1. Antidepressants in Pregnancy Nicole Harrington Cirino MD Reproductive Psychiatrist Assistant Professor, Dept. of Psychiatry and Ob/Gyn. Chief, Women's Mental Health and Wellness OHSU Center for Women’s Health

2. PMADs- Perinatal Mood and Anxiety Disorders Antenatal Depression (AND) Baby blues Postpartum depression (PPD) Postpartum psychosis *Perinatal PTSD, *Panic Disorder *Perinatal OCD (obsessive compulsive disorder) Perinatal Bipolar Disorder –mania, hypomania 2 *also treated with antidepressants during pregnancy

3. Antenatal Depression (AND) Can be MDD Major Depressive Disorder or BPD Bipolar Disorder Often undiagnosed or undertreated – of 1837 pregnant women with depression, 30% were receiving adequate treatment (Flynn 2006) Incidence 3-10%, similar to non-pregnant controls. Those who stop medication in the first trimester are –5 times increased risk for depression during pregnancy (65% risk) –57% of women went back on their antidepressant Over 50% will develop postpartum depression. Perinatal Suicide is the leading cause of MATERNAL MORTALITY in the 1 st year postpartum.

4. Antidepressant AD medications during pregnancy SSRI’s by far are the most studied medication in pregnancy than any other class of medication >200,000 pregnancy outcomes studied. Antidepressants are the 2nd most prescribed class of drugs in the world. *50% pregnancies in the U.S. are unplanned Increased use of SSRI in pregnancy in US: 6.0% of pregnant women 1999 to 10-13% in 2003

5. 2016 Documented Risks of SSRI exposure in utero Major malformations/cardiac malformations Behavioral Functional Risks –Developmental delay –Psychiatric Illness in offspring –Autistic Spectrum Disorder (ASD) Miscarriage SGA/LBW/PTL Neonatal Abstinence Syndrome PPHN

6. Autism Risk/Benefit ratio of AD use in Pregnancy

8. 2012 Summary AJOG

9. Known: Teratogenic exposures produce a specific pattern of malformation and do not increase incidence of all defects.

10. Thalidomide A sedative that was first marketed in the late 1950s. Used widely in Germany prior to being pulled from US market in 1962. Associated with limb reduction defects, esophageal and duodenal atresia, Tetralogy of Fallot, and renal agenesis. 20-25% of pregnancies exposed result in children with anomalies. Limb reduction was not observed in mice and rats and in many cases no sign of teratogenicity.

11. History of SSRI’s and Teratogenesis Prozac launched 1980’s Baseline rate of birth defects 3-4%. Cardiac Anomalies 1% 1980-2004 “No increased risk for malformations” 2005: GSK report to FDA – Paxil leads to increased risk of VSD. Retrospective database. 2005 – 2013: 30+ studies examining link between SSRI’s and malformations, mainly Heart Defects - conflicting results. 6/2014 Huybrechts NEJM Cohort 64,000 women exposed to AD “No substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester of pregnancy.” 4/2016 Judge dismisses 200 SSRIs related birth defect claims

12. Zoloft Lawsuits Dismissed: No Link to Birth Defects, Says Judge- Medscape April 11 th, 2016

13. Literature regarding Antidepressants in Pregnancy- Strengths and Limitations Studies are observational -retrospective, rely on prescription databases, teratology services, birth registries or population records of birth defects Thus little is known about medical, psychiatric, addiction condition of the mother or other exposures Gold Standard-Prospective RCTs do not include pregnant women and may never. Observational studies are designed to show association but not causation Literature changes often Animal studies tell us very little Many positive reports never replicated. Selection Bias: Positive studies over reported. Law firms seized this information – widely publicize. Hot topic in the media Physicians and patients use the media reports or advertisements from law firms to inform their judgment.

14. Limitations of using registries to explain associations between antenatal Antidepressant use and infant outcomes Variables not controlled for or unable to be assessed without clinical interviews antidepressant dose and actual use comorbid general medical disorders (including obesity) comorbid psychiatric disorders exposure to tobacco, alcohol, and illicit drugs exposure to other prescription and nonprescription medications nutritional status inadequate prenatal care delivery complications

15. Pharmacologic Risks during Pregnancy 1st Trimester - Morphologic risk <2 weeks No maternal/ fetal exposure 1-5 weeks Neural Tube Development 3-8 weeks Cardiac 6-9 weeks Lip and Palate 2nd-3rd Trimester (> 14 weeks) Neonatal Behavioral/Cognitive/Affective Risks Neonatal effects (toxicity/withdrawal) Maternal side effects Maternal Outcomes (preeclampsia, PTL)

16. Risk of Untreated Antenatal Depression (Fields 2006, 2011) Decreased prenatal care, poor nutrition Increased maternal use of tobacco, alcohol or cocaine Maternal suicidal/homicidal behavior increased Premature delivery, Lower birth weight and smaller head circumference Increased risk of preeclampsia. Diabetes, cesarean delivery Developmental delays in the infant Poor maternal infant bond and infant attachment Decreased rates of breastfeeding Increase in affective disorders in children and adolescents (Buss 2012) Alterations in the right amygdala of the neonate (Graboi 2013) Maternal Treatment of antenatal depression appears to help normalize cortisol levels (O’Hara 2013)

17. Risk of Untreated Postpartum Depression Subjective Report of Sleep Difficulties Colic Child development –Ineffective emotional regulation /Behavior Disturbance –Greater anxiety –Attachment difficulties (secure versus avoidant or disorganized attachments) –Higher cortisol levels in infants through adolescents –Poor social interactions –Delays in both cognitive and language development Bayley Mental Development Index – 18 mo (Boys>girls) General Cognitive Index –4 y/o McCarthy Scales of Children’s Abilities –4 y/o

18. = ? Risk Benefit

20. 2016 Documented Risks of SSRI exposure in utero Major malformations/cardiac malformations Behavioral Functional Risks –Developmental delay –Psychiatric Illness –Autism Miscarriage SGA/LBW/PTL Neonatal Abstinence Syndrome PPHN

21. Behavioral Functional Risks in Offspring SSRI exposed infant TCA’s, SSRIs, SNRIs: 72 month follow-up cognitive function (IQ), temperament and behavior – No effect. (Nulman 1997, Nulman 2002, 2012) No differences in cognitive function, verbal comprehension, expressive language, mood, arousability, distractibility, behavior problems (TCA, FLX) (Byatt 2013) In utero SSRIs have not been linked to long term neurobehavioral deficits but untreated depression has.

23. MMR and Autism

24. Serotonin Hypothesis: Autism and SSRIs Serotonin modulates brain development SSRIs block reuptake and increase serotonin in the intracellular space Reports that ASD patients have higher platelet serotonin levels termed hyperserotoninemia ASD associated with –Decreased capacity to synthesize serotonin –Altered serotonin 2A binding

25. Autism effects 1 in 68 in 2016

27. GMO’s and autism?

28. Graphic – Diagnosis of Autism

30. ASD Pathogenesis: Largely genetic ASD has a genetic etiology, which leads to altered brain development, resulting in the neurobehavioral phenotype. Epidemiologic studies indicate that environmental factors account for few cases. Genetics: ASD linked to tuberous sclerosis complex, fragile X syndrome, 15q duplication/triplication or deletion, Smith-Lemli-Opitz syndrome, and untreated phenylketonuria. Multiple studies that found higher rates of depression and other psychiatric illnesses in mothers of autistic children than mothers of controls (Daniels 2008, Piven 1999)Daniels 2008Piven 1999

31. Prenatal SSRIs and risk of ASD (Autistic Spectrum Disorders) 8 studies thus far: 5 show an association( not causation) (OR 2.54, 2.2, 1.85), 3 do not. Confounding factors that were difficult to/not controlled for –underlying burden of maternal psychiatric illness including Major Depressive Disorder (Daniels 2008) –underlying indication for antidepressant use –genetic history of ASD –maternal illness/stress during perinatal period ASD also linked to SSRI use before – but not during — pregnancy (OR 1.46) Summary - The rise in ASD disorders have been consistently linked to maternal obesity, advanced maternal and paternal age, gender, family history of ASD and maternal and perinatal stress. Risk with SSRIs likely either no increased risk or minor increased risk after confounding factors controlled for. Croen 2011, Rai 2013 Boukhris 2016, Sorenson 2013, Larrson 2005)

32. Proposed 87% increased risk w/ SSRI exposure

33. JAMA study specifics: “87% increased risk of ASD” Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children. JAMA Pediatr 2016; 170:117. Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children. JAMA Pediatr 2016; 170:117. Observation design from Canadian registry: Prospective Cohort. AD exposed (n >4700) or not exposed (n >140,000). N=31 exposed infants with ASD 3.2% use of antidepressants – measured using prescription drug registry (single prescription) Potential confounding factors adjusted for: maternal age, maternal psychiatric and general medical illnesses, and gender of the child Potential confounding factors not adjusted for: illicit drugs, ethanol, or tobacco; maternal body mass index; use of assisted reproduction; maternal autoimmune illness; paternal psychiatric illness; paternal age, autistic siblings; severity of depression; maternal ASD Results: Exposure to any antidepressant during the second and/or third trimester (but not 1 st trimester_ was associated with an increased risk of autism spectrum disorder. (hazard ratio 1.87, 95% CI 1.2-3.0). In addition, exposure to SSRIs during the second and/or third trimester was associated with an increased risk (hazard ratio 2.2, 95% CI 1.2-3.9). After adjusting for maternal depression (hazard ratio 1.75 95% CI 1.03-2.97) Absolute risk: Control ASD 0.72% ASD with AD Exposure: 1.26%

34. Study Population Results Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of ASD in Children. JAMA Pediatr 2016; 170:117.

35. Evaluation of sample AD-exposed mothers are Older Less educated More disadvantaged More psychiatric morbidity (affective disorders and others) More medical morbidity > Used with permission Eric Fombonne MD OHSU

36. Detection bias Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of ASD in Children. JAMA Pediatr 2016; 170:117 Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of ASD in Children. JAMA Pediatr 2016; 170:117 Children with AD expsosure are diagnosed earlier than in the unexposed group 322.69/82= 3.93 years 145.64/40= 3.64 years 11.30/31= 3.59 years In Table 3, mothers exposed to ‘Combined use’: 11.73/5= 2.34 years Used with permission by Eric Fombonne M.D. OHSU

37. Results Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of ASD in Children. JAMA Pediatr 2016; 170:117 Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of ASD in Children. JAMA Pediatr 2016; 170:117 Association Between Antenatal AD Exposure and the Risk of ASD

38. Other issues Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of ASD in Children. JAMA Pediatr 2016; 170:117 Boukhris T, et al Antidepressant Use During Pregnancy and the Risk of ASD in Children. JAMA Pediatr 2016; 170:117 Used with permission by Eric Fombonne M.D.

39. Take Home messages: SSRIs and ASD 1.Eight large studies thus far have shown inconsistent results. 2.Risk with SSRIs likely either no increased risk or minor increased risk after confounding factors controlled for. 3.Likely there is an association, but we can not prove causation. 4.Absolute risk: Control ASD 0.72% ASD with AD Exposure: 1.26% 5.Relative Risk/ OR/ HR: 1.87 or 87% increased risk 6.(Bourkhris et al JAMA) has not changed my treatment. 7.(Bourkhris et al JAMA) has changed my informed consent discussion and documentation.

40. Poor Neonatal Adaptation, Poor neonatal adjustment syndrome (or neonatal behavioral syndrome) Agitation and restlessness Irritability and continuous crying Insomnia or somnolence Poor feeding, vomiting, and diarrhea Hypoglycemia Hypothermia Respiratory distress Altered muscle tone, hyperreflexia, jitteriness, shivering, and tremors Seizures

41. Neonatal Adaptation Syndrome (NAS) – Inconsistent findings and methodological errors Failure to blind investigators, non standardized measures and failure to control for maternal depression have led to inconsistent findings Incidence varies from 5 to 85 percent. Approx. 25% of infants with late SRI exposure vs 10% no exposure Premature infants higher risk Concomitant medications (eg, benzodiazepines) increase risk Defined as immediate (first 48 hours) early (first 14 days) or late (first 30 days). Unclear if withdrawal or toxicity Symptoms largely resolved with minimal interventions. (Warburton 2010 and Salisbury 2016 )– Stopping AD at 38 weeks did not improve neonatal outcome.

42. Salisbury Am J Psychiatry 2016 RCT compared neurobehavioral outcomes in 243 infants in the first 30 days of life using Neonatal Intensive Care Unit Network Neurobehavioral Scale. No Exposure _____________ Depression ______________ SSRI __________________ SSRI+ BDZ _____________

43. Salisbury Am J Psychiatry 2016 No Exposure _____________ Depression ______________ SSRI __________________ SSRI+ BDZ _____________ Conclusion: No evidence of NAD first 48 hours or 7 days. SSRI exposed infants had higher CNS stress signs, poorer self regulation and higher arousal at day 14. Quality of movement is poorer throughout the first 30 days. Depression exposed infants has overall lower arousal scores.

44. Kieviet N, Hoppenbrouwers C, Dolman KM, et al. Risk factors for poor neonatal adaptation after exposure to antidepressants in utero. Acta Paediatr 2015; 104:384. Prospective observational study that examined infants (n = 247) exposed to antidepressants (largely SSRIs) during the third trimester, the incidence of poor neonatal adaptation was lower among infants who were breastfed or fed both breast milk and formula, compared with infants exclusively fed formula (odds ratio 0.3, 95% 0.1-0.7)

45. SSRI’s and PPHN Persistent Pulmonary HTN Newborn 2006 FDA issues a public health advisory Risk of PPHN general population 1.2-2/1000 (Chambers 2006): SSRI’s taken >20 weeks gestation may be associated with 1% absolute risk of PPHN (OR 6.1) N=377 infants. Case controlled, retrospective. (Kallen 2008) showed a much lower risk marginally clinically significant than the 1% originally reported. (Odds Ratio 2.01) SSRI was associated with a 0.15% Absolute risk (1.5 per 1000) (Andrade 2009, Wichman 2007): 2 larger studies have found no association between antidepressant use during pregnancy and PPHN, (Kieler et al 2012) prospective, national registry with 1.6 million controlled for OR 2.1. Absolute risk increased from 1.2 to 3.0/1000. Not controlled for depression. (Stephansson 2013) No increased rate of neonatal mortality associated with SSRI (Huybrechts 2015) Controlled for depression severity No increased risk. OR 1.1 Absolute risk increased to 2.1/1000 from 3.1/1000 (OR 1.5) C-section and BMI had greater risk than SSRI exposure. SSRI exposure may lead to small increased risk for PPHN, Absolute risk from 2/1000 to 3/1000 (OR 1.5) but not as high as Chambers original report.

46. SSRI and Preterm labor/ Miscarriage/ Birth Weight/APGAR Miscarriage -Although controversial, several studies link increase risk of miscarriage with SSRI use from 8 vs. 12 %. Poorly controlled studies. Anderson et al (2014) compared miscarriage rate of women who continue SSRI use versus those that discontinue SSRI’s prior to pregnancy. No increased rate of miscarriages. (N=1,279,840) Decreased gestational age (3-5 days) linked to SSRI use LBW risk appears clear but incidence small– Seen in illness state and with SSRI exposure. 75g lower birth weight. APGAR Decrease of 0.5 points on 1 and 5 minute Apgar

47. Psychotropics in Pregnancy-Basic Principles Nothing is “Safe” Avoid first trimester exposure if possible for known teratogens. If you are going to treat – TREAT. Don’t expose women to AD and illness state. Preconception counseling-Gold Standard Reconfirm diagnosis Maximize non-psychopharm approach Avoid polypharmacy if possible Do not wean at 38 weeks Define and discuss R/B ratio

48. Basic Prescribing Guidelines based on data limitations Use older medications over newer medications –~800 cases can detect a two fold increase in malformation risk –~10 year window to obtain this data “Unknown” does not mean safe Human data over animal data Know how to quickly access resources –www.womensmentalhealth.orgwww.womensmentalhealth.org –reprotox.org through Micromedex

51. Managing antidepressants in pregnancy Dose increase needed in the late 2 nd /3 rd trimester- Pharmacokinetics Using the EPDS to monitor medication response. –3 weeks should see partial remission, if no response consider changing agents. –If partial response 3-6 increase dose. –Goal is to achieve full remission, not just response. Do not wean 38 weeks or change at delivery

52. Common medications for antenatal depression SSRI’s Fluoxetine (Prozac) Paroxetine (Paxil) Sertraline (Zoloft) Citalopram (Celexa) Escitalopram (Lexapro) Others Venlafaxine (Effexor) Duloxetine (Cymbalta) Mirtazapine (Remeron) Bupropion (Wellbutrin) TCA’s Tricyclic Antidepressants Nortriptyline (Norpramin) Amitriptyline (Elavil) Trazodone

53. Non SSRI antidepressants in pregnancy- What do we know? TCA’s; 10 retrospective studies show no risk of malformation. Nortriptyline and Desipramine believed to be no increased risk. Buproprion GSK pregnancy registry and Cole et al 2007– no increased risk. Venlafaxine: Included in many SSRI studies, same risk as SSRIs. Mirtazepine with single prospective study, a few retrospective reports – (n<200 cases). Duloxetine 2004, generic 2013– three prospective studies to date n=650 women, shows no increase rate major malformations. Long term data not available.

54. What’s not on the list Vilazodone (Viibryd) -SNRI Asenaprine (Saphris) - AP Vortioxetine (Brintellix )- SSRI Lithium (Lithobid, Eskalith) Lamotrigine (Lamictal) Aripiprazole (Abilify)

55. Non Pharm Treatment for PPD IPT/CBT therapy Group and couples therapy Other psychotherapy/social interventions Light therapy (20 minutes qam) Exercise (40 minutes 3-4 days a week) Acupuncture ECT

56. Depression and Sleep Sleep preservation is a common strategy for treatment of perinatal mood disorders Depression and sleep inexplicably linked in pregnancy and postpartum Consider adjunctive sleep medication third trimester (Khazaie et al 2013) RCT Trazodone and Diphenhydramine vs placebo protective against PPD

57. L-methylfolate for depression in pregnancy: Deplin 15 or 30mg (15,000 or 30,000 mcgs) in dietary supplement Used for partial- or non-response to selective serotonin reuptake inhibitors (SSRIs) in MTHFR enzyme gene mutations Folates are converted to the active form of l-methylfolate by 5,10- methylenetetrahydrofolate reductase (MTHFR). 50% Caucasians have a mutation on MTHFR gene, Individuals with these less efficient forms of the MTHFR gene may be more prone to folate deficiency L-methylfolate is the naturally occurring, biologically active form of folic acid, Recommended Dietary Allowance (RDA) 1000 mcg for pregnant and lactating women. No published studies have assessed the safety of high doses of l-methylfolate in pregnancy. Certain cases where high doses (usually 4 to 5 mg) “under medical supervision” used.Recommended Dietary Allowance (RDA)

58. Yonkers et al 2009 Patient is contemplating pregnancy and currently on antidepressants

59. Yonkers, et al 2009 Patient with MDD who is pregnant and on antidepressants

60. Resources for Medications in Pregnancy and Breastfeeding Reprotox: www.reprotox.orgwww.reprotox.org Motherisk.org: www.motherisk.org 1-877-439-2744www.motherisk.org www.infantrisk.com ; (806) 352-2519; phone app also availablewww.infantrisk.com Organization of Teratology Information Services: www.mothertobaby.org; good handouts www.mothertobaby.org MGH Women’s Mental Health Program: www.womensmentalhealth.org www.womensmentalhealth.org LactMed: www.lactmed.nlm.nih.govwww.lactmed.nlm.nih.gov E-Lactania: http://www.e-lactancia.org/ingles/inicio.asphttp://www.e-lactancia.org/ingles/inicio.asp Tox Net www.toxnet.nlm.nih.govwww.toxnet.nlm.nih.gov 60 (c) PSI 2014 ~ PostpartumSupportInternational