2/28/2018. Objectives. Clinical Case: Lisa. What next? Perinatal Mental Illness Can (& Does) Happen To Anyone

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1 Objectives Clinical Considerations in the Treatment of Pregnant & Postpartum Women with Bipolar Disorder Elizabeth M. LaRusso, MD March 2018 Identify the key symptoms and risks associated with perinatal bipolar disorder (BPAD). Understand key aspects of medication management of bipolar disorder in pregnant & breastfeeding women. Formulate a bio psycho social treatment plan that incorporates a woman s entire support system in order to optimize the wellbeing of the family unit. 2 Clinical Case: Lisa 32 yo woman 4 days postpartum brought by husband to your office Has had significant anxiety since delivery, repeatedly checks baby overnight, basically not sleeping; one episode of agitation Pt endorses feeling keyed up & unable to shut off her brain No PPH beyond mild depression &anxiety What next? What diagnoses are you considering? What else do you want to know? What should be offered in terms of treatment/follow up? What factors would influence your decision regarding admission vs discharge? How would you handle this situation if she presented to your clinic alone? 3 4 Perinatal Mental Illness Can (& Does) Happen To Anyone Peak onset of psychiatric illness in women occurs during childbearing years Postpartum depression (PPD) is one of the most common complications of pregnancy (1/5 women) Large OB patient study: 20.4% high depression scores 13.8% receiving treatment Bonari et al, Can J Psychiatry Marcus et al, J Women s Health Yonkers et al, APA/ACOG report, Obstet Gynecol What do we know about perinatal bipolar disorder? Affects % of US population Typically presents in women during reproductive years Female patients more likely to be rapid cyclers & have depressive sx Pregnancy likely not protective, & postpartum period is a particularly high risk time for relapse Yonkers et al, AJP

2 What are the risks of BPAD to women & children? Pregnancy Addictive substance use (cigarettes, alcohol, etc.) Increased BMI Instrumental delivery/c section Pregnancy complications: Preterm birth, small for gestational age Postpartum Severe symptoms, including psychosis May include heightened risk to babies if there are delusions/hallucinations related to harming the baby What factors are associated with relapse of affective symptoms? Bipolar II diagnosis Earlier onset of illness High number of recurrences/year Recent history of depression or (hypo)mania Use of antidepressants Discontinuation of effective mood stabilizers 7 Bodén R et al, BMJ Azorin JM et al, Spinelli MG, Am J Psychiatry Viguera et al, AJP What factors should prompt you to consider a bipolar diagnosis? Family history of BPAD Personal history of poor response to antidepressant monotherapy (i.e., insomnia, agitation, etc.) History of (hypo)mania D: Distractibility I: Irresponsibility/erratic behavior G: Grandiosity F: Flight of Ideas A: Activity (increased) S: Sleep (decreased) T: Talkativeness Mood Disorder Questionnaire (MDQ) 9 10 MDQ Scoring Postpartum Psychosis is a psychiatric emergency 1 2/1000 births in the general population 100 times higher in women with BPAD Risk of recurrence 30 50% Frequently associated with thoughts of killing self or baby Data suggests 4% of women with PPP commit infanticide but this statistic is disputed DSM IV TR. Spinelli, Am J Psych

3 What are the hallmarks of postpartum psychosis (PPP)? Generally presents abruptly in the first two postpartum weeks Thought disorganization, delusions, hallucinations, rapid mood shifts, SI/HI May resemble delirium (memory loss, confusion, altered sensorium) Severe insomnia is a risk factor for the development of psychosis and should be treated aggressively Psychiatric emergency requiring hospitalization for maternal/infant safety Intrusive images of harm (or, Am I crazy? ) It s very common for women to experience intrusive thoughts or images of harm befalling their baby, for example, dropping the baby down the stairs. Has this happened to you? How frequently? Getting worse or better? Influencing behavior? Spinelli, Am J Psych Thoughts of harming the baby: low risk Thoughts of harming the baby: high risk Common in non psychotic PPD 41% of depressed mothers versus 7% of controls Delusional beliefs about the baby Thoughts are ego dystonic Mother experiences the thoughts as intrusive & frightening Ego syntonic thoughts of harming baby (mother thinks they are reasonable and/or feels tempted to act on them) Mother has not acted on the thoughts, and has often taken steps to protect baby No delusions or hallucinations related to harming the baby History of violence Labile mood and/or impulsive behavior 15 Jennings KD et al, J Affect Disord. 16 Wisner KL et al, Postpartum disorders: phenomenology, treatment approaches, and relationship to infanticide. In Spinelli MG, ed: Infanticide, Washington DC: American Psychiatric Press, What are some red flags that suggest patient/infant may be at high risk? Clinical Case, continued History of violence Chemical dependence Overt psychosis Domestic violence Lack of supports Lisa has been breastfeeding exclusively Maternal aunt and cousin have BPAD No past trials of SSRIs, no history of CD Open to seeing a psychiatrist but likely to be a long wait for an appointment Supportive husband and extended family

4 Clinical Case, continued What are your options for medication management? Would you start an antidepressant? Why/why not? How would you council your patient about breastfeeding? What are the most critical elements of a comprehensive treatment plan? What do we know about psychiatric medications in pregnancy? Quite a bit, actually Majority of the data is reassuring Physicians and patients perceive psychotropics as more dangerous than other classes of medication Impact of the disease itself is frequently overlooked as focus is on medication risks Why is the data so confusing? No randomized, double blind, controlled trials Inconsistent findings Methodological limitations: Small sample sizes Retrospective Confounding, including untreated illness Monitoring diagnoses & prescriptions, not medication exposure & symptoms What about FDA labeling? Current labeling system of 5 pregnancy & lactation categories (A, B, C, D, X) is misleading In 2008, FDA proposed major revisions which are starting to take effect (2016) New guidelines will include Risk Summary Clinical Considerations Pregnancy Registry Information Lactation Subsection What happens when women discontinue mood stabilizers? Nothing good During Pregnancy: 2x rate of recurrence 4x shorter time to recurrence (11x shorter if medication was discontinued abruptly) 5x proportion of weeks ill during pregnancy Postpartum: 2.9x recurrence in postpartum (70%) vs control (24%) women Viguera AC et al, AJP Viguera AC et al, AJP General Framework for Treatment Avoid antidepressant monotherapy Continue effective mood stabilizer (anticonvulsant/antipsychotic) Some women on a mood stabilizer will also need an antidepressant All women on a mood stabilizer will need PRN medications (benzo/ap) for acute symptoms Women on lithium will likely need to continue on lithium

5 What potential risks should I address with patients? Obstetric outcomes Congenital malformations Neonatal outcomes Long term neuro cognitive effects Is lithium a teratogen? Fully equilibrates across placenta Is it a cardiovascular teratogen? Studies have found increased risk of CV defects, especially right sided, like Ebstein s anomaly Baseline risk of Ebstein s anomaly in the general population is 1:20,000 ( %) Several studies & registry data showed an increased risk of 2.7 7% Most prospective studies and meta analysis suggest risk is lower than previously identified One recent prospective study showed increased CV defects but not after excluding those that spontaneously resolved Newport DJ et al, Am J Psychiatry McKnight RF et al, Lancet Yonkers et al, Am J Psychiatry Diav-Citrin et al, AJP in advance Are there other risks? How can risks of lithium be minimized? 27 Transient fetal nephrogenic diabetes insipidus Transient neonatal hypothyroidism Premature delivery Neonatal complications Respiratory problems, jaundice, tremor, tachy, hypoglycemia, sedation Toxicity: cyanosis & hypotonicity No effects on neonatal growth or neurodevelopment Krause S et al, Obstet Gynecol Troyer WA et al, J Perinatol Frassetto F et al, Ann Pharmacother Kozma C, Am J Med Genetics Yonkers, Am J Psychiatry Van der Lugt NM et al, Early Hum Dev Diav-Citrin et al, AJP in advance Folate 5mg QD prior/during pregnancy Divide dose to BID/TID to maintain steady state Avoid sodium restriction/diuretics Monitor serum levels & change dose Maternal renal excretion increases by 30 50%, so usually need to increase dose during pregnancy Weekly levels in the last month Fetal Level II US & echo at weeks Diav-Citrin et al, AJP in advance Pinelli What about lithium & lactation? Infant serum levels approx. 1/4 1/2 maternal Infants can develop lithium toxicity if dehydrated Side effects include elevated TSH, BUN, Cr Recommendations: AAP recommends breastfeeding be undertaken with caution due to increased neonatal risk Often discouraged due to destabilizing risk of maternal sleep deprivation Monitor infant serum lithium levels, TSH, BUN, Cr What do we know about anticonvulsants? May cause increased risk of miscarriage; unclear if associated with increased risk of stillbirth As a group, associated with increased risk of: Fetal malformation (but vast majority of babies don t develop this) Neonatal toxicity Neurobehavioral teratogenicity Risk varies with medication, dose, & timing of exposure 29 Viguera AC, Am J Psychiatry Bech et al, BMJ Yonkers et al, Am J Psychiatry Meador et al, NEJM Campbell et al, JNNP,

6 Comparative MCM results from the main epilepsy pregnancy registries Is lamotrigine a good choice? Campbell, J Neurol Neurosurg Psychiatry UK Epilepsy and Pregnancy Register North American AED Pregnancy Registry5 International Registry of Antiepileptic Drugs and Pregnancy (EURAP)6 International Lamotrigine Pregnancy Registry7 Valproate Carbamazepine Lamotrigine 82/1220 (6.7%) 43/1657 (2.6%) 49/2098 (2.3%) 30/323 (9.3%) 31/1033 (3.0%) 31/1562 (2.0%) 98/1010 (9.7%) 79/1402 (5.6%) 37/1280 (2.9%) N/A N/A 35/1558 (2.2%) 32 Association with oral clefts Baseline risk is /1000 in general population Some studies have found mildly increased risk (1 7.3/1000) Other studies, including those from large pregnancy registries, did not find this association Behavioral teratogenicity No increase in neurodevelopmental or cognitive abnormalities in exposed children Cunnington MC et al, Neurol Meador et al, NEJM Campbell et al, JNNP, What should I know about using lamotrigine in pregnancy? 5mg folate QD before & during pregnancy Pregnancy lowers serum level Average reduction 50% 60% but wide individual variation Most women will need increased doses Levels return to pre pregnancy levels 3 4 weeks postpartum Management Reference level preconception or in early pregnancy Monitor Q4 weeks; increase dose by 20 25% if falls below reference level Resume pre pregnancy dose postpartum Monitor for toxicity (ataxia, visual changes, nausea, sedation) Tomson T et al, Epilepsia Sabers A, Acta Neurol Scand Epub 12/9/11. Wisner KL et al, AJP What about lamotrigine & lactation? Relatively high transmission in milk Case reports of infant thrombocytosis, apnea, cyanosis Theoretical risk of SJS but no cases Many women have breastfed successfully No negative neurocognitive effects in children at 6 years Monitor infant for apnea, poor sucking, sedation, rash & check a lamotrigine level if concerns Meador et al, JAMA Pediatr Meador et al, NEJM Yonkers et al, AJP Wisner KL et al, AJP TOXNET, LactMed: What do we know about second-generation antipsychotics (SGAs) during pregnancy? What about the FDA warning? No increased risk of birth defects in several studies One study showed mildly increased risk of CV malformations; still overall low rates Can t rule out teratogenicity but currently no data to suggest major teratogenic risk Some increased risk of adverse pregnancy outcomes Miscarriage, premature delivery, low birth weight, high birth weight, gestational DM One study suggested lower scores in infant cognitive, motor, social, emotional, behavioral measures at 2 & 6 months but normalized at 12 months FDA, 2/22/11: The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays. Based on adverse event reporting in 69 infants Findings confounded by maternal illness & poly pharmacy Follow up study shows increased rates of impaired neuro motor performance at 6 months Haberman J et al, Clin Psychopharm Cohen LS, ObGyn News Johnson KC et al, Arch Gen Psychiatry McKenna et al, Peng M et al, Psychopharmacology Habermann J Clin Psychopharm

7 37 Individual SGAs during pregnancy Agent aripiprazole clozapine olanzapine risperidone quetiapine ziprasidone Considerations during Pregnancy Not systematically studied May increase risk of neonatal seizures, agranulocytosis, gestational diabetes mellitus; may accumulate in fetus No increased risk of anomalies based on prospective, controlled study & registry data; may increase risk of gestational diabetes mellitus May reduce fertility due to effects on prolactin. No increased risk of anomalies based on prospective, controlled study Sedation may interfere with parenting. No increased risk of anomalies based on prospective, controlled study; crosses placenta less than others Not systematically studied Goldstein 2000; Koren et al. 2002; Gentile 2004; McKenna et al What do we know about SGAs & lactation? Very limited data, lack of long term infant followup Generally low levels found in milk Few adverse effects reported Sedation is most commonly reported adverse infant effect TOXNET, LactMed: Is it okay for pregnant women to take benzos? Short answer: Yes Studies suffer from methodological flaws Early reports suggested increased rates of cleft lip/palate, but still very low (0.7%) Subsequent studies do not support risk Are there other potential risks? Neonatal toxicity = Floppy Baby Syndrome Infant hypothermia, apnea, hypotonia Likely only with high doses near delivery Neonatal withdrawal Infant restlessness, tremor, hypertonia, poor feeding Generally absent or mild at low doses Increased incidence with antidepressant use Acs N et al, Birth Defects Res A Clin Mol Teratol Enato J et al, Obstet Gynec Can. Acs N et al. Birth Defects Res A Clin Mol Teratol. Calderon Margalit R et al, Am J Obstet Gynecol How can potential risks be minimized? Don t discontinue abruptly; taper slowly if you are going to discontinue Palate closes around 13 weeks GA; consider avoiding in first trimester Use lowest effective dose and divided dosing Ativan and klonopin are agents of choice; avoid valium and xanax if possible Can women breastfeed on benzos? Short answer: Yes Very low rates of adverse infant effects Infant sedation is most common adverse effect (still rare) Case reports of apnea, irritability, poor weight gain Ativan in divided doses is best choice if effective 41 Stahl MM et al, Br J Obstet Gynaecol Iqbal, Psych Services Kelly J et al, Pediatr TOXNET, LactMed: 7

8 Insomnia is Terrible Breastfeeding is Best (?) Maternal sleep deprivation is a major risk factor for psychiatric decompensation Women with BPAD require minimum 5 6 hours/night of consolidated sleep Most medications are compatible with breastfeeding if sleep can be protected Women taking sedating medications need assistance with overnight infant care/feeding Enlist partner, family, friends, night nurse/doula 43 I dreamed I got eight hours of sleep. 44 How can postpartum psychosis be prevented? Remember that hx of BPAD or previous PPP are strongest predictors of recurrence Relapse prevention + planned pregnancy = best strategy Women with prior PPP need prophylaxis (AP) immediately after delivery Women with BPAD need prophylaxis during pregnancy & the postpartum Protecting sleep is critical! Elements of a comprehensive treatment plan Pre Pregnancy During Pregnancy Postpartum Pregnancy planning visit Start PNV Start folate supplementation for women on mood stabilizers (5mg/day) Sustain psychiatric stability for 3 6 months prior to attempting to conceive Refer to psychotherapy Continue effective mood stabilizer Continue folate supplementation Increase frequency of clinical monitoring as indicated Begin postpartum planning with patient & partner Protect sleep Reasonable breastfeeding routine Initiate adjunctive medication for acute symptoms (ex: benzo, antipsychotic) Engage social supports Two week f/u and frequent clinical monitoring (including nursing calls) Contraception Bergink et al, AJP Lisa, Conclusion Decision made to d/c home from clinic with husband & extended family to help Overnight breastfeeding discontinued Seroquel started in your clinic (50 150mg at HS, 25 50mg TID PRN) Next day RN f/u call; Lisa slept 8 hours & was calmer F/U visit in your clinic the next week Psychiatric visit scheduled in 2 weeks

9 Resources My world view TOXNET LactMed Drug & Lactation Database, Postpartum Support International (PSI), Thank You! Please contact us directly with questions or suggestions for questions about the Mother Baby Mental Health Program, Minneapolis 51 9