Medications for the Treatment
of Perinatal Mood Disorders
• Principles of medication use for perinatal mood • Teratogenic concerns with psychiatric • Review of third trimester risks of psychiatric • Safety of psychiatric medications during lactation • Efficacy of medications for treatment of Medication Considerations in Pregnancy
• Need to weigh risks and benefits carefully with both maternal and fetal well-being in mind • Involve patient in the decision-making process incorporating their goals, values, concerns and • Avoid use of medications if possible, especially in • If benefits outweigh risks, use lowest effective • Information about safety constantly changing, When Making Decisions about Medications
– Severity of the disorder, current symptoms – Past psychiatric history – Patient attitude toward and past experience with – Risk of fetal exposure to medications – Risk of untreated psychiatric il ness to the mother – Risk of relapse associated with discontinuation of SSRI’s in Pregnancy
• All FDA Pregnancy class C except for • However, generally considered safe as a class • Large case-control study showed any 1st TM SSRI use not associated with increased risk of birth defects – Louik et al, 2007 • Cohort study of 462 Norwegian women taking SSRI’s in 1st TM did not show any increase in birth defects – Nordeng et al, 2012 Specific SSRIs in Pregnancy
Paroxetine (Class D)
– 1986-2006 meta-analysis showing 1st trimester paroxetine exposure associated with increased risk cardiac defect (odds ratio 1.72; 95% CI, 1.22-2.42) – Bar-Oz et al, 2007. – 1997-2006 Case-control study, Netherlands, significant increase in atrial septal defect for women using Paroxetine first trimester (AOR, 5.7; 95% CI, 1.4–23.7) – Bakker et al, – 2007 Case-control study showed dose-response relationship, women exposed to >25mg/day of paroxetine in the 1st TM had increased risk of infant with any major congenital malformation (OR 2.23; 95% CI 1.19-4.17) or major cardiac malformation (OR 3.07; 95% CI 1.00 – 9.42) – – 2007 Case-control study with increased ventricular outflow tract obstruction defects (odds ratio, 3.3; 95% CI, 1.3 to Specific SSRIs in Pregnancy
Sertraline (Class C)
– 2007 Case-Control study, 1st TM sertraline associated with omphalocele (odds ratio, 5.7; 95% CI, 1.6 to 20.7) and septal defects (odds ratio, 2.0; 95% CI, 1.2 to 4.0) • Fluoxetine (Class C)
– Longest used and most studied – No increased risk of spontaneous pregnancy loss or – Taking fluoxetine in the third trimester associated with increased risk of premature delivery, low birth weight, admission to special care nursery and poor neonatal adaptation including respiratory difficulty, cyanosis on feeding, and jitteriness – Chambers et al, 1996 SSRIs – withdrawal syndrome
• The SSRI neonatal withdrawal syndrome is characterized by characterized by convulsions, irritability, abnormal crying, and tremor. • 2005 Study: 93 reported cases, 64 of the cases were associated with paroxetine (Paxil), 14 with fluoxetine (Prozac), 9 with sertraline (Zoloft), and 7 with citalopram (Celexa) – Sanz et al, 2005 • In most cases, these symptoms are mild and disappear by two weeks of age with no treatment or with only supportive care. SSRIs and Persistent Pulmonary
Hypertension (PPHN)
• PPHN = failure to transition adequately from fetal to neonatal circulation at birth causing hypoxia and • Scandinavian Cohort Study 1996 and 2007 – Exposure to SSRIs in late pregnancy associated with an increased risk of PPHN: 33 of 11,014 exposed infants - – (absolute risk 3 per 1000 liveborn infants compared with the background incidence of 1.2 per 1000) – Risks of PPHN for each SSRI (sertraline, citalopram, paroxetine, and fluoxetine) were of similar magnitude – Women who took an SSRI after 20 weeks had increased risk of an infant with PPHN (OR 6.1; 95% CI, 2.2 to 16.8) – Antidepressants and Neurodevelopment
• Antidepressant exposure during pregnancy does not appear to have major adverse effects on indices of early infant neurobehavioral development during the first 2 months of life – Suri et al, 2011. • Cohort Study comparing development of infants exposed to tricyclic antidepressants, fluoxetine or nothing in utero – Nulman et al, 2002 – Neither tricyclics nor fluoxetine adversely affected the child’s global IQ, language development, or behavior. – IQ was significantly and negatively associated with – Language was negatively associated with number of Antidepressants and fetal growth
• Case-control study looking at babies born small-for-gestational age – Ramos et al, 2010 Venlafaxine (Effexor) of the serotonin-norepinephrine reuptake inhibitor (SNRI) class use in the second trimester was associated with SGA (OR 2.55; 95% CI 1.04 to 6.27) • SSRI and tricyclic antidepressants not associated with SGA Bupropion (Wellbutrin)
• Case control study of 1213 infants with 1st TM bupropion exposure showed no evidence of teratogenic effect – Cole et al, 2007 • Prospective cohort study of 136 women exposed – no increased risk of major malformation – increased risk of miscarriage similar to rates of other antidepressants – 20 (14.7%) Bupropion vs 6 (4.5%) control; p =.009 – Chun-Fai-Chan et al, 2005 • Formerly class B, recategorized as C in 2006 Mood Stabilizers
– Increased incidence of congenital defects when – Use in second and third trimester associated with – Higher risk of spina bifida – Associated with intrauterine growth retardation, hyperbilirubinemia, hepatotoxicity, skeletal Anxiolytics
– Limited data reveal no increased risk of teratogenic – Major neonatal side effects including sedation and – Some early studies concern for teratogenicity though – Shorter acting benzodiazepines preferred agents – More data needed: Patients can enrol in the AED Pregnancy Registry by calling 1-888-233-2334 or visit Risk of Stopping Antidepressants in Pregnancy
• Prospective cohort study of 201 pregnant women with a history of pre-pregnancy major depression – Cohen et al, – Women who discontinued medication were 5 times as likely to
relapse as compared to women who maintained their antidepressant treatment across pregnancy (hazard ratio, 5.0; • Women who stopped their antidepressant “cold turkey” in pregnancy because fear of harming their baby had higher rates of morbidity, hospitalization, suicidal ideation and suicide attempts and lower compliance with medical therapy and pregnancy management – Koren et al, 2012 Antidepressants for Postpartum
• Start treatment at half-doses for four days • Increase doses by small increments weekly as • Slow increases helpful for side effects • If patient responds, continue same dose at least • If no improvement after 6 weeks, or if response • Average duration of a postpartum episode of depression (without treatment) is seven months Lactation and Antidepressants
• No controlled trials • Multiple case reports and case series • Many case reports are on 1-2 infants, short-term • Studies measure infant serum levels • May not be indicative of infant brain levels • Not necessarily related to patient-oriented Lactation and Antidepressants
• No published reports of adverse effects in breast- fed infants whose mothers took sertraline, • Tricyclic antidepressants not typically found in • Nortriptyline studied most in breast-feeding • Children exposed to TCAs through breast milk have no developmental problems thru school-age Fluoxetine and Lactation
• Colic reported in three infants breast-fed by mothers – infants had serum levels of fluoxetine and norfluoxetine (the active metabolite of fluoxetine) in adult therapeutic – Unlike most antidepressants, fluoxetine has a highly active metabolite (norfluoxetine), and both agents have very long half-lives (84 and 146 hours, respectively) • Chambers (1999) reported that breast-fed infants of fluoxetine-treated mothers gained significantly less • Hendrick (2003) no difference in weight related to fluoxetine , but low weight was associated with long period of maternal depression (>2 months) • Psychosocial or psychotherapy reasonable for • Weigh risks and benefits of antidepressant for • SSRIs (except paroxetine) and tricyclic antidepressants are first line in pregnancy • Bupropion is reasonable second-line agent • Cessation of antidepressants associated with higher rates of relapse and poorer pregnancy Bakker M, Kerstjens-Frederikse W, Buys C, de Walle H, de Jongvan den Berg L. First-trimester use of paroxetine and congenital heart defects: a population-based case-control study. Birth Defects Res A Bar-Oz B, Einarson T, Einarson A, Boskovic R, O'Brien L, Malm H, et al. Paroxetine and congenital malformations: meta-Analysis and consideration of potential confounding factors. Clin Ther Bérard A, Ramos E, Rey E, Blais L, St-André M, Oraichi D. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Chambers C, Hernandez-Diaz S, Van Marter L, Werler M, Louik C, Jones K, et al. Selective serotonin- reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med Chambers CD, Anderson PO, Thomas RG, Dick LM, Felix RJ, Johnson KA, Jones KL, Weight gain in infants breastfed by mothers who take fluoxetine. Pediatrics. 1999;104(5):e61. Chambers C, Johnson K, Dick L, Felix R, Jones K. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996;335:1010-1015. Chun-Fai-Chan B, Koren G, Fayez I, Kalra S, Voyer-Lavigne S, Boshier A, et al. Pregnancy outcome of women exposed to bupropion during pregnancy: a prospective comparative study. Am J Obstet Cole J, Modell J, Haight B, Cosmatos I, Stoler J, Walker A. Bupropion in pregnancy and the prevalence of congenital malformations. Pharmacoepidemiol Drug Saf 2007;16:474-484. Cohen L, Altshuler L, Harlow B, Nonacs R, Newport D, Viguera A, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA Hendrick V, Smith LM, Hwang S, Altshuler LL, Haynes D. Weight gain in breastfed infants of mothers taking antidepressant medications. J Clin Psychiatry. 2003;64(4):410. Kieler H, Artama M, Engeland A, Ericsson O, Furu K, Gissler M, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. BMJ 2012;344:d8012. Koren G, Nordeng H. Antidepressant use during pregnancy: the benefit-risk ratio. Am J Obstet Gynecol 2012. Louik C, Lin A, Werler M, Hernández-Díaz S, Mitchell A. First trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007;356:2675-2683. Nordeng H, van Gelder M, Spigset O, Koren G, Einarson A, Eberhard-Gran M. pregnancy outcome after exposure to antidepressants and the role of maternal depression: results from the Norwegian Mother and Child Cohort Study. J Clin Psychopharmacol 2012;32:186-194. Nulman I, Rovet J, Stewart D, Wolpin J, Pace-Asciak P, Shuhaiber S, et al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002;159:1889-1895. Ramos É, St-André M, Bérard A. Association between antidepressant use during pregnancy and infants born small for gestational age. Can J Psychiatry 2010;55:643-652. Sanz E, De-las-Cuevas C, Kiuru A, Bate A, Edwards R. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 2005;365:451-453. Suri R, Hellemann G, Stowe Z, Cohen L, Aquino A, Altshuler L. A prospective, naturalistic, blinded study of early neurobehavioral outcomes for infants following prenatal antidepressant exposure. J Clin Psychiatry 2011;72:1002-1007. • Jennifer Silverstein, LCSW: Vista Family Health • Maria Zavala, MSW Trainee: California • Erin Lunde, MD: Vista Family Health Center –


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