Affective Disorders in Women Risk for Depression by Age and Sex Kessler R. J Affect Disord. 1993;29: Female Male Hazard Rate Age Category

Are pregnant women protected against relapse or new onset of major depression? Major Depression During Pregnancy O’Hara et al. J Abnorm Psychol. 1990;99:3-15. Evans et al. BMJ. 2001, 23:

© 2006 American Medical Association. All rights reserved. JAMA, February 1, 2006—Vol 295, No Relapse of Major Depression During Pregnancy in Women who Maintain or Discontinue Antidepressant Treatment ORIGINAL CONTRIBUTION Cohen LS, Altshuler LL, Harlow BL, Nonacs RM, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonis AF, Stowe ZN.

Relapse of Major Depression During Pregnancy No RelapseRelapse Medication StatusAll1 st Trimester2 nd Trimester 3 rd Trimester All Women115 (57.2)86 (42.8)44 (51.2)31 (36.0)11 (12.8) Maintained 61 (74.4)21 (25.6)11 (52.4) 9 (45.0) 1 ( 4.8) Increased 11 (55.0) 9 (45.0) 7 (77.8) 2 (22.2) -- Decreased 22 (64.7)12 (35.3) 5 (41.7) 3 (25.0) 4 (33.3) Discontinued 21 (32.3)44 (67.7)21 (47.7)19 (43.2) 4 ( 9.1) Cohen et al. JAMA

Time to Relapse in Patients Who Maintained or Discontinued Antidepressant Cohen LS, et al. JAMA. 2006:295; Gestational Age Percentage of Patients Remaining Well Maintained (N = 82) Discontinued (N = 65)

Viguera AC, et al. Am J Psychiatry. 2000;157: Relapse of Bipolar Disorder During Pregnancy Following Lithium Discontinuation Weeks at Risk off Lithium Percent Remaining Stable Weeks 1-40 Nonpregnant (n=59) Pregnant (n=42)

Relapse of Bipolar Disorder during Pregnancy Presented at NCDEU, Viguera et al, June 2006 Viguera, et al, Am J Psychiatry, 2008

Identification and Treatment of Antenatal Depression  Routine screening for antenatal depression is uncommon  Identified antenatal depression is typically untreated or incompletely treated  Prevalence of SSRI use during pregnancy is 3-7% SSRI = selective serotonin reuptake inhibitor. Andrade SE, et al. Am J Obstet Gynecol. 2008;198:194.e1-194.e5. Marcus SM, Flynn HA. Int J Gynaecol Obstet. 2008;100:

Psychotropic Drug Use in Pregnancy n Drugs used when risk to mother and fetus from disorder outweighs risks of pharmacotherapy n Optimum risk/benefit decision for psychiatrically ill pregnant women n Patients with similar illness histories make different decisions regarding treatment during pregnancy n No decision is risk free Henshaw SK. Fam Plann Perspect. 1998;30(1):24-9,46.

Impact of Untreated Depression in Pregnancy n Some data support increased rates of obstetrical complications and poor neonatal outcome in depressed pregnant women Steer RA et al. J Clin Epidemiol

Maternal Depression in Pregnancy: Obstetric Outcome Preterm=<37 weeks estimated gestational age; LBW=low birth weight (<2.5 kg); SGA=small for gestational age (<10th percentile); CES-D=Center for Epidemiologic Studies-Depression; BDI=Beck Depression Inventory. Orr S, Miller C. Epidemiol Rev. 1995;17: Steer RA, et al. J Clin Epidemiol. 1992;45: Steer et al, 1992 (N=389) Orr and Miller, 1995 (N=186) Preterm delivery Percentage Overall CES-D score<16 CES-D score> PretermLBWSGA Percentage BDI<21 BDI>21

What is the safest antidepressant for women of childbearing age?

Psychotropic Drug Use in Pregnancy (cont’d) n Category Labeling: Does the current system inform clinical care? n Standard language: “use the medication in pregnancy when clearly needed”; when risk of treatment is outweighed by risk of underlying disorder

FDA Pregnancy Categories CategoryInterpretation A Controlled studies show no risk: Adequate, well-controlled studies in pregnant women have failed to demonstrate risk to the fetus. B No evidence of risk in humans: Either animal findings show risk, but human findings do not; or, if no adequate human studies have been done, animal findings are negative. C Risk cannot be ruled out: Human studies are lacking, and animal studies are either positive for fetal risk or lacking as well. However, potential benefits may justify the potential risk. D Positive evidence of risk: Investigational or postmarketing data show risk to the fetus. Nevertheless, potential benefits may outweigh risks. X Contraindicated in pregnancy: Studies in animals or humans, or investigational or postmarketing reports, have shown fetal risk that clearly outweighs any possible benefit to the patient. Physicians’ Desk Reference. 57th ed. Montvale, NJ: Thomson Healthcare; 2003.

Hallberg P, Sjoblom V. Journal of Clinical Psychopharmacology. 2005; 25 (1):

SSRI Use During Pregnancy  Recent meta-analysis of cohort studies does not support teratogenicity (Einarson )  Is paroxetine particularly teratogenic? Hallberg, Sjoblom. Journal of Clinical Psychopharmacology. 2005; 25 (1): Einarson, Einarson. Drug Saf.2005; 14(12 ): Wogelius et al, Epidemiology,

SSRI Use During Pregnancy  New findings and more data inform the pharmacologic treatment of depression during pregnancy  Reproductive safety data on SSRI’s exceeds what is known about most other medicines which women take during pregnancy Hallberg P, Sjoblom V. J Clin Psychopharmacol. 2005;25: Einarson TR, Einarson A. Pharmacoepidemiol Drug Saf. 2005;14: Wogelius P, et al. Epidemiology. 2006;17: Dear Healthcare Professional. Available at: V4.pdf. Accessed March 17, Dear Healthcare Professional. Available at: Accessed March 17, 2008.

SSRI Use During Pregnancy ( cont’d)  Emerging reproductive safety data from recent studies of SSRI’s do not make risk-benefit decision easier  Majority of data on SSRI’s support particularly low risk for teratogenicity

Evidence for Increased Risk of Cardiac Malformations and Paroxetine Exposure?  Epidemiologic data suggesting increased relative risk (1.5) associated with first trimester exposure to paroxetine (VSD,ASD)  Absolute risk of 1/50 vs. background risk of 1/100  Implications of Category Label change from C to D FDA Guidelines: Wogelius et al, Epidemiology, 2006 Kallen et al,

Teratogenicity of Paroxetine  Recent data from global teratovigilance programs do not support increased risk of overall or cardiac malformations Einarson A, et al. Am J Psychiatry Apr 1 [Epub ahead of print].

Source of CasesExposuresCases Teratogen information services Florence, Italy Rome Lausanne, Switzerland Sydney, Australia Toronto Ravensburg, Germany Tel Aviv, Israel San Diego, California Helsinki Total Previously published cases from database studies Malm et al Wilton et al Källén and Olausson Wogelius et al GlaxoSmithKline Total * † Paroxetine Exposure During Pregnancy and Cases of Cardiovascular Birth Defects (N = 3379) *Incidence = 0.7%; 95% confidence interval (CI) = † Incidence = 1.5%; 95% CI = Einarson A, et al. Am J Psychiatry Apr 1 [Epub ahead of print]. Risk of Cardiac Malformations Following Paroxetine Exposure?

SSRIs During Pregnancy (Cont’d)  Recent case-control studies reveal inconsistent data regarding teratogenic risk of SSRIs, including paroxetine  Consistent conclusions regarding the small absolute risk of SSRI exposure Louik C, et al. N Engl J Med. 2007;356: Alwan S, et al. N Engl J Med. 2007;356: Greene MF. N Engl J Med. 2007;356: Cohen LS, Nonacs R. Accessed March 17, 2008.

Risk for Perinatal Distress (Neonatal Abstinent Syndromes) and Persistent Pulmonary Hypertension of the Newborn (PPHN) associated with late trimester exposure to antidepressant Should women be treated with antidepressant late in pregnancy and during the peripartum period? Levinson-Castiel R, et al. Arch Pediatr Adolesc Med Feb;160(2): ; Chambers et al, NEJM, 2006

SSRI Use Across Labor and Delivery n Increased rates of special care nursery admissions across SSRIs? n Potential for discontinuation (neonatal abstinent syndrome) syndromes? (paroxetine, venlafaxine) n Are reported symptoms clinically relevant? n Most studies do not factor in maternal depression Chambers CD. NEJM ; Goldstein DJ. Clin Psychopharmacol Cohen LS et al. Biol Psychiatry Simon, 2002, Am J Psychiatry; Laine, 2003, Zeskind, 2004, Pediatrics.

Levinson-Castiel R, et al. Arch Pediatr Adolesc Med Feb;160(2):173-6.

Risk for Persistent Pulmonary Hypertension of the Newborn (PPHN) associated with late trimester exposure to antidepressant Chambers et al. NEJM ; Hernandez-Diaz, Pediatrics, 2007

Chambers CD et al. N Engl J Med Feb 9;354(6):

Risk for PPHN Associated With Late Trimester Exposure to SSRI Limitations:  Small number of SSRI exposures  Recall bias with respect to early versus late SSRI exposure  PPHN correlated with cesarean section, race, body mass index, and other factors not related to SSRI use** ** Hernández-Díaz S, et al. Pediatrics. 2007;120:e272-e282.

Should women be treated with an antidepressant across labor and delivery?

What are the long-term neurobehavioral effects of prenatal exposure to an antidepressant?

Neurobehavioral Follow-up of Antidepressant-Exposed Children l Limited conclusive data: TCAs and SSRI’s l Fluoxetine  Two studies demonstrating absence of neurobehavioral differences in TCAs Vs fluoxetine exposed vs nonexposed children Nulman et al, Am J Psychiatry,1997,2002 Oberlander 2004,2007, Misri 2006

Results of Neurobehavioral Tests in Infants According to Whether They Were Exposed In Utero to Antidepressants* TCAsProzacControls Tests**(N=80)(N=55)(N=84) Bayley Mental Development Index118 ± ± ± 14 McCarthy General Cognitive Index117 ± ± ± 13 Reynell Verbal Comprehension Scale 1.3 ± ± ± 0.9 Reynell Expressive Language Scale 0.3 ± ± ± 1.0 *Mean ± SD; **Children were tested between 16 and 86 months of age (mean, 33 ± 14). Bayley & McCarthy scores are typical for this age. Normal range for both tests is 100 ± 1 SD. Lower scores mean lower cognitive function. Mean Reynell score in normal children of this age is 0 ± 1 (range of possible scores, –3 to +3). Nulman et al. N Engl J Med. 336: , 1997 Neurodevelopment of Children

Long Term Impact of Antidepressant Exposure in Pregnancy Oberlander et al Prospective (2 months; 4-8 months) SSRI (n=28) SSRI+clonazepam (n=18) Healthy (n=23) BayleyNo differences Misri et al Prospective (48-60 months) SSRI (n=13) SSRI+clonazepam (n=9) Healthy (n=14) Internalizing Behaviors – Child-Teacher Report, CBCL No differences Oberlander et al Prospective (48-60 months) SSRI (n=13) SSRI+clonazepam (n=9) Healthy (n=14) Externalizing and Attentional Behaviors – CBCL, Weschler IQ, laboratory assessment Higher aggressiveness scores in children with poor neonatal adaptation at birth

Antidepressant Use During Pregnancy: Treatment Guidelines To discontinue or to maintain antidepressant treatment, consider: 1. Maternal illness history (past and present) 2. Patient wishes 3. Fertility status 4. Available reproductive safety data Cohen et al, CNS Spectrums, 2004 Expert Consensus Guidelines: Postgraduate Medicine

Antidepressant Use During Pregnancy: Treatment Guidelines (Cont.) n Switch antidepressant before or during pregnancy?  Pregravid  Switch to safest treatment that affords efficacy  During pregnancy  Avoid switching compounds

SSRI Use During Labor and Delivery: Treatment Implications n Treat across labor and delivery to minimize risk for puerperal illness n Depression during pregnancy strongest predictor of postpartum depression n Adverse effects of postpartum depression on infants and families

Treatment of Bipolar Disorder During Pregnancy

Cohen LS, et al. JAMA. 1994;271: Steer RA, et al. J Clin Epidemiol. 1992;45: ; Orr ST, et al. Am J Prev Med. 1996;12: ; Suppes T, et al. Arch Gen Psychiatry. 1991;48: ; Faedda GL, et al. Arch Gen Psychiatry. 1993;50:448-55; Baldessarini RJ, et al. J Clin Psychiatry. 1996;57: Pharmacologic Treatment of Pregnant Women with Bipolar Disorder: Weighing Imperfect Options  Commonly employed antimanic agents are either known teratogens or have sparse available reproductive safety data  Risks of untreated psychiatric illness  Risk of discontinuing maintenance psychotropic medications

Pharmacologic Options for Pregnant Bipolar Women: How does the clinician weigh available pharmacologic treatment options so that fetal exposure to psychotropics is minimized while maintaining maternal well-being?

Altshuler LL, et al. Am J Psychiatry. 1996;153: Antipsychotic Use During Pregnancy  Teratogenic risk  Typicals: high vs. low potency  Data support safety of typical antipsychotics with respect to teratogenicity

Atypical Antipsychotic Use During Pregnancy  Postmarketing surveillance data limited to case reports and small series  Conclusions regarding reproductive safety of these agents not possible with currently available data Altshuler LL, et al. Am J Psychiatry. 1996;153: Goldstein DJ, et al. J Clin Psychopharmacol. 2000;20: Cohen LS, J Clin Psychiatry 2007;68 ( suppl 9).

1 Cohen LS, et al. JAMA. 1994;271: Lithium and Pregnancy  Revised risk based on meta-analysis (.05%) 1  Relative risk  rate in general population (i.e., first trimester exposure, risk: 1/1000 – 1/2000)  Relative vs. absolute risk

Time Off Lithium (Months) First Year Off Lithium Time (Months) % Recurrence Proportion in Remission Proportion Remaining in Remission *Suppes et al. Arch Gen Psychiatry Lithium Use During Pregnancy: Relative Risks and Clinical Dilemmas LV RV TV RA Ebstein’s Anomaly Relapse Following Discontinuation of Lithium in Bipolar Patients*

Pregnancy Registries for Anticonvulsants  Central Registry of Antiepileptic Drugs and Pregnancy (EURAP)  North American AED Pregnancy Registry  UK Epilepsy and Pregnancy Registry  Australian Pregnancy Registry  Lamotrigine Pregnancy Registry

North American AED Pregnancy Registry: Valproate  10.7% ( 16/149; 95% CI ) of infants of pure prospective enrollees had a major malformation  Spina bifida, heart defects, urogenital defects, and multiple anomalies  No differences in VPA doses or folic acid supplementation  Increased risk  RR 7.3 (95% CI 4.4–12.2) compared to external comparison group (1.62%) Wyszynski DF, et al. Neurology. 2005;64:

North American AED Pregnancy Registry: Lamotrigine (LTG)  2.7%(15/564) infants exposed to monotherapy had major malformations (vs. 1.62% unexposed controls)  Increased risk for a specific malformation  Prevalence of oral clefts 8.9/1000 with vs. 0.16/1000 controls  Among 1,623 lamotrigine exposed infants from other registries, frequency of oral clefts was 2.5/1000 vs. 0.37/1000 among controls  Findings from five registries show an increased risk for oral clefts among LTG exposed infants Holmes LB: Birth Defects Research : Clinical and Molecular Teratology 76:318,2006

UK Epilepsy and Pregnancy Registry (N = 3607)  Physician directed registry  Infants are followed for three months after birth  Malformations rates for monotherapy  Valproic acid 6.2% ( 95% CI 4.6–8.2)  CBZ 2.2% (95% CI 1.4–3.4), OR 2.78 (P <.001)  VPA > LTG 3.2% (2.1–4.9), adjusted OR 0.59 (P =.064)  Malformation rates for polytherapy significantly higher than monotherapy, especially if combined with valproic acid Morrow JI, et al. J Neurol Neurosurg Psychiatry

Australian Pregnancy Registry  Prospective, observational cohort study  Women taking anticonvulsants for epilepsy and other indications  754 enrolled women with 662 birth outcomes  Risk for major malformations with valproate monotherapy (16.0%) compared with other anticonvulsants (2.4%) or with no anticonvulsant exposure (3.1%)  Effect of valproate appears dose dependent (>1100 mg/day) Vajda FJ, et al. J Clin Neurosci. 2004;11: Vajda FJ, et al. Epilepsia. 2005; Meeting Abstract.

GSK International Lamotrigine Pregnancy Registry  International Lamotrigine Pregnancy Registry  414 first trimester exposure as monotherapy  Prospective  Risk 2.9% for major malformation (12/414);95%CI %  No distinctive pattern of malformations  Wide range of dose: 25mg to 500mg/day  What is the most appropriate comparison group? Cunnington M. Neurology. 2005;64: GlaxoSmithKline

Pregnancy Registry Findings: Conclusions  Valproic acid exposure associated with an increased risk for major malformations  Lamotrigine risk has been re-evaluated – increased risk for oral clefts ?  CBZ and LTG have lower risk than VPA

Neurobehavioral Teratogenicity and Anticonvulsants Emerging data suggests that valproic acid may be associated with cognitive and developmental adverse effects.

Increased Additional Educational Needs by Treatment Adab et al. J Neurol Neurosurg Psychiatry No drugsVPA mono CBZ mono Other mono Polytherapy with VPA Polytherapy without VPA Odds Ratio * Children exposed to VPA in utero have at least 3 times greater risk of having developmental difficulties

Proportion of Children with Verbal IQ < % 7.7% 0.0% 8.2% 7.5% 0% 5% 10% 15% 20% 25% VPACBZPHTPolytherapyNo AED % Patients Adab N, et al. Neurol Neurosurg Psychiatry. 2004;75:

Clinical Implications  Pre-pregnancy consultation  Risk of anomalies discussed with patient in relation to background risk and specific drug(s)  Discuss risks of untreated condition to both mother and fetus  Discuss types of prenatal testing available  Defer pregnancy until disease control optimal

Treatment of Bipolar Disorder in Pregnancy: Mild to Moderate Bipolar Disorder  Gradual taper and discontinuation of antimanic prophylaxis (lithium, sodium valproate) prior to pregnancy?  Discontinuation of mood stabilizer after pregnancy is documented? Problematic with sodium valproate  Reintroduce mood stabilizer as needed or during second trimester; concerns regarding reintroduction of sodium valproate given data suggesting behavioral teratogenicity. Cohen LS, J Clin Psychiatry 2007;68 ( suppl 9).

Treatment of Bipolar Illness During Pregnancy: What Is a Reasonable Strategy? Lithium may be the safest alternative for women dependent on mood stabilizers Lithium nonresponders Consider lamotrigine monotherapy Consider lamotrigine and typical or atypical antipsychotic Use of atypicals across pregnancy? Little role for monotherapy with typical antipsychotics Cohen LS, J Clin Psychiatry 2007;68 ( suppl 9).

Altshuler, Cohen et al. Am J Psychiatry Dolovich, et al. BMJ Benzodiazepines l Methodologic issues have confounded reports: dose, duration, class, other drug exposure l Risk of oral clefts following first trimester exposure (0-.6%)

ECT During Pregnancy l Treatment of choice when expeditious management is imperative l Use in delusional depression, mania l External fetal monitoring, ultrasonography l Comprehensive treatment team

Treatment of Mood Disorders During Pregnancy: What Have We Learned? Pregnancy is not protective with respect to new onset or recurrence of mood disorders Thoughtful treatment decisions can be made during pregnancy including those which involve use of psychotropics Weighing relative risks of pharmacologic treatment during pregnancy is best carried out on a case by case basis CONCLUSIONS

Treatment of Mood Disorders During Pregnancy: What Have We Learned? No decision is risk free No decision is perfect Patients and their clinicians will make treatment decisions based on perceived risk of pharmacologic therapy Importance of sustaining euthymia during pregnancy can not be overestimated CONCLUSIONS ( Continued)

Conclusions ( cont’d) Treatment of Mood Disorders During Pregnancy: What Have We Learned?  New studies will likely refute current associations between antidepressant exposure and particular outcomes of concern and at the same time identify new ones

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