1. Maternal-Fetal Dyad : Risks and Benefits of Prescribing Psychotropics During Pregnancy Natalie Rasgon, M.D., Ph.D. Professor Professor Department of Psychiatry and Behavioral Sciences Department of Obstetrics and Gynecology Stanford School of Medicine Palo Alto, California

2. Learning Objectives To update knowledge about the epidemiology, risk factors and clinical course of perinatal mood disorders To learn about controversies regarding treatment issues in women with perinatal mood disorders

3. Untreated Major Depression in Pregnancy Major Depression associated with an increased incidence of preterm delivery compared to nondepressed patients in a large registry study Major Depression during pregnancy has been associated with adverse obstetrical outcomes in small prospective studies but results differ in larger prospective studies (Chung et al, 2001; Andersson et al, 2004) Major depression in pregnancy is clearly associated with an increased risk for postpartum depression (Oberlander et al, 2006)

4. Cohen, L. S. et al. JAMA 2006;295:499-507. Relapse of Major Depression During Pregnancy

5. Depression in Pregnancy: Risk of Treatment vs No Treatment With Medications Teratogenesis “Behavioral teratogenesis” Perinatal complications Miscarriage Endocrine effects Mothers’ poor self care ? Low birth weight ? Premature labor Pharmacotherapy Risks Depression Risks

6. Effects of Antenatal Depression and Antidepressant Treatment on Gestational Age at Birth and Risk of Preterm Birth Prospective study of 93 women Group 1: Depressed with antidepressants Group 2: Depressed without antidepressants Group 3: Controls Study controlled for risk factors for prematurity Results: Antidepressant exposure associated with 1) Lower mean gestational age at birth (38.5 vs. 39.4 vs. 39.7 weeks) 2) Higher percentage of preterm deliveries (14.3% vs. 0% vs. 5.32%) 3) Higher percentage of special care nursery admits (20% vs. 9% vs. 0%) Suri R. Am J Psychiatry 2007; 164: 1206-1213

7. Are Antidepressants Associated with Congenital Malformations? History of the Controversy Pre-2005: –No studies showed an increased risk of major congenital malformations –Chambers et al. reported an increased risk of “minor” malformations ( Chambers et al, 1996 NEJM; 335: 1010-5) in babies exposed to fluoxetine in utero September 2005: Preliminary GSK Report: –Increased rate of congenital malformations in paroxetine exposed infants compared to other antidepressants (4%) OR=1.82 –Increased risk of cardiac malformations compared to other antidepressants (2%) OR=1.79

8. Teratogenicity Time Table DaysOrgan SystemAssociated Defects 10-32CNSNeural Tube 20-56CardiacEbsteins Anomaly 42-63Lips and palateCleft lip and palate 24-56Limbs 60-140CraniofacialCraniofacial

9. Gestational Age Effects Effects of Selective Serotonin Reuptake Inhibitors (SSRIs) on gestational age are dependant on the duration of in utero antidepressant exposure. Longer exposure – more likely to decrease gestational age 10 [10] Oberlander T, Warburton W, Misri S, Aghajanian J, Hertzman C. Effects of timing and duration of gestational exposure to serotonin reuptake inhibitors: population based study. Br J Psychiatry 2008;192: 338–43.

10. Risks Associated With Pharmacotherapy During Pregnancy Teratogenicity: gross evidence of organ dysgenesis (e.g., Ebstein’s anomaly with lithium) –Occurs 2-8 weeks after conception, but can extend into 2nd trimester (craniofacial) “Behavioral teratogenicity”: subtle functional disturbances (eg, developmental delays, neurologic deficits) –Occurs throughout pregnancy Perinatal complications: effect of drug on labor and delivery and immediate neonatal outcomes

11. Risks Associated with Antidepressant Use in Pregnancy Antidepressants and Spontaneous Abortion (SA) –Variable findings in individual studies of differing antidepressants –Results of met analysis evaluating all published studies reported the following risks for SA in 6 carefully evaluated cohort studies: Nonexposed = 8.7% (7.5%-9/9%); N=1,534 Exposed= 12.4% (8.8%-14/1%); N=2,033 Relative Risk = 1.45 No difference between antidepressants (Nefazadone. Trazodone, Venlafaxine, SSRIs) Hemels et al, 2005; Ann Pharmacother 39: 803-9

12. 937 women on antidepressants (AD) vs. 937 not on antidepressants (NAD) 338 women in the sample had h/o miscarriage Comparison SA in women with history of SA: 20% AD vs. 13% NAD (RR=1.63) Unanswered questions: What is the contribution of depression? What comorbidities are associated with increased risk of SA ?(i.e. subclinical hypothyroidism? ) Einarson et al. J Obstet Gynaecol Can 2009; 31: 452-6. Getting Closer… ….

13. Paroxetine and Cardiac Congenital Malformations Swedish Medical Birth Registry –6,481 women delivered 6,555 infants exposed to SSRIs during 1st trimester of pregnancy –No increased relative risk for any cardiac defect in SSRI exposed infants compared to unmedicated total population RR=.7 (78/6,555 vs. 11,367/873,876) –Relative risk for any cardiac defect in Paroxetine subgroup compared to Sertraline or Fluoxetine or Citalopram: 1.63 –Paroxetine infants w/cardiac defect in select group (normal BMI) compared to general population RR = 2.63 (13/405 vs. 4.9/405) Kallen and Olausson, 2007 Birth Defects Re A Clin Mol Teratol

14. Estimated to occur in 1% of births in general population Most common congenital heart defect Small defects are most common (80-90%) 30-50% small defects close spontaneously prior to 4 years old Small muscular defects are more likely to close than small membranous (80% vs. 35%) Risk factors include maternal alcohol use, valproic acid Williams et al, 2004

15. National Birth Defects Prevention Study 9622 infants with major birth defects compared to 4092 control infants without defects No significant associations found between maternal use of SSRIs overall in early pregnancy and congenital heart defects Alwan S, et al. NEJM 2007; 356:2684-2692

16. Slone Epidemiology Center Birth Defects Study Case control surveillance study of 9849 infants with and 5860 infants without birth defects Overall SSRI use not associated with a significantly increased risk of omphalocele, craniosynostosis or heart defects Significant associations found between specific SSRIs and specific defects Louik C, et al. NEJM 2007; 356:2675-2683

17. Update: Conflicting Findings Methods: Metanalysis Subjects: Unpublished cases from teratology services (prospectively identified) and published database studies Results: 2,061 unpublished cases cardiac deficit rate of infants exposed to Paroxetine: 1.5% 1,174 teratology register cases cardiac defect infants exposed to Paroxetine: 0.7%, Bar-Oz et al. Clin Ther. 29:918-26, 2007

18. What Is Category Labeling? Key to FDA Use-in-Pregnancy Ratings Controlled human studies have demonstrated no fetal risk Animal studies indicate no fetal risk, but no human studies OR adverse effects in animals, but not in well-controlled human studies No adequate human or animal studies OR adverse fetal effects in animal studies, but no available human data Positive evidence of risk, but benefits outweigh risks Contraindicated in pregnancy InterpretationCategory A B C D X

19. Prospective Studies of Antidepressants and Preterm Delivery AuthorMedicationStudy DesignNResults Kulin et al, 1999SSRIsSSRIs vs. MC267No difference Einarson et al, 2001Venlafaxine V vs. SSRI vs. NT150/grpNo difference V vs. NT Hendrick et al, 2003SSRIsNo controls1476.5% SSRI Suri et al, 2004FLXDEF vs. DE59No difference VS. ND Chun-Fai-Chen,2005BuproprionB vs. NT136No difference B vs. OAD vs NT Djuluk et al, 2006MirtazapineM vs. OA vs. NT 10410% M vs. NT 2% p=. 04

20. Antidepressants and Preterm Delivery: Results of Large Birth Registry Studies AuthorRegistryNResults Malm et al, 2005Finnish Registry1,782 SSRINS Oberlander et al, 2006Canadian Health1,451 S-EDp=.001 Care Registry14,234 DE 92,192 NE

21. Relative Safety of Antidepressants in Pregnancy: Neurobehavioral Sequelae StudyNMedResults Nulman et al., 1997 805584TCAsFLXControl IQ, Bayley, McCarthy similar up to age 7 Mattson et al., 1999 6630FLXControl WPPS-RI no differences Nulman et al., 2002 464036TCAFLXControl IQ, Bayley no differences between groups at 15-71 months Number of depressive episodes since delivery associated with lower language development Casper et al., 2003 Casper et al., 20031331ControlSSRIs Lower Bayley psychomotor developmental indexes and motor quality in f/u (6-40 mo)

22. StudyNMeasuresResults Misri et al. (2006)13914SSRI SSRI + Klonopin Controls No differences in ratings of internalizing behaviors between groups (Child/Teacher Behavioral Checklist) at 4 years old Maternal depression associated with increased internalizing behaviors Oberlander et al. (2007)2214SSRIControls No difference in ratings of externalizing behaviors between groups (CBCL) at 4 years Maternal stress, anxiety and depression associated with higher scores Mattson et al. Teratology 1999; 59: 378-389; Nulman et al. N Engl J Med. 1997;336:258-262; Casper et al. J Pediatr. 2003; 142: 402-408 ; Nulman et al. Am J Psychiatry. 2002; 1889-1895; Misri et al., Am J Psychiatry. 163: 1026-1032, 2006; Oberlander et al. Arch Pediatr Adolesc Med. 161: 22-29, 2007. Relative Safety of Antidepressants in Pregnancy: Neurobehavioral Sequelae

23. Persistent Pulmonary Hypertension of the Newborn Rare condition in the general population: estimated 1/1000 births Cause: Unknown Possible Causes: –Hypoxia and hypercarbia at birth (meconium aspiration, complicated deliveries) –Increased medial muscle thickness of pulmonary arteries –Vasoactive mediator abnormalities (nitrous oxide, leukotrienes, platelet activating factor)

24. Chambers, et al., NEJM 2006 Risk of Persistent Pulmonary Hypertension and SSRIs

25. Conflicting New Report: Retrospective follow up study Infants exposed to SSRIs during last trimester of pregnancy compared to unexposed infants No increased prevalence of PPHN (2.14/1000 vs. 2.7/1000 Andrade SE et al. Pharmacoepidemiol Drug Saf 18: 246-52, 2009

26. So, to treat or not to treat? What is the Evidence for the Efficacy of Antidepressants in the Treatment of Antenatal Depression? NONE! To date: No randomized, placebo-controlled studies of antidepressant treatment in antenatal depression No randomized, placebo-controlled studies of antidepressant treatment in antenatal depression No comparative studies of antidepressant treatment versus psychotherapy in antenatal depression No comparative studies of antidepressant treatment versus psychotherapy in antenatal depression Coverdale JH, et al. The ethics of randomized placebo-controlled trials of antidepressants with pregnant women: a systematic review. Obstetrics & Gynecology. 112: 1361-1368, 2008.

27. Neonatal SSRI “Adaptation” Syndrome Clinical characteristics: Respiratory distress Autonomic instability Poor feeding Neurologic symptoms: tremor, myoclonus, seizures Neonatal adaptation syndrome occurs in 30% of neonates exposed to SSRIs in utero, leading to NICU and SCN admits Etiology controversial: SSRI withdrawal or serotonergic toxicity? Self limited, supportive treatment

28. Retrospective cohort study of 76 mothers treated with SSRIs of Venlafaxine during third trimester Results: –100% of premature infants presented neonatal adaptation symptoms compared to 69% of term infants –Median length of stay in hospital was almost 4 times longer for preterm compared to term infants (14.5 vs. 3.7 days) –95% of premis demonstrated CNS symptoms (abnormal movements and agitation) vs. 30.9% of term (p=<.001) –66.7% of premis demonstrated respiratory symptoms vs. 25.5% of term (p=<.001) Effects of Selective Serotonin Reuptake Inhibitors and Venlafaxine During Pregnancy in Term and Preterm Neonates Ferreira et al., 2007 Pediatrics 119: 52-57

29. Buproprion and Pregnancy United Healthcare Registry (2007) 1213 infants exposed to Buproprion in first trimester compared with other antidepressant exposure during the first trimester (4743 infants): Adjusted Odds Ratio for all congenital malformations was 0.95 (prevalence 23.1 per 1000 vs. 23.3 per 1000) Cole et al. Pharmacoepidemiol Drug Saf 2007; 16:475-84 Prospective Study (2005) No significant differences between 136 women exposed to Buproprion and nonteratogen group or other antidepressant group in rate of major malformations, mean birth weight or mean gestational age at delivery Buproprion associated with significantly more spontaneous abortions (20/136) Chun-Fai et al. Am J Obstet Gynecol 200; 192: 932-6

30. Atypical and Typical Antipsychotics Atypicals associated with gestational diabetes!!! Increased and decreased birthweight have both been found in AAP exposed infants High potency typical antipsychotics appear to be safe--no increased risk of congenital malformations, but risk of EPS

31. Atypical Antipsychotic Use During Pregnancy Study by McKenna et al. (2005): –151 pregnant women on an atypical antipsychotic, age-matched with a control group –Followed through pregnancy and birth –No difference in rates of major malformations, complications during labor, rates of hospitalization during pregnancy, neonatal complications, diabetes, or hypertension –Higher rates of low birth weight among exposed women, although no difference in mean birth weight –Exposed women less likely to take vitamins during pregnancy –No differences between drugs emerged McKenna et al. J Clin Psychiatry 2005

32. Risperidone and Pregnancy Review of large data base of 713 infants exposed to Risperidone in pregnancy revealed no increased risk of congenital malformations or spontaneous abortions Possible neonatal adaptation syndrome, including jitteriness, poor feeding, tremor, somnolence Coppola, D. et al. Drug Safety 30: 247-64, 2007

33. Atypical Antipsychotics in Late Pregnancy 50 women prospectively followed (52% BAD; 25%psychotic; 19% depressive) Note: not monotherapy in 75% Maternal and umbilical samples at delivery Placental passage determined as umbilical cord:plasma ratio Obstetrical outcome measures: maternal reports and maternal chart review Results: Olzanzapine>Haldoperidol>Risperidone>Quietapine x=72.1% vs. 65.5% vs. 49.2% vs. 23.8% SD=42% SD= 40.3% SD= 33.9% SD=11% Trend for lower birth weight (30.85) in olanzapine exposed babies (p=.06) Population norms=4-8% as well as NICU admits of 30.8% vs.population norms of 7-8% Newport DJ et al. Am J Psychiatry 2007; 164:1214-20.

34. Teratogenicity, Perinatal Complications and Mood Stabilizers Lithium (D) Ebstein’s anomaly in general population 1/20,000 Reanalyzed rate in Lithium exposed infants is 1/1000 or 2/1000 (.1-.05%) (Cohen, 1994) Counsel that risk is very low, but still 20-40 times the rate in general population Increased overall risk of congenital malformations 4-12% lithium exposed infants vs. 2-4% nonexposed Perinatal complications include “floppy baby” syndrome, nephrogenic diabetes insipidus, thyroid dysfunction, polyhydramnios--rates unknown Gentile, S. Bipolar Disord 8: 207-20, 2006 Yonkers et al. American J Psychiatry, 2004

35. Teratogenicity, Perinatal Complications and Mood Stabilizers Valproic Acid (D) Rates of major malformations 6-20.3% Rates of neural tube defects 5-9% Spina Bifeda is 50 X background rate “Fetal Valproic Acid Syndrome:” irritability, jitteriness, poor feeding Neurodevelopmental problems--lower IQ scores, autism Supplement with Vit K and folate Yonkers et al. American J Psychiatry, 2004 Vajda, 2005; Morrow, 2006

36. Carbamazepine (D) Overall rates of major malformations 2.2-8.2% Rates of craniofacial defects 11% Rates of developmental delay as high as 20% Supplement Vit K and Folate Oxcarbazepine is category C: produces no epoxide metaolites, theoretically less teratogenic, but no confirmatory studies Gentile, 2006

37. Lithium Management Guidelines Fetal US and ECHO at 16-18 weeks Plasma volume and renal clearance increase during pregnancy so higher doses may be needed Divided doses recommended to maintain stable serum levels Decrease dosage prior to delivery due to increased risk of lithium toxicity Yonkers, 2004

38. Treatment with Lithium During Pregnancy Levels in umbilical cord blood=maternal blood levels Avoid toxicity at delivery by discontinuing the dose for approx. 48 hours Neonatal toxicity is directly related to maternal blood levels Newport et al., Am J Psychiatry, 2005

39. Treatment of Insomnia in Pregnancy Zolpidem: Very limited safety data, but category B Trazadone: limited safety data: 58 infants prospectively followed-no increased congenital malformation risk. Category C Einarson A. et al. Can J Psych 48:106-10, 2003 Diphenhydramine: Limited studies despite widespread use, Category B Benzodiazepines: Category D –Largest study to date is 1,944 exposed infants from Swedish Birth Registry Cleft palate association not as strong as previously thought ? Associated with low birth weight and preterm delivery ? Associated with alimentary tract abnormities Wilkner BN et al. Pharmacoepidemiol Drug Safety 2007 16(1): 1203-10

40. Patient is contemplating pregnancy and is undergoing pharmacological treatment for depression. Yonkers, et al, 2009

41. Patient with MDD pregnant not taking antidepressants Yonkers, et al, 2009

42. Patient with MDD, pregnant currently on antidepressants. Yonkers, et al, 2009