motherisk Program, Hospital for Sick Children Mental health disorders such as schizophrenia and bipolar disorder are common among the women of child bearing age. Obstetric complications and infant outcome of untreated psychiatric illnesses have been studied. Meanwhile there is limited information on the safety of psychotropic medications in pregnancy. Studies demonstrated that treatment with conventional antipsychotics causes infertility due to hyperprolactenemia, extrapyramidal symptoms (ETS), and tardive dyskinesia (TD). Second generation, or atypical antipsychotics were developed in response to these side effects. Therefore, there has been a significant increase in the rate of fertility, and a large number of unplanned pregnancies have been reported in this population. The second generation antipsychotics include: clozapine, olanzapine, risperidone, quetiapine, aripiprazole, and ziprasidone. The importance of maternal mental health as well as fetal health urges the need for further investigation on the safety of atypical antipsychotics in pregnancy. To review the data regarding fetal and pregnancy outcomes after exposure to atypical antipsychotics during pregnancy. Data on the safety of atypical antipsychotics are limited, but fairly reassuring. Studies, so far, have not demonstrated an increased risk in the rate of malformations. Due to a higher BMI it may be beneficial that women on these medications take higher doses of folic acid pre-conception and at least in their first trimester. Women on atypical antipsychotics should be monitored for gestational diabetes while infants should be monitored for size. Longitudinal studies are also needed to determine effects of atypical antipsychotics on neurodevelopment after in-utero exposure. Given the dramatic increase in pregnancy rates in women on atypical antipsychotics, more research is required in order to draw more definitive conclusions on their safety. Proper control of maternal psychiatric condition during pregnancy is vital to ensure best outcome for the mother and infant. Therefore, it is very important that health care professionals balance the risks of untreated psychiatric illnesses against the potential benefits/risks of taking psychotropic medications. MEDLINE and EMBASE were searched for studies examining safety of the use atypical antipsychotics during pregnancy. The search terms used were atypical antipsychotics and pregnancy, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and /or their various combinations. To date, studies and manufacturer data on clozapine, olanzapine, quetiapine, risperidone and ziprasidone do not suggest an increased risk in the rate of congenital malformations. Women on atypical antipsychotics have been reported to have a higher body mass index (BMI), and an increased risk for gestational diabetes has been observed. A recent study found a short-term delayed development at 2 months of age, but not observed at one year of age. See table for a summary of these results. Published data on aripiprazole and ziprasidone are limited. There are seven case reports on aripiprazole exposure during pregnancy without adverse pregnancy outcomes attributed to the medication. There are three case reports with in-utero exposure to ziprasidone resulting in two healthy infants and one child with an isolated cleft palate. In the third case the patient was taking diazepam occasionally during the pregnancy. Other studies have reported altered fetal growth (large/small for gestational age) in infants exposed to atypical antipsychotics in-utero suggesting some possible signalling pathways that may link these medications to placental functioning. STUDYSTUDY DESIGNSAMPLE SIZERESULTSCONCLUSIONS Pregnancy Outcome of Women Using Atypical antipsychotics McKenna et al. 2005 Prospective comparative cohort Group 1: Exposed to atypical Antipsychotics in T1 Group 2: Not exposed to atypical antipsychotics (no disease) N=151/group Medications: O:60,R:49,Q:36,C:6 Exposed vs. Comparison: Maternal BMI: 27.8 vs. 22.92 kg/m2 p<.001 Mean GA: 39 wks both groups LB: 110(72.8%) vs. 135 (89.4%), p<.001 SA: 22(14.5%) vs. 13 (8.6), p=0.15 TA:15(9.9%) vs. 2 (1.3%), p=0.003 SB:4(2.6%) vs. 4 (2.6%), p=1 Mean BW:3341±685g vs. 3411 + 534 g, p=0.38 LBW : 10% vs. 2%, p=0.05 MM:1(0.9%) vs. 2 (1.5%), p=1 No increased risk for MM. The increased risk of low birth weight, requires further investigation. Limitations: Polytherapy Effects of underlying condition Sample size Evaluating the Post-Marketing Experience of Risperidone use during pregnancy Coppola et al. 2007 Comprehensive Review of the Benefit Risk Management Worldwide Safety Database Prospective: N=68 Retrospective: N=197 Prospective: LB: 43 (81.1%) SA:9 (16.9%) Elective Abortion:15 SB:1 (1.9%) MM:2 (3.8%) Perinatal syndromes: 4 Retrospective: LB:145 (80%) SA:33 (18.2%) Elective Abortion:16 SB:3 (1.6%) MM:12 (6.6%) Perinatal syndromes: 37 No clear pattern of birth defects identified in association with taking risperidone. Limitations: Bias to reporting adverse events Effects of underlying condition Sample size Retrospective reports Atypical antipsychotic use in pregnancy: a retrospective Review Wichman 2009 Retrospective Review N=16 Medications: Q: 10,R:4, A:2,Z:1 GA: 37.5±2.54 wks PB:3(18.75%) BW: 3,188±615g NICU: 4 (25%) MM:1 Small number of exposures unable to interpret results. Pregnancies exposed to the SSRI or atypical antipsychotic drugs: small CZTIS prospective study Manakova, Hubickova 2011 Prospective study; Abstract only Group 1: SSRI Group 2: Atypical Antidepressant or Antipsychotic (A, R, O, Z, mirtazapine, venlafaxine, trazadone) Group 1: N=39 Group 2: N=35 Group 1: LB: 24 SA:5 Elective Abortion:9 SB:1 MM:2 Group 2: LB:25 SA:10 Elective Abortion:1 MM:1 No increased risk for birth defects. Higher elective abortions in SSRI group may be due to poly-therapy (60%) or improper disease treatment. Poly-therapy 60%Poly-therapy 45% Prenatal Antipsychotic Exposure and Neuromotor Performance During Infancy Johnson et al. 2012 Prospective Controlled Study Group 1: Antipsychotics Group 2: Antidepressants Group 3: no psychotropic Group 1: N=22 Medications: Haloperidol:9, A:1, O:5, Q:5, R: 3. Group 2: N=202 Group 3: N=85 INFANIB (Infant Neurological International Battery) scores among 6-month-old infants: Group 1: 64.71 Group 2: 68.57 Group 3: 71.19 No difference in weight,gestational age at birth, pregnancy and delivery complications. Antipsychotic exposure group had significantly lower INFANIB scores than the controls. If effects are transient or permanent not known. Limitations: Polytherapy Sample size Variability of maternal condition Antipsychotics During Pregnancy; relation to fetal and maternal metabolic effects Boden et al. 2012 Population-based comparative cohort study Group 1: O, C Group 2: other antipsychotics (including other AA) Group 3: no antipsychotic Group 1: N=169 Group 2: N=338 Group 3: N=357 696 GDM Group 1 and 2: OR:1.94 [95% CI, 0.97- 3.91], and 1.77 [95% CI, 1.04-3.03] respectively Group 1: LGA for head circumference OR:3.02 [95% CI, 1.60-5.71] Pregnant women treated with antipsychotics should be monitored for GDM. The risk for macrocephaly with olanzapine and clozapine needs to be further investigated. Limitations: Confounding factors (smoking) Late pregnancy use not confirmed Underlying maternal condition Effects of prenatal exposure to atypical antipsychotics on postnatal development and growth of infants: a case controlled, prospective study Peng et al. 2013 Prospective Case-controlled Group 1: infants exposed to AA in- utero Group 2: Infants not exposed to AA N=76 infants in each group Exposed vs. Comparison group Bayley-III scores: At 2 months of age p<.0.001: Cognitive: 90.33 vs. 97.84 Motor scale: 92.28 vs. 97.53 Social Emotional Scale: 95.68 vs.101.89 Adaptive Behaviours : 93.14 vs. 99.32 At 12 months of age: No differences between groups Infants exposed to AA may have short-term delayed development in cognitive, motor, social emotional and adaptive behavior. Limitations: Small sample size Underlying maternal condition Short term follow-up of infants Polytherapy Manufacturer’s reports (Personal Communications) RetrospectiveClozapine N=523MM=22 No clear pattern of defects. Retrospective Recall bias Prospective Olanzapine N=516 (431 T1 exposure) MM: 24 (4.7%) SA: 45 (8.7%) PB: 53 (10.3%) SB:4 (0.8%) No increased risk for adverse pregnancy outcomes when compared to the general population Retrospective and prospective Quetiapine N=477 known outcomes prospective =224 retrospective=253 MM=24 (prospective=6, retrospective=18) No increased risk for major malformations compared to general population Ziprasidone N=57 Normal outcome=50 SA=5 SB=1 MM=1 No increased risk for adverse pregnancy outcomes when compared to the general population Abbreviations: AA: Atypical Antipsychotic, O:Olanzapine, C: Clozapine, Q: Quetiapine, R: Risperidone, A: Aripiprazole, Z: Ziprasidone, SSRI: Selective Serotonin Reuptake Inhibitor, BMI: Body Mass Index, LB: Live Birth, GA: Gestational Age, SA: Spontaneous Abortion, TA: Therapeutic Abortion, SB: Still Birth, BW: Birth Weight, LBW: Low Birth Weight, LB: Live Birth, PB: Preterm Birth, LGA: Large for Gestational Age, MM: Major Malformations, GDM: Gestational Diabetes Mellitus, T1: 1 st Trimester, OR: Odds Ratio. Pregnancy Outcomes with in-utero Exposure to Atypical Antipsychotics