2015 Updates: Psychopharmacology of Pregnant & Postpartum Women

Transcription

1 2015 Updates: Psychopharmacology of Pregnant & Postpartum Women Judy A. Greene, M.D. Director, Women s Mental Health Director, Reproductive Psychiatry Fellowship Program Clinical Assistant Professor, NYU School of Medicine

2 Disclosures None This presentation will include off-label use of medications in pregnancy and breastfeeding.

3 Overview Introduction to Reproductive Psychiatry SSRIs in pregnancy Bipolar Disorder in pregnancy and postpartum Antipsychotics in pregnancy and postpartum Recent Updates Resources Questions

4 General principles Assess possibility that your patient is pregnant Monotherapy when possible Avoid newer medications Limited or no data on use during pregnancy and breastfeeding Risk/benefit analysis No psychotropics are safe in pregnancy There is no risk free decision

5 Unplanned pregnancy

6 Weighing the Risks Fetal exposure to psychotropic medication Versus Untreated psychiatric illness in mother Poor compliance with prenatal care Increase rates of substance abuse, tobacco use, OTCs Suicidality, self injurious behavior Poor neonatal outcomes ***Document discussion of risks vs benefits*** Depression is an exposure

7 To medicate or not to medicate? How severe and or recurrent is maternal illness? Has medication been effective in past? Have other treatments been effective? How strong are psychosocial supports? How supportive is partner/spouse? How severe are current stressors? How does the patient and the fob/partner feel about medication in pregnancy?

8 Medico-legal considerations Discussion & Documentation of: Known risks of medication Risks of untreated illness 2-4% baseline risk of malformations Capacity- mother is capable of understanding the information provided Involve the father of the baby/partner when possible Provide written materials for patients Coordination of care with Obstetrician-Gynecologist and Pediatrician Consultation

9 FDA Pregnancy Labels Category A Adequate controlled studies in women Category B 1) Animal studies show risk; Human studies do not, or 2) Animal studies negative and adequate human studies do not exist Category C 1) Animal studies show fetal risk or 2) No studies available Category D Evidence of risk to human fetus, but benefit may outweigh risk Category X 1) Evidence of risk to fetus, benefit does not outweigh risk or 2) drug has no utility in pregnancy Essentially no meds in this category! Buspirone Ambien Clozapine Lurasidone!!?? Lamotrigine TCAs SSRIs (except Paroxetine) Risperidone, Ziprasidone, Quetiapine, Olanzapine, Perphenazine, Benzodiazepines, Lithium Paroxetine Eg: OCPs (no increase in risk of birth defects, but no utility in pregnancy) for migraine prophylxis

10 New and hopefully Improved Effective June 2015 FDA system No more A, B, C, D, and X categories Three subsections: including a summary of the risks of use in pregnancy and lactation Pregnancy General statement about background risk, fetal risk summary, clinical considerations, data Information re: current registry Lactation Information about amount of drug in breast milk and potential effects on the breastfed child Females and Males of Reproductive Potential Information about pregnancy testing, contraception, and infertility as it relates to the drug

11 DSM-IV to DSM-5 Onset specifier Time frame Mood disorders with specifier added DSM-IV With postpartum onset Within four weeks of delivery Major Depressive Bipolar I Disorder Bipolar II disorder Brief Psychotic Disorder DSM-5 With peripartum onset During pregnancy or in the four weeks following delivery Major Depressive Bipolar I Disorder Bipolar II disorder Brief Psychotic Disorder

12 Perinatal Depression: Recognition, Risks, and Treatment

13 Perinatal Depression: Risk Factors Hx. of MDD Hx. of PMS PMDD Family History of MDD or Bipolar Dysfunctional marital/partner relationship Inadequate social supports Stressful life events during pregnancy Discontinuation of Antidepressant

14 Perinatal Depression: Diagnostic fine points 1. Anxiety often prominent: Panic attacks, worry, agitation. Intrusive, unwanted obsessional thoughts/images of harm coming to baby. 2. Guilt/Shame often prominent: Ambivalent or negative feelings toward pregnancy/infant. Doubts about ability to be a good mother.

15 Too many pills in pregnancy?

16 Prescribing Antidepressants in Pregnancy SSRIs amongst the best studied medications in pregnancy & lactation. Individualized decision. Discussion of current evidence-based information Careful weighing of risks of medicine versus risks of untreated depression.

17 NYTs article

18 Untreated antenatal depression Non-adherence to prenatal care Tobacco, etoh, and drug use Poor appetite and poor weight gain Insomnia Anxiety (frequently comorbid with depression) Suicidal ideation and suicide Increased risk of Postpartum depression Impaired maternal-infant bonding

19 Cohen JAMA 2006: Relapse Risk 201 women with recurrent Major Depression stable on antidepressants prior to conception. Group that stopped AD near conception: 68% relapsed (most in 1 st TM). Group that stayed on AD: 26% relapsed over course of their pregnancy.

20 Relapse of MDD during Pregnancy

21 ACOG-APA Joint Report

22 APA-ACOG Report Findings 1. Structural Malformations 2. Gestational age effects 3. Poor Neonatal Adaptation Syndrome 4. Persistent Pulmonary Hypertension of the Newborn (PPHN)

23 SSRIs and Risk of Birth Defects Current data on SSRI exposure show no consistent information to support specific morphological teratogenic risks.

24 N Engl J Med 2014; 370(25):

25

26 Ross LE, Grigoriadis S, Mamisashvili L, et al. JAMA Psychiatry. 2013; published online. SSRIs and Adverse Pregnancy Outcomes Meta-analysis including 23 studies Risk of spontaneous abortion: No significant association (OR, 1.47; 95%CI, 0.99 to 2.17; P=.055) Gestational age and risk of preterm delivery: about 3 days shorter gestational age Birth Weight 75 g lower birth weight Apgar scores Less than half a point at 1- and 5-minutes (normal range)

27 Neonatal Symptoms: Neonatal Adaptation Syndrome Increased muscle tone, tachypnea, irritability, insomnia, feeding problems, temperature instability, seizures (rare) 10-30% of newborns with SSRI exposure in late pregnancy. Symptoms transient with no lasting effects. Average duration of symptoms 48 hours At 8 months, exposed babies with syndrome indistinguishable from babies with no exposure Also reported with Tricyclics as early as the 1970s.

28 Neonatal Symptoms: PPHN Failure of relaxation in fetal pulmonary vascular bed at birth resulting in hypoxia 10% fatality Baseline rate: 1-2 / 1000 Exposure to SSRIs during pregnancy may elevate risk to 3 / 1000 = <1% absolute risk. (meta analysis) Grigoriadis et al BMJ 2014

29 SSRIs & PPHN Chambers, N Engl J Med 2006 SSRI in final 20 weeks = 6-12/1000 with exposure Kallen, Pharmacoepidem Drug Safety 2008 Mild increase in risk: 2-4/1000 Wichman, Mayo Clin Proc 2009 No association found Andrade, Pharmacoepidem Drug Safety 2009 No association found Wilson, Am J Perinatol 2010 No association found Kieler, BMJ fold increased risk; absolute risk 3/1000 with exposure compared with 1.2/1000 in controls

30 SSRIs and Risk of Autism Spectrum Disorders? Population-based case-control study 298 cases with ASD vs 1507 controls Prenatal exposure to SSRIs reported for 20 cases (6.7%) and 50 controls (3.3%) 2-fold increased risk of ASD associated with SSRI tx during pregnancy Strongest effect associated with 1TM exposure (adjusted OR 3.8) Limitations: confounders- illness burden, prenatal maternal stress, small n Croen et al. Arch Gen Psychiatry 2011

31 Antidepressant Use in Pregnancy and Author Croen et al 2011 Risk of ASD Study Design Case control Cases of ASD N=298 AD use and association with ASD OR 2.0 (1 yr prior to delivery) OR 3.5 (1 st trimester exposure) Rai et al 2013 Case control N=4,429 OR 2.54 Hviid et al 2013 Cohort N=3,892 No sig assoc between AD exposure and ASD Sorensen et al 2013 Cohort N=5,437 No sig assoc between AD exposure and ASD

32 How to think about the risk of Autism Sam Wang, NYT March 29, 2014

33 A limited number of studies have shown a potential association with small increased risk of ASD in children exposed to SSRIs in utero, however, these studies have not adequately controlled for other conditions and behaviors that could contribute to increase risk of autism, including maternal depression/psychiatric illness. Other studies have not supported this association. Currently there is no evidence to suggest causality between SSRI use in pregnancy and ASD. Given the number of genetic and environmental factors that may influence risk for ASD, it is difficult to differentiate the impact of prenatal antidepressant exposure from other prenatal exposures/genetic factors, and the association noted in some studies between SSRI use and increased rates of ASD may be all or in part the result of confounding.

34 Long term postnatal development and SSRI exposure

35 Antidepressants in Pregnancy Risk Summary Discontinuance of Antidepressant 68% relapse across pregnancy (most in 1 st TM) SSRIs best studied Not teratogens 25% Poor neonatal adaptation syndrome (PNAS) - mild, transient Increase in absolute risk of PPHN (3/1000) with SSRI in final 20 weeks No long term neurobehavioral effects out to 7 years Bupropion, Venlafaxine, Mirtazapine, Duloxetine, TCAs Less well studied, but no glaring problems

36 Antidepressants: Pregnancy General Guidelines For mild-moderate depression and/or anxiety: Consider non-pharmacological interventions For moderate-severe depression and/or anxiety (suicidality, psychosis, poor weight gain, impaired self-care, inability to function) continue or initiate antidepressant treatment * Use what has worked in the past * In antidepressant naïve patients, use best studied drugs = SSRIs. * Avoid multiple exposures when possible.

37 Antidepressants and Pregnancy: Clinical Considerations Deciding whether to switch antidepressant: Preconception: switch to safest treatment that is effective During pregnancy: consider previous history of response Deciding whether to taper of discontinue prior to delivery date No data to support this recommendation Lowest effective dose to minimize risk of neonatal adaptation syndrome

38 Antidepressants: Breast-Feeding AD exposure via Placenta >>>exposure via breast milk. Studies evaluating nursing infants find low to undetectable serum concentrations of Paroxetine and Sertraline. Reports of Adverse effects in nursing infants with SSRIs are rare.

39 Sleeping Rx in Pregnancy and Breastfeeding Diphenhydramine 25-50mg prn Decades of use Not associated with malformations Lorazepam 0.5-1mg prn Decades of use Not associated with malformations (OTIS, Reprotox) Low dose/hs use not associated with neonatal complications Zolpidem Limited, but reassuring data Wang et al study* with >2,000 exposures for >30 days, no increase in congenital anomalies in exposed group Possible increase risk of LBW, preterm delivery Clin Pharm Ther 2010

40 New Data on Anxiolytic and Hypnotics in Pregnancy PLoS One Jun 25;9(6):e

41 Anxiolytics/Hypnotics cont. Singleton children born to women aged years between United Kingdom primary care database Absolute risks of major malformations calculated for children with 1TM exposure to anxiolytic and hypnotic drugs Overall prevalence of malformations: 2.7% in 1,159 children exposed to diazepam 2.9% in 379 children exposed to temazepam 2.5% in 406 children exposed to zopiclone (stereoisomer, eszopliclone available in US) 2.7% in 19,193 comparison group, mothers with dx MDD and or anxiety but no 1TM drug exposure

42 Bipolar disorder in pregnancy

43 Epidemiology of Perinatal Bipolar Disorder Overall prevalence rate is approximately 0.5-1% in general population Bipolar disorder (BD) in puerperium may present as postpartum psychosis, yet not all women with postpartum psychosis have BD Misdiagnosis as unipolar depressive disorder High rates of medication discontinuation increases risk of relapse for BD 25-30% women with BD who become pregnant and deliver will experience an episode of depression or mania Yonkers et al. Obstetrics & Gynecology 2011 Vol 117, No4

44 Bipolar disorder in pregnancy Viguera et al. Am J Psychiatry 164:12, December 2007

45 Lithium 1TM exposure has times greater relative risk of cardiovascular malformations (Epstein s anomaly*) Baseline risk 1/20,000 Absolute risk with exposure to Li = approx 1/1000 Pregnancy monitoring High-resolution U/S at weeks of gestation to detect cardiac anomalies Fetal echocardiography TSH (every 3 months) Dosage requirements change during pregnancy, labor, and delivery Monitor levels closely (monthly in 1TM, weekly in 3TM) due to increase GFR in pregnancy Reduce dose prior to labor Behavioral teratogenicity- none known

46 Valproic Acid 6-10% risk of major congenital malformations Cardiac defects associated w/1tm exposure Craniofacial anomalies 2% risk of neural tube defects including spina bifida Behavioral teratogenicity Lower IQs Poorer cognitive functioning Risk increases with dose and duration of exposure

47 VPA- European Medicine Agency If possible, an alternative to VPA should be used in women of reproductive age If VPA is the only option, women should use effective contraception and should be closely supervised. Doctors who prescribe VPA to women of reproductive age must review the reproductive risks associated with this drug and must clearly explain the reason for choosing VPA over other options. Women taking VPA should also take 4mg of folic acid daily to reduce the risk of birth defects in the setting of unplanned pregnancy

48 Carbamazepine 1.0% risk of spina bifida (1TM exposure) Craniofacial anomalies and microcephaly Oxcarbazepine, Gabapentin, Topiramate Insufficient data, not recommended Increased risk of oral clefts with topiramate exposure (Veiby et al J Neurol. 2014)

49 Lamotrigine Most registries find no increase in birth defects: n>1000 Overall risk for major malformations 2.7% Possible increased risk of oral clefts with 1TM exposure NA Antiepileptic Pregnancy Registry: 10x increased incidence of oral clefts (1/1000 baseline risk) If true, absolute risk remains small More data needed Behavioral teratogenicity- none known Dosage adjustment may be necessary to maintain clinical response; Serum levels

50 Treating the Bipolar Pregnant Patient: General Principles Bipolar II: Attempt to taper off mood stabilizers prior to conception or during first trimester Monitor carefully for early relapse Optimize sleep hygiene, stress levels Resume monotherapy during second trimester (or earlier if necessary) Bipolar I: Continue mood stablizers and other medications as needed to maintain stability throughout pregnancy Monotherapy when possible

51 Antipsychotic Agents in Pregnancy Higher rate of perinatal death in offspring of women with schizophrenia vs offspring of matched normal comparison subjects (Rieder et al 1975) Psychotic women with and without chlorpromazine exposure during pregnancy (Sobel 1960) Rates of malformations or death in the two groups were similar Rates of malformations or death were 2X the general population Factors other than med exposure may account to higher rates of malformations in offspring of psychotic patients

52 Antipsychotic Agents in Pregnancy Low-potency antipsychotics (phenothiazines) Meta-analysis with 2,591 exposures: relatively small increase in absolute risk of congenital malformations (2.4% risk vs baseline risk of 2.0%) Increased risk for nonspecific anomalies High-potency antipsychotics No increased risk for major malformations Limited data on behavioral teratogenesis No prospective developmental studies to date Altshuler et al. Am J Psychiatry 1996

53 Antipsychotic Agents in Pregnancy As a group, chronically mentally ill women are at higher risk for poor fetal outcome Women with repeated decompensations are best maintained with antipsychotics throughout pregnancy Maintenance antipsychotic treatment may minimize overall fetal drug exposure By avoiding intermittent administration of higher doses Discontinuation of medication prior to delivery puts mother and newborn at clinical risk Altshuler et al. Am J Psychiatry 1996

54 Atypical antipsychotics during pregnancy

55 Antipsychotics: Relation to Fetal and Matern Metabolic Effects Population-based cohort study, Sweden Three groups: Olanzapine and/or Clozapine (n=169) Other antipsychotics (n=338) No antipsychotics (n=357,696) Exposure to Other antipsychotics was associated in increased risk of gestational diabetes (adjusted OR 1.77) Increased risks of being SGA (birth weight), but not when adjusted for maternal factors (eg: smoking) Exposure to Olanzapine and/or Clozapine associated with increased risk of LGA (head circumference only) Boden et al. Arch Gen Psychiatry Vol 69 (7) July 2012

56 Atypical Antipsychotics and Pregnancy Outcome Habermann et al. Journal of Clin Psychopharmacology Vol 33, 4, August 2013

57 Habermann 2013 cont. SGAs such as quetiapine, risperidone, and olanzapine are among the tx of choice for pregnant women requiring antipsychotic therapy High resolution U/S in first trimester to confirm normal cardiac development Delivery should be planned in a facility with a NICU Risk of neonatal EPS

58 Antipsychotics, cont. FDA Warning about EPS and withdrawal symptoms with third TM exposure* Agitation Increased or decreased muscle tone Tremor Sleepiness Difficulty breathing Difficulty feeding * Some newborns may require longer hospital stays

59 Data collection

60

61 Lithium and breastfeeding No clear consensus Am Academy of Pediatrics: Lithium is incompatible with breastfeeding -> Associated with Sig effects on some nursing infants use with caution Adverse effects: cyanosis, hypotonia, heart murmur, T-wave changes, lethargy, hypothermia, Li toxicity Close infant monitoring required: serum Li levels, Bun/Creatinine, TSH Collaboration of care with pediatrician Viguera AC. Am J Psychiatry. 2007: 164(2):

62 Lamotrigine and Breastfeeding Infant serum levels approximately 1/3 of maternal levels Theoretical risk of Steven s-johnson rash in the infant One case report of apnea (maternal dose was >800mg/day for seizure prophylaxis)

63 Atypical Antipsychotics in Breastfeeding Limited to Case reports or small case series Clozaril: Contraindicated due to risk of agranulocytosis in infant Olanzapine: Case reports of EPS in infants Aripiprazole, Risperidone, Quetiapine: Limited data No conclusions can be drawn given lack of data Gentile, S. J Clinical Psychiatry 2008, 69(4)

64

65 Methylphenidate Use During Pregnancy Data from from Danish National Patient Register, the Danish National Prescription Registry, the Medical Birth Registry, and the Danish Civil Registration System Exposure defined as redeeming 1 or more Rxs within the 1TM 222 exposed and 2,220 unexposed pregnancies included in analysis No statistically significant difference btwn groups in terms of risk of major malformations or cardiac malformations Pottegård A, Hallas J, Andersen JT J Clin Psychiatry Jan;75(1):e88-93

66 Omega-3 Fatty Acids and Pilot study Antenatal stress Cohort of 64 low-income African American women receiving or Medicaid eligible; urban, ages Randomly assigned to receive 450 mg DHA per day (n=43) or placebo (n=21) at weeks pregnancy Weekly telephone assessments Self report stress levels Salivary cortisol At 30 weeks; perceived stress sig lower in DHA group Cortisol output in response to a stressful situation was 20% lower in DHA group Keenan K, Hipwell AE, Bortner J, Hoffmann A, McAloon R. Obstet Gynecol Dec;124(6):1080-7

67 Resources Lactmed

68 Questions