1. 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.

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

4. 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:

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

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

7. 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

8. 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:
Headley J, et al. Eur J Clin Pharmacol 2004;60:

9. SSRI Use During the First Trimester

10. 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:

11. 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:

12. 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.

13. 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:
Alwan S, et al. NEJM 2007;356:
Einarson A, et al. Am J Psychiatry 2008;165:
Yonkers KA, et al. Gen Hosp Psychiatry 2009;31;

14. 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:

15. SSRI Use During the Third Trimester

16. 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:
Lund N, et al. Arch Pediatr Adolesc Med 2009;163:

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

18. 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:

19. 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:

20. 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:
Andrade S, et al. Pharmacoepidemiol Drug Saf 2009;18:

21. 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:

22. 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

23. Neonatal SSRI Withdrawal
Typically evident within 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

24. 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:

25. 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;

26. 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

27. SSRI Use During Breastfeeding

28. 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

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

30. 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:
Ellfolk M, et al. Reproductive Toxicol 2010;30:

31. 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

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

33. Additional Resources Drugs@FDA
Organization of Teratology Information Specialists (OTIS)
National Library of Medicine Developmental and Reproductive Toxicology Database and Drugs and Lactation Database (LactMed)