Depression In Pregnancy and Postpartum: Screening, Diagnosis, Consequences of Untreated Illness, Engagement, and Traveling the Road to Recovery

Transcription

1 Depression In Pregnancy and Postpartum: Screening, Diagnosis, Consequences of Untreated Illness, Engagement, and Traveling the Road to Recovery Dayna J. LePlatte, MD Department of Psychiatry & Depression Center Clinical Instructor, Department of Psychiatry Child, Adolescent, and Adult Psychiatry

2 Faculty Disclosures Dr. LePlatte has disclosed no relevant financial relationships with any commercial interests

3 Case: Mary 29 year old single woman 2 weeks after the birth of her third child She had one prior severe depressive episode that started while she was pregnant with her 2 nd child. She also has a diagnosis of GAD No prior hospitalizations or suicide attempts, but she does have a history of SI Family History: bipolar in aunts and several cousins Prior medication trials: bupropion, fluoxetine, and clonazepam

4 Case: Mary Today you note the following: Mood, irritable, sad, anhedonic, stressed, can t relax, racing thoughts, hopelessness, overwhelmed, poor sleep, fleeting thoughts she would be better off dead She notes that she stopped the medication because, I m good. I don t need it anymore. She goes on to state, "I am scared the medications will harm by baby.

5 Key Point #1 When treating maternal illness in pregnancy or postpartum there is the mother and the baby to consider.

6 Risk-Benefit Ratio Risk of Untreated Illness Risk of Untreated Illness s

7 Outline Brief Review of Common Mood and Anxiety Disorders Consequences of Untreated/Under-treated Depression and Anxiety Screening and Treatment Options Helping Families Recover Issues Around Engagement in Treatment

8 What are the Most Common Perinatal Mood and Anxiety Disorders? What are Potential Consequences if Left Untreated?

9 Mood Disorders Most often occur during developmental and hormonal transitions: Adolescence Premenstrual Peripartum Perimenopause Hypotheses: Increased sex-steroid sensitivity as a susceptibility factor? Women with postpartum depression increased sensitivity to estrogen signaling Rawana JS, et al. J Youth Adolesc. 2014;43(4): Borrow AP, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2014;54C: Mehta D, et al. Psychol Med. 2014;[Epub ahead of print].

10 Postpartum Blues 50-85% of all new mothers Labile mood Emotional hypersensitivity Tearful Mild sleep disturbance No major change in functioning Generally responds to support and reassurance No treatment necessary, except if severe and >14 days Begins 2-4 days after birth Resolves days later Burt, Vivien. Mood Disorders in Women: Focus on Postpartum Women s Health in Primary Care. 2006:12-23.

11 Postpartum Depression Begins a little later ~ a few weeks 10-15% Often not detected until much later Symptoms: sleep disturbance, anhedonia, hopelessness, worthlessness, energy changes, appetite changes, concentration difficulties, and SI/HI/SIB. Burt, Vivien. Mood Disorders in Women: Focus on Postpartum Women s Health in Primary Care. 2006:12-23.

12 % 1-2 per 1,000 births Postpartum Psychosis Rate is 100 times higher in women with BP or a previous history of postpartum psychosis Extremely disturbed mood Highly agitated Severely disturbed sleep Delusions/hallucinations Suicidal thoughts Major loss of functioning Rapid decline over 1-2 weeks Psychiatric emergency Burt, Vivien. Mood Disorders in Women: Focus on Postpartum Women s Health in Primary Care. 2006:12-23 Spinelli, Margaret. Postpartum Psychosis: Detection of Risk and Management. AmJ Psychiatry 166:4, April 2009

13 Don t Forget About The Fathers More than 10% of fathers suffer from psychiatric morbidity in the postnatal period. Depression amongst fathers is associated with: having depressed partners having an unsupportive relationship being unemployed. Ballard C, Davies R, Postnatal Depression In Fathers. International Review of Psychiatry Vol 8. No1. Pages 65-71

14 Perinatal Anxiety and OCD GAD: Most common anxiety disorder in perinatal period 8.5% to 10.5% of pregnant and postpartum women meet criteria (5.2% general population) OCD: <1% in pregnancy; 3-4% postpartum (<2% in general population) Panic Disorder: 1-2% (general population) Key symptom: Scary thoughts negative, unwanted, repetitive, and/or intrusive thoughts/images Rawana JS, et al. J Youth Adolesc. 2014;43(4): Borrow AP, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2014;54C: Mehta D, et al. Psychol Med. 2014;[Epub ahead of print].

15 Perinatal Anxiety and OCD Obsessive thoughts 91% Intrusive memories of birth 15-37% Excessive worry 15-37% Rumination Catastrophic misinterpretation of bodily sensations Ross LE, et al. J Clin Psychiatry. 2006;67(8): Hall PL, et al. J Midwifery Womens Health. 2006;51(5): Abramowitz JS, et al. Behav Res Ther. 2006;44(9): Creedy DK, et al. Birth. 2000;27(2): Wenzel A, et al. Arch Womens Ment Health. 2003;6(1):43-49.

16 Scary Thoughts of Harming the Baby >90 % of postpartum women have intrusive thoughts of accidental harm to their babies (illness, fall abduction, suffocation) 50% of postpartum mothers have intrusive thoughts about intentionally harming their baby OCD OCD Intrusive thoughts cause distress (ego dystonic) Fear of acting on intrusive thoughts, avoidance behaviors/rituals Psychosis Psycho Low likelihood to act; mom otherwise in touch with reality Not associated with distress (ego syntonic) Other associated symptoms of psychosis (confused, agitated, hallucinations, loss of reality) Increased likelihood that mother may act on thoughts Fairbrother N, et al. Arch Womens Ment Health. 2008;11(3): Barr JA, et al. Can Fam Physician. 2008;54(12): Abramowitz JS, et al. J Anxiety Disord. 2003;17(4):

17 PTSD = posttraumatic stress disorder. Menage J. Journal of Reproductive and Infant Psychology. 1993;11(4): Resnick HS, et al. J Consult Clin Psychol. 1993;61(6): Loveland Cook CA, et al. Obstet Gynecol. 2004;103(4): Ayers S, et al. Birth. 2001;28(2): Trauma and PTSD Obstetric/labor trauma 20% of women Interpersonal trauma 28% have been sexually abused in childhood 20% experience intimate partner violence 4-8% are abused during pregnancy Peripartum PTSD 12.3% - PTSD lifetime 2-7% PTSD in pregnancy and postpartum 1.5-3% new onset PTSD after birth trauma

18 Time To Relapse of Depression 26% 68% N = 201. Cohen LS, et al. JAMA. 2006;295(5):

19 Consequence of Untreated Depression and Anxiety Pregnancy: Inadequate weight gain Risk for preeclampsia Pre-term birth Low birth weight Small for gestational age Increased uterine artery resistance Elevated maternal perinatal cortisol and neonatal cortisol Bonari L, et al. Can J Psychiatry. 2004;49(11): Grote NK, et al. Arch Gen Psychiatry. 2010;67(10): Bansil P, et al. J Womens Health. 2010;19(2): O Donnell K, et al. Dev Neurosci. 2009;31(4): Cripe SM, et al. Paediatr Perinat Epidemiol. 2011;25(2): Jensen HM, et al. Psychopharmacology. 2013;228(2): Davalos DB, et al. Arch Womens Ment Health. 2012;15(1):1-14.

20 Consequences of Untreated Depression and Anxiety Postpartum Difficult infant temperament Increased risk for later child behavior problems Negative effects on child cognition Impaired mother-infant interaction Prenatal effects moderated by mother-infant attachment Davis EP, et al. J Am Acad Child Adolesc Psychiatry. 2007;46(6): O Connor TG, et al. Br J Psychiatry. 2002;180: Van den Bergh BR, et al. Neurosci Biobehav Rev. 2005;29(2): Deave T, et al. BJOG. 2008;115(8): Bergman K, et al. Biol Psychiatry. 2010;67(11): Lovejoy MC, et al. Clin Psychol Rev. 2000;20(5):

21 Key Point #2: Screening is not enough The potential effectiveness of screening for Postpartum Depression appears to be related to the availability of systems to ensure adequate follow-up of women with positive results. Myers ER, et al. Efficacy and Safety of Screening for Postpartum Depression. Comparative Effectiveness Review 106. AHRQ Publication No. 13- EHC064-EF. Rockville, MD: Agency for Healthcare Research and Quality; April

22 When to Screen? OB visit and at 6 weeks Pediatrician well-baby visits up to 6 months Continuously when engaged in a treatment relationship Postpartum depression presents within the first weeks, but peaks around 3-6 months Screening took easily available ( EPDS, PHQ-2,PHQ-9) Only 5 % of screen-positive women receive adequate treatment. Screening alone in OB does not yield higher rates of treatment engagement, need for collaborative care models: Barriers: low rates of referrals, off-site mental health, stigma, undertreatment, low access to a variety of personalized treatment options, treatment delivery in a timely fashion

23 Screening Measures EPDS Sensitivity = 0.86; Specificity 0.78 For positive screen >10 Take 5-10 minutes, self administered, could be self-scored PHQ-2 Sensitivity = 0.83; Specificity = 0.92 For positive screen >3 Takes Less than 1 minutes, self administered and can be asked PHQ-9 Sensitivity = 0.88; Specificity = 0.88 For positive screen >10 Takes 5-10 minutes, self administered, could be self-scored Muzik M, et al. Ment Health Fam Med. 2010;7(4):

24 ACOG/APA GUIDELINES Mild or moderate depression but no personal or family history START WITH THERAPY such as Self-help strategies (support groups, yoga, mindfulness) Counseling (IPT, CBT) Moderate depression and personal or family history of depression, or active severe depressive episode Start THERAPY AND MEDICATIONS at once Treatment-resistant depression Consider augmenting with mood stabilizer/antipsychotics or ECT ACOG = American College of Obstetricians and Gynecologists; APA = American Psychiatric Association; IPT = interpersonal psychotherapy; CBT = cognitive-behavioral therapy. Yonkers KA, et al. Gen Hosp Psychiatry. 2009;31(5):

25 Treatment Options

26 Psychotherapies Interpersonal psychotherapy (IPT) Cognitive-behavioral therapy (CBT) Behavioral activation (BA) Dyadic relational/attachment interventions Home based interventions Grote NK, et al. Psychiatr Serv. 2009;60(3): Spinelli MG, et al. Am J Psychiatry. 2003;160(3): O Hara MW, et al. Arch Gen Psychiatry. 2000;57(11): O Mahen H, et al. Depress Anxiety. 2013;30(7): Dimidjian S, et al. Clin Obstet Gynecol. 2009;52(3):

27 Antidepressants vs. CBT Vs. Placebo for Moderated to Severe Depression 60% 8 Weeks 16 Weeks Responders (%) 50% 40% 30% 25% 50% 46% 43% 40% 20% 10% 0% Placebo (n = 60) ADM (n = 120) CT (n = 60)

28 Complementary and Alternative Treatments Light therapy Exercise Mindfulness Yoga Omega 3 Fatty Acids SAM-e 1600mg/day 70% in depression over 30 days in women with postpartum depression St. John s wort (mild depression) N-acetylcysteine Vitamin D (treat if deficient) Vitamin B12 (treat if deficient) ADM = antidepressant medication; CT = cognitive therapy. DeRubeis RJ, et al. Arch Gen Psychiatry. 2005;62(4): ; Qureshi, NA, et al. Neuropsychiatric Disease and Treatment 2013;

29 Not the primary treatment for mood disorders. More research necessary. COMPLEMENTARY AND ALTERNATIVE MEDICINE

30 Severe depression, bipolar disorder, and treatment resistant depression require antidepressants, mood stabilizers, and atypical antipsychotics

31 Mary is No Getting Better Mary is now 2 months postpartum. She has met with her therapist a couple of times but she is getting more depressed and dysfunctional She and her husband are now worried about postpartum depression given her prior history She agrees to start medicine now She still desires to breastfeed? Prior medication trials: sertraline, bupropion, clonazepam, fluoxetine (remission), venlafaxine (remission) How do you address the risk-benefit discussion?

32 Key Point #3 Use what worked in the past! Encourage families to be open Encourage families to reflect on family history

33 Consult with Doctor We can use antidepressants and mood stabilizers during pregnancy and in postpartum. Always important to weight risks and benefits

34 Breastfeeding All medications transferred to breast milk, but concentrations are far less than in utero exposure. Drug transfer to the breast milk and to baby is variable by medication but ranging from <1-20% Least likely to transfer: paroxetine, sertraline, TCAs Avoid drugs with a long half-life; possibility of accumulation in breast milk Check baby for adverse effects: drowsiness, poor feeding, monitor CBC, comp, TSH. Fortinguerra F, et al. Pediatrics. 2009;124(4):e547-e556. Payne JL, et al. Clin Obstet Gynecol. 2009;52(3): Eberhard-Gran M, et al. CNS Drugs. 2006;20(3):

35 ECT Safe application in pregnancy No teratogenic effects No intrauterine growth restriction No neurodevelopmental toxicity Some adverse effect on neonate: cyanotic, low muscle tone 2 nd and 3 rd trimester: Women should be positioned slightly toward left side with support under the right hip to prevent vena cava compression syndrome

36 Practical Take Aways Always balance the risks of medication and reoccurrence of illness Aiming to minimize fetal/neonate exposure to both maternal mental illness and medication Avoid polypharmacy Non-pharmacological interventions should be a key component of the treatment plan. Use lowest effective dose BUT dose adequately Use medications with the lowest teratogenic risk History of previous treatment response should help guide decisions Provide written materials to explain the risks Document in your notes that you discussed and they voiced understanding

37 Road to Recovery and Treatment Engagement One small crack does not mean that you are broken, it means that you were put to the test and you didn t fall apart Linda Poindexter

38 Acceptance Road to Recovery Mental Illness is REAL It cannot be ignored Sooner you accept; the easier recovery will be Remove judgement and negative emotion Mental Illness does not define you

39 Overcoming Fear Road to Recovery Fear, embarrassment, guilt are often preventing people from getting help Educate, Educate, Educate! Increase support Groups, therapist, other providers, family, friends

40 Being Patient Road to Recovery Every step is putting you closer to the goal of recovery Some frustration is Normal Recognize the old you returning Engage family members Keep note of initial symptoms of relapse Recovery is not always perfect There is not always a right way

41 Road to Recovery Encourage positive thinking Be kind to yourself Celebrate success! Stay in the present Empower them to be their own advocate Review Distress Tolerance Skills Use Motivational Interviewing

42 Talk to them What can you do Express concern and support Opportunity to provide information, support, and guidance Improved recognition of early signs Earlier treatment Greater understanding and compassion Connect them to other supports School counselor, primary care provider, spiritual leader, etc

43 What Can Family/Friends Do Offer to help with every day tasks Including your friend or family member in your plans: Continue to invite him or her without being overbearing Continue to invite them even if they resists your invitations Educate other people so they understand the facts about mental health and do not discriminate Treat people with respect, compassion, and empathy

44 Other things that are helpful? Know how to connect people to help Communicate in a straightforward manner Speak at a level appropriate to a person s age and developmental level Discuss the topic when and where the person feels safe and comfortable Watch for reactions during the discussion and slow down or back up if the person becomes confused or looks upset.

45 Similar to Other Health Problems Cold vs. Flu Management of High Cholesterol Management of Diabetes Just like people need to take medicine and get professional help for physical conditions, someone with a mental health problem may need to take a medicine and/or participate in therapy to get better

46 Key Point #4 Building a Good Relationship is Key? (Think about Your Favorite Teacher or Favorite Boss)

47 Risk Factors Biopsychosocial Risk Factors Hopelessness Impulsive and/or aggressive tendencies History of trauma or abuse Family history of suicide Past behavior Alcohol and other substance use disorders Environmental Risk Factors Relational or social loss Easy access to lethal means Local clusters of suicide that have a contagious influence Sociocultural Risk Factors Lack of social support and sense of isolation Stigma associated with help-seeking behavior Certain cultural and religions beliefs Barriers to assessing substance abuse health care treatment

48 TREATMENT ENGAGEMENT We should no longer whisper about mental illness

49 Key Point #5 Do not forget about yourself!

50 Take Care of Yourself Eating right Sleep well Exercise Take breaks when necessary It is okay to ask for help Do things you enjoy Use coping techniques Talk to someone Do things you enjoy!

51 Thank you Michigan Home Visiting Conference Organizers Dr. Muzik and Dr. Rosenblum Mary Ludtke Thank you to my patients! (Always teaching me about how to be a better clinician and how to improve mental wellness).

52 Questions?

53 IF YOU ARE INTERESTING IN LEARNING MORE ABOUT MEDICATION MANAGEMENT

54 What Do You Have to Consider When Treating with Medications? Teratogenicity (congenital malformations) Toxicity for pregnancy/fetal outcomes SA PTB LBW SGA Neonatal syndrome Neurobehavioral/developmental effects SA = spontaneous abortion; PTB = preterm birth; LBW = low birth weight; SGA = small for gestational age.

55 Teratogenity Baseline Risk Baseline population risk for any malformation is 2-4% among healthy, unexposed women Thus, any medicine risk must be measured against this baseline risk

56 FDA Pregnancy Categories Are not enough information and misleading A Well controlled studies in human pregnancy show no increased risk (<1% of medications) B Animal studies show no risk OR While animal data show risk well controlled human studies do not C Animal studies show risk and no well controlled human studies available OR There are no animal or well controlled human studies (66% of medications) D Human data show risk OR Benefits may outweigh known risk X Animal or human data show fetal risk positive; the risk clearly outweighs the benefit

57 Problems with Studies Confounding factors are not taken into account in studies Maternal age Other prescription and non-prescription drugs Nutrition ETOH/cigarettes Genetic influences Effects of mental illness or comorbid health conditions Environmental toxins Stress Socioeconomic status Method of delivery

58 Teratogenicity TCA overall risk is low SSRIs overall risk is low Other antidepressants less data but assuring Bupropion: cardiac malformation risk minimal (2/1000) Venlafaxine, duloxetine, mirtazapine: no malformation risk TCA = tricyclic antidepressant; SSRI = selective serotonin reuptake inhibitor. Altshuler LL, et al. Am J Psychiatry. 1996;153(5): Einarson A. Can J Clin Pharmacol. 2009;16(1):e58-e65. Alwan S, et al. N Engl J Med. 2007;356(26): Louik C, et al. N Engl J Med. 2007;356(26): Lennestal R, et al. J Clin Psychopharmacol. 2007;27(6): Grigoriadis S, et al. J Clin Psychiatry. 2013;74(4):e293-e308. Byatt N, et al. Acta Psychiatr Scand. 2013;127(2): Einarson A. Acta Psychiatr Scand. 2013;127(2): Myles N, et al. Aust N Z J Psychiatry. 2013;47(11): Alwan S, et al. Am J Obstet Gynecol. 2010;203(1):52.e1-52.e6. Einarson A, et al. Am J Psychiatry. 2001;158(10): Way CM. Pharmacotherapy. 2012;27(4): Djulus J, et al. J Clin Psychiatry. 2006;67(8):

59 The Paxil Story In 2005 GlaxoSmithKline analyzed own data on N = 815 exposed infants, and found that these infants had 1.5- to twofold increased risk for heart defects, specifically atrial and ventricular septal defects paroxetine became FDA Category D Since 2005 many contradicting studies. Some found Increased risk for unspecific malformations Increased risk for specific cardiac malformations No risk for malformation (risk.7%) Risk is dose-dependent(>25 mg/day) and only when exposed in first trimester US Food and Drug Administration. Accessed July 7, Cole JA, et al. Pharmacoepidemiol Drug Saf. 2007;16(10): Kallen BA, et al. Birth Defects Res A Clin Mol Teratol. 2007;79(4): Wurst KE, et al. Birth Defects Res A Clin Mol Teratol. 2010;88(3): Reis M, et al. Psychol Med. 2010;40(10): Bakker MK, et al. Birth Defects Res A Clin Mol Teratol. 2010;88(2): Einarson A, et al. Am J Psychiatry. 2008;165(6): Berard A, et al. Birth Defects Res B Dev Reprod Toxicol. 2007;80(1): Painuly N, et al. Psychiatric Bulletin. 2013;37:

60 Most Recent Study on Paroxetine Large, population-based cohort study b/w 2000 to 2007 Participants: 949,504 pregnant women who were enrolled in Medicaid during the period from 3 months before the last menstrual period through 1 month after delivery and their live born infants How many exposed? 64,389 women (6.8%) used ADs during the first trimester Finding: RR for cardiac malformation was 1.06 (95% CI, ) in the fully adjusted analysis restricted to women with depression Conclusion: no substantiated risk between AD (in particular sertraline and paroxetine) and cardiac risk AD = antidepressant; RR = relative risk. Huybrechts Funded KF, et by al. N the Engl J Agency Med. 2014;370(25): for Healthcare Research and Quality and

61 Neonatal Syndromes NAS in 25-30% for SSRIs and more common TCAs With 2nd (?) or 3rd trimester exposure Jitteriness, irritability, difficulty with feeding, breathing, hypotonia, temperature instability, seizure Long-term effect (19 months): no developmental effect Does not typically require NICU admission, transient ~2 weeks One study showed no difference in NAS rates with stopping medication 2 weeks prior to delivery (retrospective registry study) NAS = neonatal abstinence syndrome; NICU = neonatal intensive-care unit. Oberlander TF, et al. Arch Gen Psychiatry. 2006;63(8): Moses-Kolko EL, et al. JAMA. 2005;293(19): Way CM. Pharmacotherapy. 2007;27(4): Warburton W, et al. Acta Psychiatr Scand. 2010;121(6): Levinson-Castiel R, et al. Arch Pediatr Adolesc Med. 2006;160(2): Grigoriadis S, et al. J Clin Psychiatry. 2013;74(4):e309-e320. Pedersen LH, et al. Pediatrics. 2010;125(3):e600- e608.

62 Neonatal Syndromes (continued) Persistent pulmonary hypertension At birth the normative closure of ductus arteriosus and foramen ovale does not happen and they stay open leading to a left-to-right shunting of blood causing Hypoxia in neonatal organism If chronic: right ventricle failure Base rate: 2/1000 Absolute risk with exposure to SSRIs 6 x higher but still rare Other possible risk variables: C-section, BMI, race Revised FDA communication in 2012 noting that earlier the risk was overestimated BMI = body mass index. Chambers CD, et al. N Engl J Med. 1996;335(14): Chambers CD, et al. N Engl J Med. 2006;354(6): Kallen B, et al. Pharmacoepidemiol Drug Saf. 2008;17(8): Andrade SE, et al. Pharmacoepidemiol Drug Saf. 2009;18(3): Occhiogrosso M, et al. Am J Psychiatry. 2012;169(12): Wilson KL, et al. Am J Perinatol. 2011;28(1): Grigoriadis S, et al. BMJ. 2014;348:f6932. Hernandez-Diaz S, et al. Pediatrics. 2007;120(2):e272-e282. US Food and Drug Administration. Accessed July 7, 2014.

63 Spontaneous Abortion Antidepressant-related to increased risk for SA N = % on antidepressants vs 8.7% off No difference between various classes of antidepressants None of the studies took confounders into consideration such as Poor health habits, psychiatric illness, smoking, etc This reduces the clinical utility of findings Bupropion appears to have higher risk for SA than SSRIs Hemels ME, et al. Ann Pharmacother. 2005;39(5): Ross LE, et al. JAMA Psychiatry. 2013;70(4): Chun-Fai-Chan B, et al. Am J Obstet Gynecol. 2005;192(3): Einarson A, et al. J Obstet Gynaecol Can. 2009;31(5):

64 Preterm birth, low birth weight Antidepressant-related to near-term PTB (defined as birth >35 weeks but <37 weeks) Gestational age dependent on duration of exposure to antidepressant; longer exposure related to shorter gestation Antidepressant-related to increased risk for SGA Antidepressant exposure related to LBW; effect is minimal (~75 g less) and disappears when control group are untreated depressed mothers Wisner KL, et al. Am J Psychiatry. 2009;166(5): Suri R, et al. Am J Psychiatry. 2007;164(8): Lund N, et al. Arch Pediatr Adolesc Med. 2009;163(10): Oberlander TF, et al. Br J Psychiatry. 2008;192(5): Oberlander TF, et al. Arch Gen Psychiatry. 2006;63(8): Kallen B. Arch Pediatr Adolesc Med. 2004;158(4):

65 Neurobehavioral Toxicity TCA or fluoxetine exposure no global IQ, language, or behavioral problems at 15 months and 7 years of age (N = 219; N = 122) No effects on motor performance and attention/learning tasks in 6-month-old babies who were SSRI exposed; but, babies exposed to antipsychotics did worse on neurological motor tasks Minor motor developmental delay in toddlers exposed to SSRIs Nulman I, et al. N Engl J Med. 1997;336(4): Nulman I, et al. Am J Psychiatry. 2002;159(11): Nulman I, et al. Am J Psychiatry. 2012;169(11): Johnson KC, et al. Arch Gen Psychiatry. 2012;69(8): Casper RC, et al. J Pediatr. 2008;142(4): Gentile S, et al. J Affect Disord. 2011;128(1-2):1-9.

66 Neurobehavioral Toxicity (continued) Two large population-based case-control studies hint at association between SSRI use and ASD in offspring However, while significant SSRI explain only.6% of cases with ASD A study of nearly 1000 mother-child dyads suggested that boys are significantly more at risk for ASD than girls if their mothers took an SSRI during pregnancy, especially during the first trimester Recent review concludes that exposure during the first trimester may increase the risk of ASD, however confounders were not assessed ASD = autism spectrum disorder. Croen LA, et al. Arch Gen Psychiatry. 2011;68(11): Rai D, et al. BMJ. 2013;346:f2059. Harrington RA, et al. Pediatrics. 2014;[Epub ahead of print]. Andrade C. J Clin Psychiatry. 2013;74(9):

67 Case: Mary Mary and her husband agree that she will start an antidepressant Which one? Past trials: sertraline, fluoxetine, bupropion XL, venlafaxine

68 Use what has worked in the past (Single exception: valproate in pregnancy) KEY POINT #3

69 Case: Mary Previously euthymic on fluoxetine 40 mg Plan: restart fluoxetine 10 mg x 5 days, then 20 mg and titrate to 40 mg START LOW, GO SLOW, KEEP GOING I am so anxious that I am crawling out of my skin! Every time I increase the dose, I get more anxious and my sleep is even worse for a few days.

70 Are anxiety meds safe? No evidence of congenital malformation Initial concern cleft lip/palate, disproven Lorazepam and clonazepam preferred Less likely to accumulate in fetus/neonate Alprazolam rapid on/off = unknown fetal effects 550 infants with normal development to 4 yo Iqbal MM, et al. Psychiatr Serv. 2002;53(1): McElhatton PR. Reprod Toxicol. 1994;8(6): REPROTOX. April 2013.

71 Sleep and Perinatal Depression 70% of pregnant women report poor sleep Women with poor sleep have higher EPDS score 10 (39% vs 20% HC; P <.01) Women with sleep <6 hours/night compared to 7-9 hours/night have more depressive symptoms (60% vs 31%, P =.03) 45% of pregnant and 55% of postpartum women with depressive symptoms also report clinical insomnia Sleep disturbances in the 2nd trimester predict significant depressive symptoms in the 3rd trimester Sleep disturbances during pregnancy predict significant OlBrien depressive LM, et al. Am J symptoms Obstet Gynecol. 2012;207(6):487.e1-487.e9 postpartum. Swanson LM, et al. J Womens Health. 2011;20(4): Kamysheva E, et al. J Affect Disord. 2010;123(1-3): Dorheim SK, et al. Sleep. 2009;32(7): Okun ML, et al. Depress Anxiety. 2011;28(8):

72 Clinical Pearl: Insomnia x 4 Nights = Red Flag Treatment in Pregnancy Stress reduction Massage, relaxation, and meditation techniques Sleep hygiene Warm bath 1 hr before bed raises core temp and stimulates sleep response CBT-I or medications Diphenhydramine Zolpidem Trazodone Tranquillizer Treatment while Breastfeeding Stress reduction Massage, relaxation, and meditation techniques Sleep hygiene Warm bath 1 hr before bed raises core temp and stimulates sleep response Help w/ infant care and feeding Minimize use of alcohol (paradoxical effects) If 4 days CBT-I or medications Khazaie H, et al. Psychiatry Res. 2013;210(3): Wikner BN, et al. J Clin Psychopharmacol. 2011;31(3):

73 Sleep Medications Benzodiazepines Teratogenity: 1st trimester possible cleft lip malformation (old data) but this has not been replicated in later studies 3rd trimester floppy baby syndrome, withdrawal symptoms and restlessness in neonates, PTB, LBW Trazodone No malformations Zolpidem Possibly some increased risk for PTB, SGA, LBW but clinically low significance; low risk for malformation Wikner BN, et al. Pharmacoepidemiol Drug Saf. 2007;16(11): Wikner BN, et al. J Clin Psychopharmacol. 2011;31(3): Einarson A, et al. Can J Psychiatry. 2009;54(4): Juric S, et al. Arch Womens Ment Health. 2009;12(6): Wang LH, et al. Clin Pharmacol Ther. 2010;88(3):

74 Valproic Acid Teratogenicity: 10%, particularly if exposure in 1st trimester Risk is dose dependent (>1000 mg/day) Midface hypoplasia and other facial anomalies Cardiac anomalies Folate supplementation up to 5 mg daily may reduce risk Intrauterine growth restriction Mental retardation independent of which trimester exposure Neonatal toxicity Irritable, jittery, hypotone, feeding difficulties, liver toxicity Hypoglycemia Single dosing causes higher peaks Mostly exposure in unplanned pregnancy end of 1st trimester Wyszynski DF, et al. Neurology. 2005;64(6): Morrow J, et al. J Neurol Neurosurg Psychiatry. 2006;77(2): Meador KJ, et al. N Engl J Med. 2009;360(16):

75 Lamotrigine Teratogenicity 3 out of 4 registries report no more than baseline population risk for malformations (2-4%) 1 out of the 4 registries suggested increase in RR for midline facial clefts with 1st trimester exposure; but absolute risk is very low (4:1000) Neonatal toxicity Transient liver toxicity Watch skin rash Increased excretion in pregnancy need to increase dose in later gestation Cunnington M, et al. Neurology. 2005;64(6): Meador KJ, et al. Neurology. 2006;67(3): Clark CT, et al. Am J Psychiatry. 2013;170(11):

76 Lithium Teratogenicity Risk for cardiac malformation Ebstein s anomaly (tricuspidal displacement/right ventricle hypoplasia) Initial risk was overstated in the 1970s Population risk is: 1 : 20,000 (.00005%) Lithium-exposed risk is: 1-2 : 1,000 ( %) Therefore, while the RR is increased by 20- to 40-fold, the absolute risk for Ebstein s anomaly is still extremely low when on lithium Risk for neonatal toxicity Floppy baby, cyanose, hypotone, hypothyroidism, nephrogenic diabetes insipidus Clearance is increased in late pregnancy dose increase! Gentile S. Expert Opin Drug Saf. 2012;11(3):

77 Carbamazepine Teratogenicity: 2.6% same as general population Neural tube exposure 1st trimester, dose related-spina bifida: risk 2.6x higher than the general population rate of 1:1000 births so absolute risk rate still small Craniofacial and other facial anomalies not confirmed higher risk Oxcarbazepine safe Screening: maternal α-fetoprotein (blood) and 2D or 3D ultrasound weeks Vitamin K prophylaxis: start week 36 to prevent hemorrhagic disease in the newborn (carbamazepine induces cytochrome P450 enzyme which degrades Vitamin K) Intrauterine growth restriction Neonatal toxicity Transient liver toxicity Neonatal bleeding, administer Vitamin K 1 mg to baby Mostly exposure in unplanned pregnancies or epilepsy patients The North American Antiepileptic Drug Pregnancy Registry. Winter www2.massgeneral.org/aed/newsletter/winter2009newsletter.pdf. Accessed July 7, Morrow J, et al. J Neurol Neurosurg Psychiatry. 2006;77(2): Harden CL, et al. Neurology. 2009;73(2): Jentink J, et al. BMJ. 2010;341:c6581.

78 First-Generation Antipsychotics Exposure to phenothiazines during pregnancy (N = 1309) No differences were found in rates of congenital malformations, perinatal mortality rate, birth weight as compared to the population Pregnancy exposure to haloperidol (N = 215) No increase risk for major malformations Increased incidence of PTB and neonatal adaptation but not malformation compared to unexposed Slone D, et al. Am J Obstet Gynecol. 1977;128(5): Diav-Citrin O, et al. J Clin Psychiatry. 2005;66(3): Habermann F, et al. J Clin Psychopharmacol. 2013;33(4): ; Gentile S. Schizophr Bull. 2010; 36(3):

79 Second-Generation Antipsychotics Limited data on exposed children! Manufacturers registries: olanzapine = 242, clozapine = 523, quetiapine = 446, risperidone = 250 Case reports: clozapine= 74, olanzapine = 69, quetiapine = 3 risperidone = 12 Prospective comparative study 151 women were followed exposed to following drugs Olanzapine = 60, risperidone = 49, quetiapine = 36, clozapine = 6 The researchers found no teratogenic effects 570 women in Swedish database were exposed to SGA: slight increased risk for major malformations (OR 1.5) Increased incidence of PTB and neonatal adaptation but not malformation compared to unexposed SGA = second-generation antipsychotic. McKenna K, et al. J Clin Psychiatry. 2005;66(4): Reis M, et al. J Clin Psychopharmacol. 2008;28(3): Habermann F, et al. J Clin Psychopharmacol. 2013;33(4):

80 Second-Generation Antipsychotics (continued) Neurobehavioral development Single study from Hong Kong Exposed = schizophrenia, 50% clozapine Control = no mental illness Exposed with significant delays at 2 to 4 months but caught up on all measures by 1 yo Aripiprazole: 3 case reports Ziprasidone: 3 case reports Overall: increased risk for EPS in neonate with antipsychotics 2011 FDA drug safety communication (EPS) EPS = extrapyramidal symptoms. Peng M, et al. Psychopharmacology. 2013;228(4): REPROTOX. April Galbally M, et al. Therapeutic Advances in Drug Safety. 2014;5(2):

81 Case: Mary Mary had an uneventful vaginal delivery at 39 weeks She experienced some worsening mood and disrupted sleep in the first week postpartum She wants to breastfeed and mild ejection is slow; this has been stressful. She is also concerned I want to breastfeed my baby Is it safe for my baby to be on clonazepam and fluoxetine?

82 Medications and Breastfeeding All medications transferred to breast milk, but concentrations are far less than in utero exposure <10% of maternal serum plasma is considered compatible with breastfeeding Fluoxetine: 5-9% of maternal dose Other SSRIs: range from 1-20% Carbamazepine: <1% Lorazepam, clonazepam: <1% Avoid drugs with a long half-life: possibility of accumulation in breast milk Check baby for adverse effects: drowsiness, poor feeding, Chad L, et al. Can Fam Physician. 2013;59(6): Fortinguerra F, et al. Pediatrics. 2009;124(4):e547-e556. monitor CBC, comp, TSH, CAVE: premies

83 Breastfeeding Antidepressants Breastfeeding OK, drug transfer to breast milk and to baby variable by medication but ranging from <1-20% Least likely to transfer: paroxetine, sertraline, TCAs Rule: continue the medicine used in pregnancy or start agent that was effective in prior medication trials Fortinguerra F, et al. Pediatrics. 2009;124(4):e547-e556. Payne JL, et al. Clin Obstet Gynecol. 2009;52(3): Eberhard-Gran M, et al. CNS Drugs. 2006;20(3):

84 Breastfeeding (continued) Benzodiazepines Breastfeeding OK as minimal excreted in breast milk (clonazepam, lorazepam OK) Fortinguerra F, et al. Pediatrics. 2009;124(4):e547-e556. Payne JL, et al. Clin Obstet Gynecol. 2009;52(3):

85 Breastfeeding (continued) Lithium Breastfeeding not recommended as baby vulnerable for dehydration and lithium toxicity If mother insists, need to perform blood draws in first weeks to check how much lithium transferred via mild; transfer is variable up to 30% Fortinguerra F, et al. Pediatrics. 2009;124(4):e547-e556. Payne JL, et al. Clin Obstet Gynecol. 2009;52(3): Viguera AC, et al. Am J Psychiatry. 2007;164(2): Eberhard-Gran M, et al. CNS Drugs. 2006;20(3):

86 Breastfeeding (continued) Valproic acid Breastfeeding OK, infant serum level 6% of mom, no adverse effects Carbamazepine Breastfeeding OK, infant serum 6-65% of mom, no adverse effects Lamotrigine Breastfeeding OK, 30% mom dose, no adverse effects Davanzo R, et al. Ital J Pediatr. 2013;39:50. Eberhard-Gran M, et al. CNS Drugs. 2006;20(3):

87 ECT Safe application in pregnancy No teratogenic effects, no intrauterine growth restriction, no neurodevelopmental toxicity Some adverse effect on neonate: cyanotic, floppy, hypotone 2nd and 3rd trimester: women should be positioned slightly toward their left side with support under the right hip when receiving ECT to prevent a vena cava compression syndrome ECT = electroconvulsive therapy. Rabheru K. Can J Psychiatry. 2001;46(8):

88 Summary 1. Treatment of perinatal mood disorders aims to minimize fetal/neonatal exposure to both maternal mental illness and medication 2. Nonpharmacologic interventions should be a key component of the treatment plan 3. Use what has worked in the past (Single exception: valproate in pregnancy)

89 Resources Pregnancy Lactation

90 Questions? THANK YOU