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  • 1. SAFETY OFANTIDEPRESSANT USEDURING PREGNANCYDaniel HuismanPharmD CandidateUIC College of PharmacyApril 26, 2012
  • 2. Objectives Describe the epidemiology, risk factors, symptoms, andconsequences of maternal depression Identify the role of SSRIs in the treatment of depression Describe the potential link between PPHN and SSRI use Evaluate clinical trials analyzing the risks of SSRIexposure in newborns regarding the development ofPPHN Apply evaluation to a patient case
  • 3. Introduction In July 2006, the U.S. Food and DrugAdministration issued a warning regarding apotential link between selective serotonin-reuptake inhibitors (SSRIs) and persistentpulmonary hypertension of the newborn(PPHN) based on a study published in theNew England Journal of Medicine that showeda 6-fold increased risk.
  • 4. Introduction In December 2011, after review of additionalstudies, the FDA revised its initial warnings,recommending physicians continueantidepressant therapy in pregnant womendue to a variety of health issues caused byuntreated maternal depression.
  • 5. Introduction In January 2012, the British Medical Journalpublished a study warning pregnant womenthat they can significantly increase the risk oftheir infants developing PPHN if they takecertain SSRIs.
  • 6. Patient CaseBV is a 27 y/o AAF presenting to clinic with plans of becomingpregnant in the near future. BV has concerns of continuing herantidepressant therapy and wants to discuss her options for treatmentduring pregnancy.HPI:BV has had 7-8 episodes of depression in the past several years. Themost recent episode was less than a year ago, and she failed therapywith fluoxetine. During these episodes, BV experienced loss ofappetite, disconnect from family, panic attacks, and drug/alcoholabuse.
  • 7. Patient CasePMH:Major depressive disorder (2003)History of panic attacks
  • 8. Patient CaseSH:(-) tobacco – quit smoking 3 months ago(+) EtOH – occasionally(+) illicits – marijuana sociallynot married; lives with boyfriend of 2 yearsAllergies/ADRs: NKDAMedications:Sertraline 50mg – 1 tab PO qdailyMultivitamin Centrum – 1 tab PO qdailyOxycodone 10mg – 1 tab PO q4h prn back pain
  • 9. Maternal DepressionAffects approximately 10-20% mothers-to-beand new mothers (up to 12 monthspostpartum)- about 18 million Americans annually Prenatal depression Postpartum depression Postpartum psychosis
  • 10. Maternal Depression – Risk Factors History of mood disorders Substance abuse problems Maternal depression from previous pregnancy Family history Life stress Poor marital status Low socioeconomic status Lack of social support/community network Unplanned or unwanted pregnancy Race/ethnicity
  • 11. Prenatal Depression Both major and minor episodes beginningduring and lasting up to 6 months afterpregnancy Period prevalence – 18.4% Incidence – 14.5% Low screening rate (23-45%) Lack of time (72%) Lack of reimbursement (48%) Stigma (45%) Only about 50% of women follow up with
  • 12. Prenatal Depression - Symptoms Crying, weepiness Sleep problems Fatigue Appetite disturbance Anhedonia Anxiety Poor fetal attachment irritability
  • 13. Prenatal Depression - ConsequencesAffects both the newborn and mother Untreated Potential poor compliance, nutrition, sleep habits, exercise habits More likely to abuse tobacco, alcohol, illicits More likely to engage in risky behavior (suicidal behavior) 3.4x more likely to deliver pre-term 4x more likely to deliver low birth weight baby Obstetrical complications (pre-eclampsia, excessive bleeding, placental rupture, premature rupturingof water) Increased risk for developing postpartum depression Increased use of health care services including emergency room visits Treated w/ SSRIs Potential increased risk for newborn developing PPHN Black Box Warning – increased risk for suicidal thinking and behavior Economic issues $83.1 billion spent on depression in 2000 26.2 billion spent on premature births in 2005
  • 14. Selective Serotonin ReuptakeInhibitors (SSRIs) citalopram (Celexa) escitalopram (Lexapro) fluoxetine (Prozac) fluvoxamine (Luvox) paroxetine (Paxil, Paxil CR) sertraline (Zoloft)
  • 15. SSRIs - Indications Major depressive disorder Others Obsessive-compulsive disorder Panic disorder Post traumatic stress disorder Social anxiety disorder Off-label Alcoholism Insomnia IBS
  • 16. SSRIs – Mechanism of Action Inhibition of CNS neuronal reuptake ofserotonin Weak affect on norepinephrine and dopaminereuptake Varying affinity for muscarinic, GABA,benzodiazepine, alpha1, alpha2, beta-adrenergic, dopaminergic, histaminergicreceptors
  • 17. SSRIs – Safety in PregnancyCategory C:CitalopramEscitalopramFluoxetineSertralineFluvoxamineCategory D:Paroxetine Cardiac malformations (primarily ventricular and atrial septaldefects
  • 18. Persistent Pulmonary Hypertension ofthe Newborn (PPHN)Overview Occurs when pulmonary vascular resistance remains elevated after birth Results in right-to-left extrapulmonary shunting of blood through fetalcirculatory pathways Leads to inadequte pulmonary perfusion  severe hypoxemia, respiratorydistress, and acidosis that may not respond to conventional respiratorysupportEpidemiology Incidence – 1-2 per 1000 births Prevalence of resulting neurologic disability – 15-60% Mortality – nearly 40%
  • 19. SSRIs and PPHNHypothesized that SSRIs accumulate in the lungs where they increasepulmonary vascular resistance due to their vasoconstrictive properties.In addition, higher circulating levels of serotonin in the fetal lung mayresult in proliferation of pulmonary smooth-muscle characteristic ofPPHN due to the neurotransmitter’s mitogenic and comitogenicproperties. SSRIs also inhibit the synthesis of nitric oxide, avasodilatorimportant to regulating vascular tone in utero and postnatal life.
  • 20. Selective Serotonin Reuptake Inhibitors andRisk of Persistent Pulmonary Hypertension ofthe NewbornChambers et al.N Engl J Med 2006; 354:579-587
  • 21. Chambers et al.Objective To assess whether PPHN is associated with exposure to SSRIs during late pregnancyStudy Design Retrospective, case-control studyMethods Subjects from 97 institutions in four major metropolitan areas were identified between1998 and 2003 Admission/discharge records and NICU logbooks reviewed for PPHN patients Weekly telephone calls made to community hospitals with PPHN patients that might nothave been referred to major centers
  • 22. Chambers et al.Selection of patients and controls Diagnostic criteria for PPHN Gestational age > 34 weeks Severe respiratory failure after birth Need for intubation and mechanical ventilation Evidence of pulmonary hypertension 5% or greater gradient between preductal and postductal oxygen saturation Echocardiographic evidence Exclusion Criteria Evidence of any cardiac anomaly except for patent ductus arteriosus, patent foramen ovale, atrialseptal defect, or a single muscular ventricular septal defect Control group Infants born after 34 weeks No malformations Matched based on hospital and date of birth (+/- 30 days)
  • 23. Chambers et al.Assessment of exposure Nurses conducted interviews with mothers of patients and controlswithin six months of delivery Demographic characteristics Medical/obstetrical history Habits and occupations Use of all medications (including OTC) from the period of two months beforeconception to the end of pregnancy Specifically asked about medication for depression (name, indication, dose, start/stop dates,frequency and amount taken) Recall was enhanced by calendar that highlighted individual menstruation history Antidepressants classified as “SSRIs” or “other” SSRIs evaluated – citalopram, fluoxetine, paroxetine, sertraline Others – amitriptyline, imipramine, nortriptyline, bupropion, venlafaxine, trazodone Late pregnancy defined as 20 weeks after the first day of the lastmenstrual period until delivery
  • 24. Chambers et al.Results637 enrolled – 377 diagnoses matched w/ 836 controlsFrequency of death up to interview- 3% in PPHN group vs. 0% in control groupCrude Any antidepressant / any time (OR 1.3) SSRIs only / any time (OR 1.5) SSRIs only / before 20th week (OR 0.3) Any antidepressant / after 20th week (OR 2.9) SSRIs only / after 20th week (OR 5.1)Adjusted Maternal diabetes, race/ethnicity, BMI, NSAIDs, alcohol, tobacco Any antidepressant / after 20th week (AOR 3.2); p=0.008 SSRIs only / after 20th week (AOR 6.1); p=0.001 SSRIs only / after 26th week (AOR 6.1)
  • 25. Chambers et al.Conclusions Findings may be consistent with transient complicationsin 20-30% of newborns with late exposure found in otherstudies tachypnea, failure to cry, cyanosis, etc. Exposure to non-SSRI antidepressants not associatedwith PPHN Exposure to SSRI in first half of pregnancy notassociated with PPHN BMI, smoking, diabetes, NSAID use in late pregnancydid not attenuate association 6-fold increased risk in developing PPHN with lateexposure to SSRIs
  • 26. Chambers et al.Limitations Retrospective design Inaccurate recall Other medications? Small amount of PPHN diagnoses in infantswith late exposure to SSRIs Difficult to analyze specific dosing/drug
  • 27. Selective serotonin reuptake inhibitors duringpregnancy and risk of persistent pulmonaryhypertension in the newborn: population basedcohort study from the five Nordic countriesKieler et al.BMJ 2012;344:d8012
  • 28. Kieler et al.ObjectiveAssess whether the use of SSRIs duringpregnancy increases the risk of PPHN, andwhether such an effect might differ betweenspecific SSRIsStudy DesignMultinational, population based cohort study
  • 29. Kieler et al.MethodsObtained data from: medical birth registers Maternal characteristics, pregnancy, delivery, neonatal period, ICD-10 codes prescription registers Dispensed substances, formulations, dates cause of death registers Date and cause Patient registers Admissions to hospital, discharge, primary/secondary diagnoses Danish Psychiatric Central Register Psychiatric diseases
  • 30. Kieler et al.ExposuresSSRIs Fluoxetine, citalopram, paroxetine, sertraline, escitalopramOther antidepressants (subanalysis) Clomipramine, venlafaxine, imipramine, amitriptyline, duloxetine, dosulepine,milnacipran, trazodone, nefazodone, moklobemideEver use Three months before start of pregnancy until deliveryLate pregnancy 140 days after start of pregnancy until deliveryEarly pregnancy Three months before start of pregnancy until pregnancy length of 55 days
  • 31. Kieler et al. Participants Identified those born after 33 weeks between1997 and 2006 in Denmark, Finland, Iceland,Norway, and Sweden Exclusions meconium aspiration most common cause of PPHN
  • 32. Kieler et al.Results1,618,255 births 11,014 with late SSRI exposure 33 (0.29%) PPHN diagnoses (AOR 2.1) 17,053 with early SSRI exposure 32 (0.19%) PPHN diagnoses (AOR 1.4) 1,588,140 with no exposure 1,935 (0.12%) PPHN diagnoses 3,130 with other antidepressant exposure 3 (0.09%) PPHN diagnoses (early AOR 0.6; late AOR 2.9) Previous hosptial stay for psychiatric disorder(not using antidepressants) AOR 1.3 Previous psychiatric hospital stay (using antidepressants in late pregnancy AOR 3.1 Absolute risk for PPHN = 3 per 1000 births
  • 33. Kieler et al.Conclusions Use of SSRI after 20 weeks gestation is associated witha risk for developing PPHN of 3 per 1000 liveborninfants Specific SSRIs have similar increased risks of PPHN suggests class effect Incidence of PPHN most likely not associated with diseasestate alone
  • 34. Kieler et al.Strengths Large study Used information from health registers (avoid inaccurate recall) Multinational, population basedLimitations Exposure measured as dispensed drugs, not ingestion No assessment of exposures to more than one antidepressant PPHN and symptomatic patent ductus arteriosus share ICD code Analysis only before 8 weeks and after 20 weeks gestation Cardiac development occurs between 5-22 weeks gestation
  • 35. Additional StudiesMaternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertensionof the newborn.Kallen B, Olausson POPharmacoepidemiol Drug Saf. 2008 Aug;17(8):801-6 SSRI use in early pregnancy (OR 2.4) SSRI use in late pregnancy (OR 3.6)Persistent pulmonary hypertension of the newborn is associated with mode of delivery and notwith maternal use of selective serotonin reuptake inhibitors.Wilson KL et al.Am J Perinatol. 2011 Jan;28(1):19-24. Epub 2010 Jul 6.11,923 births – 20 PPHN cases Cesarean delivery (OR 4.9) SSRIs used in second half of pregnancy (OR 0.0)PPHN found in 5% of controls and none of case groupsAntidepressant use and risk of persistent pulmonary hypertension of the newborn.Andrade S et al.Pharmacoepidemiol Drug Saf. 2009 Mar;18(3):246-52. Five total PPHN cases SSRI use in 3rd trimester – PPHN prevalence of 2.14 per 1000 No SSRI use in 3rd trimester – PPHN prevalence of 2.72 per 1000
  • 36. Conclusions Study results are inconsistent Sample sizes are small Larger, more detailed studies are warranted Absolute risk for PPHN remains low Several health issues resulting from untreated maternaldepression Benefit of treatment with SSRI seems to outweigh the risk Choice of specific SSRI is of minor importance Health professionals and patients should continue to discusstreatment options until further research is conducted
  • 37. Back to the patient case…Is it appropriate to use an SSRI in thispatient if she becomes pregnant?Yes. There is inadequate evidence available tosupport avoiding SSRI use in pregnancy due to anassociation with PPHN. Risks vs. benefits oftreatment should be discussed in detail with thepatient.
  • 38. Back to the patient case… Plan Continue sertraline 50mg PO qdaily Have pateitn follow up regularly with psychiatrist Discuss with family/loved ones about supportive careand monitoring for suicidal and risk-taking behaviors Counseling If patient desires to discontinue SSRI, stronglysuggest discussion with doctor first about risks vs.benefits and tapering
  • 39. References Persistent newborn pulmonary hypertension. Medscape Reference. http://emedicine.medscape.com/article/898437-overview. Accessed April 21, 2012. Drug safety and availability. U.S. Food and Drug Administration Web site.http://www.fda.gov/Drugs/DrugSafety/ucm283375.htm. Accessed April 21, 2012. Santoro K, Peabody H, Schoenman J, et al. Identifying and treating maternal depression: strategies & considerations forhealth care plans. National Institute for Health Care Management Foundation.http://nihcm.org/pdf/FINAL_MaternalDepression6-7.pdf. Published June 2010. Accessed April 21, 2012 Wickersham RM, ed. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwerhealth; 2012.http://online.factsandcomparisons.com. Accessed April 21, 2012. Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacology & Therapeutics.1999;85(2000):11-28. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistentpulmonary hypertension of the newborn. N Engl J Med. 2006;354(6):579-587. Andrade AE, McPhillips H, Loren D, et al. Antidepressant medication use and risk of persistent pulmonary hypertensionof the newborn. Pharmacoepidemiology and Drug Safety. 2009;18:246-252. Kieler H, Artama M, Engeland A, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistentpulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. BMJ.2011;344:d8012. Kallen B, Olausson PO. Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertensionof the newborn. Pharmacoepidemiol Drug Saf. 2008 Aug;17(8):801-6. Wilson KL, Zelig CM, Harvey JP et al. Persistent pulmonary hypertension of the newborn is associated with mode ofdelivery and not with maternal use of selective serotonin reuptake inhibitors. Am J Perinatol. 2011 Jan;28(1):19-24. Epub2010 Jul 6.