Treatment Considerations in Antenatal and Postpartum Psychiatric Illnesses

1. Treatment Considerations in Antenatal and Postpartum Psychiatric Illnesses APM Resident Education Curriculum Christina L. Wichman, DO, FAPM Associate Professor of Psychiatry and Behavioral Medicine Medical College of Wisconsin Updated Fall 2013 Christina Wichman, DO

2. Risk-Benefit Analysis

3. Informed Consent Discussion Risks of psychiatric illness in pregnancy and postpartum Non-pharmacological treatment options Risks of psychotropic exposure to developing fetus/breastfeeding infant Potential adverse effects to mother Benefits of psychotropic use in treatment of psychiatric illness

4. Informed Consent Discussion • “Parenthood is a journey into the unknown, but together we can try to make decisions which reduce the overall risk.” • Accepting risk is part of the process • Think of assessing risk above baseline risks • 1-3% of pregnancies which have some type of congenital malformation • Think in terms of absolute risk • Example: One retrospective study demonstrated 6x increase in omphalocele w/ use of SSRIs in early pregnancy (NOTE: didn’t control for other exposures) • BUT absolute risk is less than 3/1000

5. Antenatal Depression

6. Depression and Pregnancy • 12-20% of women will have depression at some point during pregnancy or the post-partum period • Prevalence is similar for pregnant and non-pregnant women • 2nd and 3rd trimester seem to be higher risk than 1st trimester • Prevalence of SI similar to rates of non-pregnant patients • Pregnancy is NOT protective!

7. Maternal Risks of Untreated Antenatal Depression Poor compliance with optimal prenatal care Malnutrition Self medication with drugs and/or alcohol Inability to stop smoking Failure to recognize or report signs of labor Suicide Poor parenting of other children

8. Risks of Untreated Antenatal Depression for Neonate/Infant • Increased cortisol and catecholamine levels • Increased rates of NICU admissions • Dysregulation of HPA axis • Behavioral problems • Disruption in development • Infant abuse or neonaticide Low birth weight Preterm delivery Lower APGAR scores Smaller head circumference Difficulty engaging in social and object interactions Show less positive and more negative affect Lower activity levels Greater physiologic reactivity

9. Identification and Treatmentof Antenatal Depression • Routine screening for antenatal depression is uncommon • When identified, antenatal depression is often not treated or only partially treated • Ideally should screen during pregnancy: • 30-50% of women who have postpartum depression had depressive symptoms during pregnancy

10. Symptoms of Depressionin Pregnancy • Depression may be overlooked in pregnancy • Symptoms related to somatic experiences of pregnancy often cloud diagnosis • Poor sleep, appetite changes, decreased energy, decreased libido • Use “emotional” symptoms to guide diagnosis: lack of interest in pregnancy, guilty ruminations, profound anhedonia, passive death wish, suicidal ideation

11. Somatic Symptoms Associated with Depression / Anxiety during Pregnancy *p<.05 **p<.01 ***p<.001 Diagnosis of Depression-Anxiety? Somatic SymptomYes (N=43) No (N=143) 1. Nausea 93% 66% *** 2. Back Pain 88% 78% 3. Stomach Pain 79% 50% *** 4. Headaches 71% 42% * 5. Short of Breath 71% 42% *** 6. GI Symptoms 68% 45% ** 7. Arm, Leg, Joint Pain 64% 57% 8. Heart Pounding 58% 36% ** 9. Dizziness 54% 32% ** 10. Sexual Intercourse 41% 22% * 11. Chest Pain 21% 14% 12. Fainting 10% 6%

12. Factors Associated with Increased Risk for Depression in Pregnancy • Discontinuation of antidepressants at conception • 68% relapsed • 26% relapsed if remained on antidepressants during pregnancy Lack of social support Marital discord Living alone Multiple children Unwanted pregnancy Younger age Personal or family history of affective illness

13. Bipolar Disorder During Pregnancy

14. Bipolar Disorder • Pregnancy is NOT protective for all women with bipolar disorder • Most retrospective reports suggest high risk for relapse (45-52%) • In 2 prospective studies, overall recurrence risk very high, >70% • Management most difficult when pregnancy unplanned • Majority of recurrences during pregnancy are major depressive episodes or dysphoric, mixed states • Majority of recurrences occur early in pregnancy: 1sttrimester > 2nd trimester > 3rd trimester • Significantly increased risk for postpartum psychosis • May be as high as 46%

15. Risk for Recurrence of Bipolar Disorder During Pregnancy following Medication Discontinuation

16. Recurrence in Pregnant Bipolar Women Who Continued vs. Discontinued Any Mood Stabilizer Viguera AC et al: Am J Psychiatr 2007;164:1817-24

17. Symptom Exacerbation Postpartum • 7x risk of admission for first episode, 2x higher risk for a recurrent episode in postpartum women • Compared to non-postpartum and non-pregnant women • Symptom emergence is often rapid • May begin a few weeks before or within first few days-weeks after delivery

18. Psychotic Disorders in Pregnancy and Postpartum

19. Epidemiology of Psychosis in Pregnancy Majority of women with psychotic disorders do have children Higher risk of unplanned and unwanted pregnancies More likely to be unmarried Typically have limited social support

20. Risks of Psychosis in Pregnancy • Pregnancy itself should be considered HIGH RISK • Failure to obtain prenatal care • Inability to care for oneself • Poorer nutrition • High rates of tobacco, alcohol and drug use • Inability to recognize or report labor • Fetal abuse or neonaticide • High rates for losing custody of children

21. Psychosis ITSELF harmful to fetus • Psychosis doubles risks of adverse pregnancy outcomes • Malformations • Prematurity, small for gestational age • Fetal demise • INDEPENDENT of medication exposure • Controlled for other variables as well: single motherhood, smoking, parity, age, education, pregnancy-induced HTN

22. Psychotropic Medication Use in Pregnancy

23. Embryology 101

24. Summary: Developmental Windows of Risk

25. FDA Pregnancy Categories 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 post marketing data show risk to the fetus. Nevertheless, potential benefits may outweigh risks. X: Contraindicated in pregnancy: Studies in animals or humans, or investigational or post marketing reports, have shown fetal risk that clearly outweighs any possible benefit to the patient.

26. SSRI Use in Pregnancy

27. Potential Risks of SSRIs in Pregnancy: General Outcomes • Poor pregnancy outcomes • Low birth weight • Preterm delivery • Increased risk of spontaneous abortion • Increased risk of NICU admission • Neonatal Withdrawal Syndrome • Poor neonatal adaption

28. Increased Rate of Spontaneous Abortion Increased rate of spontaneous abortion in depressed women exposed to antidepressants Unclear if association was due maternal depression or antidepressant exposure Other studies have not found this association

29. Poor Neonatal Adaptation • Symptoms may include: • Jitteriness • Constant crying • Feeding/Sleeping problems • Desaturation with feeding • Autonomic instability • Tachypnea • Hyperreflexia/hypertonia • Convulsions Occurs in 30% late-pregnancy exposed infants Begins minutes to hours after birth Lasts usually 1-4 days Can occur with any antidepressant Provide supportive care

30. Potential Risks of SSRIs in Pregnancy: Congenital Anomalies • None in prospective, controlled studies • None in meta-analyses of those studies • Retrospective case-control studies • Some have not demonstrated increased risk • Increased risk of anencephaly (RR 2.4), craniosynostosis (RR 2.5), omphalocele (RR 2.8) • Retrospective database reviews • Increased risk of septal heart defects

31. Persistent Pulmonary Hypertension of Newborn (PPHN) • Increase in PPHN in infants exposed to SSRIs after 20 weeks gestation • 14 exposed (n=377) and 6 non-exposed (n=836) • Odds ratio = 6:1 • Not associated if SSRI use ended prior to 20 week gestation. • Controversial; other studies do not demonstrate increased risk. • Risk of PPHN remains low; if looking at “worst case” data: estimated at 1% of exposed infants.

32. SSRI Use and Risk of Gestational Hypertension • Retrospective cohort, non-malformed infants (n=5912) • Peri-conceptual SSRI treatment associated with higher risk of GHTN and preeclampsia • Highest risk with women who continued SSRI treatment (15.2%) vs. those who did not receive treatment with SSRIs (2.4%) and those who discontinued treatment with SSRIs (3.7%) • Not enough evidence regarding SNRI use

33. Discontinuation Late in Pregnancy • Compared with newborns exposed to SSRIs early in pregnancy vs. during last 2 weeks… • Increased risk of respiratory distress (36% v. 30%) • Increased risk of convulsions (0.3% v. 0%) • HOWEVER, differences no longer evident when accounted for severity of maternal mental illness

34. Neurodevelopment Outcomes: Fluoxetine Prospective case-controlled (n=40) followed to 15-71 months old Did NOT adversely affect the child's global IQ, language development, or behavior IQ was significantly and negatively associated with duration of depression Language was negatively associated with number of depression episodes after delivery

35. Neurodevelopment Outcomes, cond. Children of depressed mothers treated with SSRIs (n = 31) compared with children of depressed mother who elected not to take medications (n=13) Reviewed birth outcomes and postnatal neurodevelopmental functioning between ages 6 and 40 months Subtle effects on motor development noted in group exposed to SSRIs

36. Risk of Autism Spectrum Disorder Population-based case control study 298 case children with ASD and 1507 controls 2-fold increased risk of ASD associated with SSRI use by the mother during the year before delivery Several limitations Further studies needed to replicate and extend these findings

37. Specific Antidepressants

38. Fluoxetine • Fluoxetine is the most studied • 4 prospective studies : no increased risk of major congenital malformations • Can be activating • Should be dosed in the morning • Caution initial worsening of anxiety symptoms

39. Sertraline No increased risk of anomalies in several prospective, controlled studies No increased risk of neurodevelopmental problems in children exposed in utero Fewer neonatal side effects side effects after in utero exposure than other antidepressants Higher rates of GI side effects, namely diarrhea, which can be helpful in this patient population

40. Paroxetine • Only FDA Class D SSRI • No increased risk in small, prospective controlled studies • Retrospective studies & meta-analysis demonstrate increased risk of cardiac malformations, typically VSDs • Dose response (>25 mg/day) observed in one study • Prospective, previously unpublished exposures in early pregnancy in 2008. N > 3000. No increased risk of cardiac defects following paroxetine use in early pregnancy

41. Citalopram and Escitalopram • Citalopram • No increased risk of malformations in one prospective, controlled study & large registry data base • Increased risk of QTC prolongation in dosages > 40 mg /day • Consider obtaining EKG pre- and post-initiation to document QTC • Escitalopram: not systematically studied in pregnancy

42. Venlafaxine • Two studies have not demonstrated an increased risk of congenital anomalies • Increased risk of preterm birth • Possible increased risk of hypertension • Monitor BP closely with initiation

43. Bupropion No increased risk of congenital anomalies Decreased birth weight at higher doses Elevated rate of spontaneous abortion (p=0.009) Lowers seizure threshold – possible risk in women with pre-eclampsia Bupropion registry: http://pregnancyregistry.gsk.com/bupropion

44. Mirtazapine • No increase in major malformations • Higher rate of pre-term birth noted (p = 0.04) • Higher rate of spontaneous abortions, but not statistically significant • Side effect considerations: • Nausea less likely than with SSRIs; sometimes used with hyperemesisgravidarum • Weight gain can increase obstetric complications • 40% patients have >7% increase in body weight in one year • Sedation may be difficult to tolerate in pregnancy, however can be helpful in patients struggling with insomnia

45. Tricyclic Antidepressants • Widely used in pregnancy • Initial studies suggesting limb anomalies have not been confirmed • Neurobehavioral effects from fetal exposure have not been reported • Reported acute effects: tachypnea, tachycardia, cyanosis, irritability, hypertonia, clonus, spasm • Transient withdrawal symptoms • Desipramine and nortriptyline preferred • Least anticholinergic, least likely to exacerbate orthostatic HTN & constipation

46. Other Psychotropic MedicationUse in Pregnancy

47. Benzodiazepine Use During Pregnancy • Possible increased risk for oral clefts with 1st trimester exposure • 10-fold over the general population to 0.7% • Risk may be less with high potency agents: shorter half life, less accumulation, less likely to cause sedation • Use near delivery: possible impaired temperature regulation, apnea, decreased Apgar scores, muscular hypotonicity, and failure to feed • SSRI + benzodiazepine: may produce higher risk of congenital heart defects • Limited data do not support a significant impact on neurobehavioral function

48. Stimulant Use in Pregnancy Limited data available Concerns: potential for prematurity, growth retardation, limited maternal weight gain, signs of neonatal withdrawal No clear increase in congenital abnormalities

49. Use of Mood Stabilizers in Pregnancy

50. Lithium • Considered first line in management of pregnancy • Ebstein’s anomaly • Risk = 1/1000-2/1000 with 1st trimester exposure • Risk = 1/20,000 in general population • Recommend Level II ultrasound at 16-20 weeks • Surgical repair possible • Neonatal risk • Lethargy (if level is elevated) • “Floppy baby syndrome” • Respiratory difficulties, hypotonia, and poor suck reflex • Hypoglycemia • Neonatal goiter • Increased birth weight • Monitor for lithium toxicity for up to 10 days post-delivery