Mental Health Issues Related to Pregnancy Outcomes

Transcription

1 Mental Health Issues Related to Pregnancy Outcomes Maria Muzik, MD, MSc Assistant Professor and Director, Women and Infants Mental Health Clinic Department of Psychiatry & Depression Center, University of Michigan Assistant Research Scientist in Center for Human Growth & Development

2 Faculty Disclosure Maria Muzik, MD, MSc has no financial relationships to disclose relating to the subject matter of this presentation.

3 Case: Mary Mary is a 29 yo married woman at 24 weeks gestation in her third pregnancy who presents to your office. She had 2 prior severe depressive episodes, both started in postpartum while she felt well in pregnancy. She also has a history of anxiety; was given diagnosis of GAD. No prior hospitalizations or suicide attempts, but h/o SI. Family history of bipolar disorder in aunts and several cousins. Prior meds trials: sertraline, buproprion, fluoxetine (remission), venlafaxine (remission), and clonazepam

4 Case: Mary Current presentation: moody, irritable, sad, anhedonic, stressed, cannot relax, racing thoughts of worries that baby is not developing right and that my mental health is harming the baby ; hopeless, overwhelmed, cannot sleep, fleeting thoughts she would be better off dead Presents to your clinic; she is 24 weeks gestation and is medication free as she had stopped when she learned she is pregnant. I really don t want to take medication during pregnancy. I am scared the medications will harm my baby

5 Key Point #1 Treatment of perinatal mood disorder needs to strive to minimize fetal/neonatal exposure to both maternal mental illness and medication.

6 RISK BENEFIT RATIO Risk of Untreated Illness Risk of Treatment NO RISK-FREE ZONE!!!

7 Behavioral health problems seen in the primary care in high risk childbearing women

8 Women s Mood Disorder Episodes throughout the Lifecycle Major Depression Premenstrual Dysphoric Disorder Postpartum Depression Birth Menarche Pregnancy Peri/Menopause

9 Mood Disorders Most often during developmental and hormonal transitions and periods of stress or loss Adolescence Premenstrual Peripartum Perimenopause Hypothesis: increased sexsteroid sensitivity as a susceptibility factor? Women with PPD increased sensitivity to estrogen signaling 1 Borrow & Cameron, Prog Neuropsychopharmacol Biol Psychiatry, 2014; 2 Mehta et al., Psychol Med ;

10 Mood Disorders Depression in Pregnancy 14% 1 Postpartum Blues 50%-85% 3 10%-15%, cross- Postpartum Depression culturally 2 Postpartum Psychosis 1-2/ Evans J, et al. BMJ. 2001;323: ; 2. O Hara M, Swain A. Int Rev Psychiatry. 1996;8(1): Gale & Harlow. J Psychosom Obstet Gynaecol. 2003;24(4):257-66

11 Is it the Blues or Psychosis? Blues 50%-85% Labile mood Tearful Mildly disturbed sleep No major change in functioning Begins 2-4 days after birth; maximum at end of first week Resolves by second week Physiologic reaction to birth experience, physical exhaustion and/or hormonal changes No treatment necessary, except if severe and >14 days Psychosis 0.1%-0.2% Extremely disturbed mood Highly agitated Severely disturbed sleep Delusions/hallucinations Suicidal thoughts Major loss of functioning Rapid decline over 1-2 weeks New-onset or relapse of bipolar spectrum disorder (depression with psychosis or mania) Psychiatric emergency Inpatient stabilization, medications, therapy, ECT, family support

12 Perinatal Anxiety and OCD Generalized Anxiety ~8% > in non-perinatal (~5%) 1 OCD <1% in preg/3-4% pp > in non-perinatal (~2.5%) Panic Disorder 1-2% = as in non-perinatal Key symptom: Scary thoughts : negative, unwanted, repetitive and/or intrusive thoughs and images Common, in all new parents, normal phenomenon after childbirth 2 Obsessive thoughts 91% 3 Intrusive memories of birth 15-37% 4 Excessive worry 20-50% 5 Rumination Catastrophic misinterpretation of bodily sensations 1 Ross & McLean, J Clin Psychiatry, 2006; 2 Hall & Wittkowski, J of Midwifery & Women s Health, Abramowitz et al., Beh Res & Ther Creedy, Birth, 2000; 5 Wenzel et al. AWMH, 2003

13 Scary thoughts of harming the baby >90% of postpartum women have intrusive thoughts of accidental harm to their baby (illness, fall, abduction, suffocation 1 50% of postpartum mothers have intrusive thoughts about intentionally harming their baby 1 No correlation between scary thoughts and actions 2 DDx between OCD Psychosis Intrusive thoughts cause distress aggressive thoughts without guilt/distress Fear of acting on it confused, agitated, AH Avoidance rituals bizzare/violent behavior 1 Fairbrother & Woody, AWMH, 2008; 2 Barr& Beck, Can Fam Physician, 2008

14 Trauma and PTSD Obstetric/labor trauma 1 20% of women Interpersonal Trauma 2 28% have been sexually abused in childhood 20% experience intimate partner violence 4-8% are abused during pregnancy Peripartum PTSD % - PTSD Lifetime 2-7% - PTSD in Pregnancy or Postpartum 1.5-3% - new onset PTSD after birth trauma 4 1 Menage J. J Reprod Infant Psychol 1993;11: Resnick, J Consult Clin Psychol, 1993; 3 Loveland Cook, Flick et al. 2004; 4 Ayers S, & Pickering AD. Birth 2001;

15 When to Screen? OB visit during antenatal visits and at 6 weeks Peds well-baby visits PPD presents in first weeks but peaks around 3-6 months Screening tools easily available Screening needs to be part of comprehensive, integrated care system as screening alone in OB/peds does not yield higher rates of treatment engagement Barriers: low rates of referrals, off site mental health, stigma, undertreatment, low access to variety of personalized treatment options; treatment delivery in timely fashion Only 5% of screen-positive women receive adequate treatment Yonkers et al., Psych Services 2009

16 Screening Tools

17 What about risk of NOT treating?

18 Time to Relapse of Depression in Pregnancy among euthymic women on/off meds (n=201) 26% 68% Cohen et al., JAMA, 2006

19 Consequences of Untreated Depression and Anxiety Pregnancy Inadequate weight gain Risk for preeclampsia Preterm birth (PTB) Low birth weight (LBW) Small for Gestational Age (SGA) Increased uterine artery resistance Elevated maternal prenatal cortisol and neonatal cortisol Bonari et al., Can J Psychiatry, 2004; Grote et al., Arch Gen Psych 2010; Bansil et al., JWH 2010; O'Donnell et al., Dev Neurosci, 2009 Cripe et al., Paediatr Perinat Epidemiol Jensen et al., Psychopharmacology Davalos et al. Arch Womens Ment Health. 2012;

20 Consequences of Untreated Depression and Anxiety Postpartum Difficult infant temperament 1 Increased risk for later child behavior problems 2,3 Negative Effects on child cognition 4 Impaired Mother-infant interaction Prenatal Effects moderated by motherinfant attachment 5 1 Davis et al., JAACAP, O'Connor et al., BJP, Van den Bergh et al., Child Dev, 2005; 4 Deave, et al., BJOG, Bergman et al., Biol Psych, 2010.

21 Video example of mother-infant interaction

22 Review the psychotherapy and psychopharmacology options

23 ACOG/APA guidelines mild or moderate depression but no personal or family history START WITH THERAPY first self-help strategies (support groups, yoga, mindfulness) Counseling 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/aps or ECT Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression during pregnancy: A report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Gen Hosp Psychiat. 2009;31(5):

24 Psychotherapies Cognitive behavioral therapy (CBT) Behavioral activation (BA) Interpersonal psychotherapy (IPT) Mindfulness-based cognitive therapy (MBCT) Acceptance and commitment therapy (ACT)

25 Antidepressants vs CBT vs Placebo for Moderate to Severe Depression DeRubeis et al, Arch Gen Psychiatry, 2005

26 Sustained Improvement with therapy Hollon et al. 2005, Arch Gen Psychiatry

27 Meta-Analysis: Psychotherapy for perinatal depression IPT VS CBT N studies Hedges g CBT 6.40*** IPT 5.96*** Significant difference between CBT, IPT Sockol et al, 2011 Therapy type N studies Hedges g Group + individual * Group 3.55** Individual 7.78*** Non-significant difference between modalities * p <.05, ** p <.01,*** p <.001

28 Complementary & Alternative Treatments Light therapy Exercise Mindfulness Yoga Omega-3-FA, SAM-e (S-adenosyl methionine) Vitamin D (treat if deficient) Vitamin B12 (treat if deficient) Brogan 2013, Kim DL et al 2011, Manber R et al 2010, Wirz-Justice 2011, Muzik et al 2013 Freeman, 2009

29 Case: Mary is not getting better Mary has met with her therapist 3x, but is getting more depressed and dysfunctional and both she & husband are worried about postpartum (given prior history). She agrees to start medicine now. She is 28 weeks pregnant. Prior meds trials: sertraline, buproprion, clonazepam, fluoxetine (remission), venlafaxine (remission) How do you address the risk-benefit discussion?

30 RISK BENEFIT RATIO Risk of untreated Illness Risk of medications NO RISK-FREE ZONE!!!

31 What do you have to consider when treating with medications? Teratogenity (congenital malformations) Toxicity for pregnancy/fetal outcomes Spontaneous Abortions (SA) Preterm Birth (PTB), Low Birth Weight (LBW) Small for Gestational Age (SGA) Neonatal Syndrome Neurobehavioral/developmental effects

32 Some Basics in Embryology From last menstrual period: 2 weeks: fertilization ( all or nothing ) 3 weeks: implantation 4 weeks: positive urine pregnancy test 5 weeks: neural tube closure 5-12 weeks: formation of all major organs and limbs (teratogenic period) 12 weeks +: minor/functional malformations; further brain development (neurobehavioral toxicity)

33 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.

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

35 Teratogenity Tricyclic AD (TCA) overall risk is low 1,6,7,8 SSRIs overall risk is low 2,3,4,6,7,8 Small but significant 1 st TM increased risk for paroxetine and fluoxetine 9 Other antidepressants (AD) less data but assuring Data from one Swedish registry study 5 n=732, no increased risk was found Bupropion cardiac malformation risk minimal (2/1000) 10 Venlafaxine 11, duloxetine 12, mirtazepin 13 - no malformation risk 1 Altshuler, et al AJP,1996; 2 Einerson, Can J Clin Pharmacol., 2009; 3 Alwan et al., NEJM, 2007; 4 Louik et al., NEJM, 2007; 5 Lennestal & Kallen, J Clin Psychopharmacol, 2007; 6 Grigoriadis, J Clin Psychiatry, 2013; 7 Byatt N et al., Acta Psychiatr Scand ; 8 Einarson, Acta Psychiatr Scand. 2013; 9 Myles et al., Aust N Z J Psychiatry, 2013 ; 10 Alwan et al., Am J Obstet Gynecol 2010; 11 Einerson et al., AJP 2001; 12 Way et al.,pharmacotherapy 2012; 13 Djullus et al. J Clin Psychiatry 2006;

36 The Paroxetine Story In 2005 GSK 1 analyzed own data on n=815 exposed infants, and found that these infants had 1.5 to 2-fold 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 2 Increased risk for specific cardiac malformations 3,4,5,6,9 no risk for malformation 7 (risk 0.7%) that risk is dose-dependent(>25mg daily) and only when exposed in first trimester Cole at al.,pharmacoepidemiol Drug Saf, 2007; 3 Kallen et al., Birth Defects Res A Clin Mol Teratol, 2007; 4 Wurst 2010, 5Reis 2010, 6 Bakker Einarson et al., AJP, 2008; 8 Berard et al. Birth Defects Res B Dev Reprod Toxicol, 2007; 9 Painuly et al., 2013 The Psychiatrist.

37 Newest study large, population-based cohort study period 2000 through 2007; 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 liveborn infants 64,389 women (6.8%) used antidepressants during the first trimester RR for cardiac malformation 1.06 (95% CI, 0.93 to 1.22) in the fully adjusted analysis restricted to women with depression indicating that there is no substantiated risk between AD (in particular sertraline and paroxetine) and cardiac risk Funded by the Agency for Healthcare Research and Quality and the National Institutes of Health.) Krista F. Huybrecht et al., Antidepressant Use in Pregnancy and the Risk of Cardiac Defects, NEJM 370;25June 2014

38 Problems with studies confounding factors are not taken into account in studies: Maternal age Other prescription & non-prescription drugs Nutrition ETOH/cigarettes Genetic influences Effects of mental illness or comorbid health conditions Environmental toxins Stress Socioeconomic status Method of Delivery

39 Spontaneous Abortion AD related to increased risk for SA 1,2 N= % on AD vs 8.7% off No difference between various classes of AD None of 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 that SSRI 3,4 1 Hemels, et al., Ann Pharmacother, Review Paper. 2005; 2 Ross et al., JAMA Psychiatry, 2013; 3 Chun- Fai-Chan et al, Am J Obstet Gynecol, 2005; 4 Einarson et al., J Obstet Gynaecol Can, 2009.

40 PTB, SGA, LBW AD related to near-term PTB (defined as birth >35 weeks but <37 weeks) 1,2,3 GA dependent on duration of exposure to AD; longer exposure related to shorter gestation 4 AD related to increased risk for SGA 5 AD exposure related to LBW 6 ; effect is minimal (~ 75g less) and disappears when control group are untreated depressed mothers 7 1 Wisner et al., AMJ, 2009; 2 Suri et al., AJP, 2007; 3 Lund et al., Arch Pediatr Adolesc Med, Oberlander et al., BJP, 2008; 5 Oberlander et al., Arch Gen Psych 2006; 6 Kallen et al., Arch Pediatr Adolesc Med, 2004

41 Preterm Birth (PTB) 12 studies: inconsistent Best-designed study: Euthymic women on SSRI s vs. Depressed women not on medication Same 20% pre-term delivery rate Major Depression: consistent 20-25% pre-term delivery rate Wisner, 2009

42 Neonatal Syndromes Neonatal Abstinence Syndrome (NNA) 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 Two long-term studies (7yo): 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) Misri 2006, Moses-Kolko 2005, Way 2007, Warburton 2010; Levinson-Castiel et al., 2006; Grigoriadis et al., J Clin Psychiatry 2013

43 Neonatal Syndromes 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 SSRI controversial, with 6 studies showing different risks, probably in 3rd trimester SSRI exposed babies: 3-6/ Other possible risk variables: C-section, BMI, race 6 No mortality in 50 SSRI-related cases in literature Revised FDA communication in 2012 noting that earlier the risk was overestimated ( 1 Chambers, NEJM 1996; 2006; Kallen, Pharmacoepidemiol Drug Saf., Andrade et al., Pharmacoepidemiol Drug Saf., Occhiogrosso 2012, 4 Wilson 2011; 5 Grigoriadis et al., BMJ 2014; 6 Hernandez-Diaz et al., Pediatrics 2007)

44 Neurobehavioral Toxicity TCA or fluoxetine exposure no global IQ, language or behavioral problems at 15 months 1 and 7 years of age 2 (n=219) No effects on motor performance and attention/learning tasks in 6 months old babies SSRI exposed 3 Minor motor developmental delay in toddlers exposed to SSRIs 4 Babies at 6 months exposed to antipsychotics do worse on neurological motor tasks 3 1 Nulman et al. NEJM, 1997; 2 AJP, 2002, AJP 2012; 3 Johnson et al., Arch Gen Psych., 2012; 4 Casper et al J Pediatr., ; Gentile et al., J Affective Disorder 2011

45 Neurobehavioral Toxicity Two large population-based case-control studies hint at association between SSRI use and autism in offspring 1,2 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 3 Recent review concludes that exposure during the first trimester may increase the risk of ASD, however confounders not assessed 4 1 Croen et al., Arch Gen Psychiatry, 2011; 2 Rai et al, BMJ, 2013; 3 Harrington et al., Pediatrics, 2014; 4 Andrade, J Clin Psychiatry, 2013

46 Case: Mary Previously euthymic on fluoxetine 40 mg. Plan: restart fluoxetine 10 mg x 5 days, then 20mg and titrate to 40mg. 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.

47 Benzodiazepines: Pregnancy 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 McElhatton 1994, Reprotox.org, April 2013; Iqbal et al., Psych Services 2002

48 Benzodiazepines: Pregnancy Floppy baby syndrome High dose near delivery Neonatal apnea, hypotonia Not present with once-daily use Likely only at high doses Neonatal Adaptation Syndrome Increased incidence with antidepressant use Weinstock, 2001; Iqbal et al., Psych Services 2002

49 Benzodiazepines: Pregnancy Preterm delivery Inconsistent findings If at al late preterm Low birth weight Inconsistent findings No control for mental illness Wikner, 2007; Iqbal et al., Psych Services 2002

50 Insomnia x 4 nights = crucial red flag Treatment in Pregnancy Stress reduction Massage, relaxation & meditation techniques Sleep Hygiene Warm bath 1 hr before bed raises core temp & stimulates sleep response Medications: Benadryl Ambien Trazodone Tranquillizer Treatment while Breastfeeding Stress reduction Massage, relaxation & meditation techniques Sleep Hygiene: Warm bath 1 hr before bed raises core temp & stimulates sleep response Help w/ infant care and feeding Minimize use of alcohol (paradoxical effects) If 4 days: Medications

51 Sleep medications Benzodiazepines Teratogenity: 1 st TM possible cleft lip malformation (old data) but this has not been replicated in later studies 1 ) 3 rd TM floppy baby syndrome, withdrawal symptoms and restlessness in neonates, PTB, LBW Trazodone (Desyrel) 2 No malformations Zolpidem (Ambien) 3,4 Possibly some increased risk for PTB, SGA,LBW-but clinically low significance 1 Wikner et al, Pharmacoepidemiology and drug safety, 2007; 2 Einerson et al, Canadian Journal of Psychiatry, April 2009; 3 Juric et al., AWMH, 2009; 4 Wang et al., Clin Pharmacol Ther., 2010

52 What if. Mary actually has a bipolar depression and instead of getting better deteriorates on antidepressant alone. You consider a mood stabilizer. Which one?

53 Treatment of Bipolar Disorder in Pregnancy? Prophylaxis important as relapse risk untreated ~50% and postpartum 70% 1 VPA teratogenic risk and neurobehavioral toxicity make it contraindicated Also risk for PCOS thus not a good medicine for childbearing women Lithium- highly effective for mania and as mood stabilizer, low absolute reproductive risk Lamotrigine-reasonable to prevent depressive episodes, low risk CBZ- also alternative SGA-growing body of evidence effective and safe Prophylaxis important as relapse risk untreated ~50% and postpartum 70% 1 1 Viguera et al., AJP 2000

54 Lamotrigine Teratogenity 1,2 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 relative risk for midline facial clefts with 1 st trimester exposure; but absolute risk is very low (4:1,000) Neonatal Toxicity Transient liver toxicity Watch skin rash Increased excretion in pregnancy need to increase dose in later gestation Lamotrigine is the #1 mood stabilizer for bipolar depression in pregnancy safe & works 1 Cunnington et al., 2005; 2 Meador et al., 2006

55 Lithium Teratogenity: risk for cardiac malfomation- Ebstein s Anomaly (tricuspidal displacement/right ventricle hypoplasia) Initial risk was overstated in the 1970s Population risk is: 1 : 20,000 ( %) Lithium-exposed risk is: 1-2 : 1,000 (0.001%-0.002%) Therefore while the relative risk is increased by fold, the absolute risk for Ebstein s anomaly is still extremely low when on Lithium Risk for Neonatal Toxicity: Floppy baby, cyanose, hypotone, hypothyroidism, neprogenic diabetes insipidus Clearance in increased in late pregnancy-dose increase!

56 Carbamazepine Teratogenity: 2.6% same as general population 1.2,3 Neural tube exposure 1st TM, dose related- spina bifida: risk 2.6 times higher than the general population rate of 1:1000 births so absolute risk rate still small 4 craniofacial & other facial anomalies not confirmed higher risk Oxcarbazepine (Trileptal) safe Screening: maternal α-fetoprotein (blood) and two dimensional or three dimensional ultrasound week Vit K prophylaxis: start week 36 to prevent hemorrhagic disease in the newborn. (CBZ induces Cytochrome P450 enzyme which degrates Vit K) IUGR Neonatal Toxicity Transient liver toxicity Neonatal bleeding, administer vitamin K 1mg to baby Mostly exposure in unplanned pregnancies or epilepsy patients 1 North American Antiepileptic Drug Pregnancy Registry. Winter Morrow et al., J Neurol Neurosurg Psychiatry 2006; 3 Harden et al., Neurology 2009; 4 Jentink et al., BMJ 2010

57 Valproic Acid Teratogenity: 10%, particularly if exposure in 1 st TM 1 Risk is dose dependent (>1000mg/d) 2,3 Midface hypoplasia & other facial anomalies Cardiac anomalies Folate supplementation up to 5mg daily may reduce risk Intrauterine Growth Restriction (IUGR) Mental Retardation independent of which TM exposure Neonatal Toxicity Irritable, jittery, hypotone, feeding difficulties, liver tox, hypoglycemia Single dosing causes higher peaks Mostly exposure in unplanned pregnancy end of 1 st TM 1 Wyszynski et al., 2005; 2 Cunnington et al., 2007; 3 Morrow et al., 2006; 4 Meador et al., NEJM 2009

58 First Generation APS Exposure to phenothiazines during pregnancy (n=1309) 1. 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) 2. No increase risk for major malformations Increased incidence of PTB and neonatal adaptation but not malformation compared to unexposed 3 1 Slone D. et al., Am J Obstet Gynecol., July 1977; 2 Diav-Citrin O. et al., J Clin Psychiatry., Habermann at al., J Clin Psychopharmacol 2013

59 Second Generation APS = Atypicals Limited data on exposed children! Manufacturers registries: olanzapine = 242 clozapine =523 quetiapine = 446 risperidone = 250 Case reports: clozapine= 74 Olanzepine = 69 quetiapine =3 risperidone = 12 1 Prospective comparative study 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 data base were exposed to SGA: Slight increased risk for major malformations (OR 1.5) 3 Increased incidence of PTB and neonatal adaptation but not malformation compared to unexposed 4 1 Yeager et al., Am J Psych., 2006; 2 McKenna et al., J Clinical Psychiatry, April 2005; 3 Reis M et al., J Clin Psychopharmacol, June 2008; 4 Habermann at al., J Clin Psychopharmacol 2013

60 Second Generation APS = Atypicals Neurobehavioral Development: Single study from Hong Kong Exposed = schizophrenia, 50% clozaril Control = no mental illness Exposed with significant delays at 2-4mos but caught up on all measures by 1 yo 1 Aripiprazole: 3 case reports Ziprasidone: 3 case reports Overall: increased risk for EPS in neonate with antipsychotics 2011 FDA drug safety communication (EPS) 1 Peng 2013, Reprotox.org April 2013; 2 Galbally et al., Ther Adv in Drug Safe. 2014

61 Case: Mary Mary had an uneventful vaginal delivery a 39 weeks. She experienced some worsening mood and disrupted sleep in the first week postpartum. I want to breastfeed my baby Is it safe for my baby to be on clonazepam and fluoxetine?

62 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, monitor CBC, comp, TSH, CAVE: premies

63 Breastfeeding Antidepressants Breastfeeding okay, drug transfer to breastmilk and to baby variable by medication but ranging from <1% to 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

64 Breastfeeding Benzodiazepine Breastfeeding okay as minimal excreted in breast-milk (clonazepam, lorazepam ok)

65 Breastfeeding Lithium Breastfeeding not recommended as baby vulnerable for dehydration and Lithium toxicity If mother insist need to perform blood draws in first weeks to check how much Lithium transferred via mild; transfer is variable up to 30%

66 Breastfeeding Valproic Acid Breastfeeding okay, infant serum level 6% moms, no adverse effects Carbamazepine Breastfeeding okay, infant serum 6-65% of mom, no adverse effects Lamotrigine Breastfeeding okay, 30% mom dose, no adverse effects

67 Summary Balance the risks of medication and reoccurrence of illness -discuss with woman her chances for relapse and what the treatment would be in case of relapse Avoid polypharmacy, rather single medication in higher dose Use lowest effective dose BUT dose adequately Use medications with lowest teratogenic risk The woman s history of previous treatment response should help guide decision what meds to use provide written material to explain the risks document in your notes that you discussed and patient voiced understanding

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69 Ensure continuous and reliable care through collaboration with psychiatry via use of phone and teleconnection support

70 The Michigan Child and Perinatal Collaborative Care Model (MC3) Psychiatry access program for primary care providers Just-in-time phone consultation Telepsychiatry evaluations

71 MC3 Goals Improve access to crucial mental health services for children, adolescents and high-risk women of childbearing age Encourage appropriate use of evidence-based pharmacotherapy Increase primary care provider comfort, knowledge and ability in treating mental health problems to crucial mental health services for children,

72 Who does MC3 Serve? Funded by: Medicaid Match Flinn Foundation Ravitz Foundation Primary care providers who treat: Infants and children ages infancy through 26 High risk women during pregnancy and postpartum

73 Current MC3 Counties

74 PCP Enrollment Primary Care Provider signs agreement Creates online account to access: Pre-program surveys Educational Modules FAQ/Resource site Providers can utilize service same day agreement is submitted

75 MC3 Consultation Process Information or resources provided to PCP or Family Liaison Coordinator Triages Call Crisis Intervention or Hospitalization Recommended Liaison Coordinator links Primary Care Provider to U of M Child/Adolescent Psychiatry for Telephone Consultation Telephone Consultation between Primary Care Provider and U of M Child/Adolescent Psychiatrist Liaison Coordinator documents care recommendations and provides necessary follow-up.

76 MC3 Program Population Data Total Number of Consultations N=665 Number of Consultations in Northern Michigan N= 220 Gender 41% 59% Male Female

77 Resources-webpages Pregnancy Lactation (Hale Publishing)

78 Thank you Questions: Maria Muzik;