Birdsong Conference 3/27/11 Marcia L. Buck, Pharm.D. Selective Serotonin Reuptake Inhibitors (SSRIs) in Pregnancy and Breastfeeding Birdsong Conference 3/27/11 Marcia L. Buck, Pharm.D.

I have no conflicts of interest to disclose related to this presentation. I will be discussing the off-label use of several drugs.

Incidence Up to 20% of women experience depressive symptoms during pregnancy 3-5% will be diagnosed with major depressive disorder Approximately 100,000 infants (2.3% of all infants) born in the US each year have been exposed to an SSRI during gestation Wisner KL. Depression Anxiety 2010;27:695-8. Reefhuis J, et al. NEJM 2006;354:2188-90.

SSRI Antidepressants Fluoxetine (Prozac®) 1987 Sertraline (Zoloft®) 1991 Paroxetine (Paxil®) 1992 Fluvoxamine (Luvox®) 1994 Citalopram (Celexa®) 1998 Escitalopram (Lexapro®) 2002

The Risks… Cardiac defects Preterm birth Persistent Pulmonary Hypertension Neonatal SSRI withdrawal syndrome Poor Neonatal Adaptation Impaired neurologic development

The Evidence Information Sources Case reports and case series Registries Retrospective case-controlled studies Prospective cohort studies More than 30 studies published to date, with wide variations in methodology

Confounding Variables Untreated or undertreated depression Associated with preterm birth, low birth weight, and developmental delays Smoking Exposure to other substances 80% of women take at least one medication, other than vitamins, during pregnancy 64% receive a prescription medication Andrade S, et al. Am J Obstet Gynecol 2004;191:298. Vesga-Lopez O, et al. Arch Gen Psych 2008;65:805-15. Headley J, et al. Eur J Clin Pharmacol 2004;60:355-61.

SSRI Use During the First Trimester

Cardiac Defects Examination of a US insurance claims database by the manufacturer of paroxetine revealed a 1.5-fold higher incidence in exposed infants A similar risk was found in the Swedish Medical Birth Register Septal & ventricular outflow tract defects In 2005, labeling changed to FDA Pregnancy Category D Cole JA, et al. Pharmacoepidemiol Drug Saf 2007,6:1075-85.

Cardiac Defects A 2008 multicenter prospective cohort study of 2,191 pregnancies found cardiovascular anomalies in 2.8% of the infants exposed to fluoxetine and 2% of the infants exposed to paroxetine, compared to 0.6% of the controls Smoking was the only other independent risk factor Diav-Citrin O, et al. Br J Clin Pharmacol 2008;66:695-705.

Cardiac Defects A 2009 population-based study of nearly 500,000 children in Denmark 0.9% of septal cardiac defects in infants exposed to an SSRI in early pregnancy, compared to a 0.5% in the controls The largest association found with sertraline and citalopram Pedersen LH, et al. BMJ 2009;339:b3569.

Cardiac Defects In contrast, several other large case cohort studies have failed to replicate these findings The 2009 APA, ACOG Report states that “the current data on SSRI exposure show no consistent information to support specific morphological teratogenic risks” Louik C, et al. NEJM 2007;356:2675-83. Alwan S, et al. NEJM 2007;356:2684-92. Einarson A, et al. Am J Psychiatry 2008;165:749-52. Yonkers KA, et al. Gen Hosp Psychiatry 2009;31;403-13.

Possible Mechanisms Serotonin regulates embryonic cell migration Alterations in serotonin may adversely affect cardiomyocyte differentiation May be more likely with concomitant exposure to benzodiazepines Oberlander TF, et al. Birth Defects Res 2008;83:68-76. Ellfolk M, et al. Reproductive Toxicol 2010;30:249-60.

SSRI Use During the Third Trimester

Preterm Birth Several studies suggest an association between SSRI use and preterm birth In a 2009 prospective observational study of 238 women, there was a 20% incidence of preterm birth in those taking SSRIs throughout gestation, as well as in those with untreated depression Discontinuation prior to 20 weeks resulted in rates similar to controls Wisner KL, et al. Am J Psych 2009;166:557-66. Lund N, et al. Arch Pediatr Adolesc Med 2009;163:949-54.

Wisner KL, et al. Am J Psych 2009;166:557-66.

Persistent Pulmonary Hypertension First reported in 1996 A small cohort study of 174 women who took fluoxetine during pregnancy 2 of 73 infants exposed up to the time of delivery developed PPHN No cases in the women who discontinued treatment during the first trimester Chambers CD, et al. NEJM 1996;335:1010-5.

PPHN Confirmed in a 2006 retrospective case-control study of 377 infants exposed to an SSRI and 836 matched controls 3.7% incidence in babies born to women treated after 20 weeks gestation, compared to 0.7% in controls No increase with other antidepressants Chambers CD, et al. NEJM 2006;354:579-87.

PPHN Confirmed by a recent report from the Swedish Medical Birth Register showing a 2-fold increase in PPHN with late-term SSRI use In contrast, no increase in risk found in a study of 2,208 infants (2.14 cases/1,000 in exposed infants vs 2.72 cases/1,000 controls) Reis M, et al. Psychol Med 2010;40:1723-33. Andrade S, et al. Pharmacoepidemiol Drug Saf 2009;18:246-52.

Possible Mechanisms Serotonin-induced vasoconstriction SSRI-induced inhibition of nitric oxide synthesis Variation in response may reflect polymorphisms in the promotor alleles of the serotonin transporter gene or from pharmacogenetic differences in catecholamine metabolism (mom or baby) Ellfolk M, et al. Reproductive Toxicol 2010;30:249-60.

Neonatal SSRI Withdrawal Poor Neonatal Adaptation Symptoms respiratory distress temperature instability feeding difficulties, jitteriness, irritability hypoglycemia tremors, shivering, convulsions Estimated to occur in 30% of neonates exposed to SSRIs in utero

Neonatal SSRI Withdrawal Typically evident within 24-72 hours after birth, often correlating with the elimination half-life of the SSRI May reflect maternal metabolic phenotype Resolve within 2 weeks of birth Similar to symptoms observed in the infants of mothers with untreated depression No treatment regimen

Neurologic Development Of the more than a dozen studies conducted to date, few have shown any evidence of developmental delay Findings have typically been subtle delays in motor control New research suggests an increased anxiety in some 3-year-olds exposed to SSRIs in utero, potentially linked to maternal anxiety Casper RC, et al. J Pediatr 2003;142:402-8. Oberlander TF, et al. Arch Pediatr Adolesc Med 2010;164:444-51.

2009 APA, ACOG Statement Conduct a careful risk: benefit discussion with the patient Psychotherapy alone may be appropriate for mild-to-moderate depression Before prescribing medication, document all drug and exposures Treat addictions to minimize additive risk For stable treated patients, consider a trial off therapy Yonkers KA, et al. Gen Hosp Psychiatry 2009;31;403-13.

Discussing the Options There may be a small increase in the risk for cardiac defects or PPHN The most likely risk is preterm birth No SSRI has been conclusively shown to be safer than the rest There is little evidence to suggest that dose reduction will reduce risk

SSRI Use During Breastfeeding

Evaluating the Literature Milk to Plasma Ratio (M/P) Utility of the ratio questioned Estimated Infant Dose Relative infant dose or percent maternal dose Determination of Infant Serum Concentration Limited by availability of assays Clinical Assessment

Rampono J, et al. Br J Clin Pharmacol 2006;62;316-22.

Breastfeeding Summary Drug M/P Infant Dose (% Maternal Dose) Fluoxetine 1* 0.5-5% Sertraline 1-2 3-4% Paroxetine 1 1-3% Fluvoxamine 1-4 Estimated at 2% Citalopram 2-3* 0.2-9% Escitalopram 2-2.5* 5-6% * Includes active metabolites Di Scalea TL, et al. Clin Obstet Gyn 2009;52:483-97. Ellfolk M, et al. Reproductive Toxicol 2010;30:249-60.

Discussing the Options Evaluate the risk: benefit ratio Is mom already on therapy? If so, continue current treatment If not, consider fluoxetine, sertraline, or paroxetine Monitor infant response Identify confounding variables such as other medications

Future Considerations Changes in prescribing Improved study design with EMRs Increasing use of the SNRIs Venlafaxine (Effexor®) Desvenlafaxine (Pristiq®) Duloxetine (Cymbalta®)

Additional Resources Drugs@FDA www.fda.gov Organization of Teratology Information Specialists (OTIS) www.otispregnancy.org National Library of Medicine Developmental and Reproductive Toxicology Database and Drugs and Lactation Database (LactMed) http://toxnet.nlm.nih.gov