This document summarizes key studies on the safety of antidepressant use during pregnancy. It describes the risks of untreated maternal depression as well as the potential link between SSRI exposure and persistent pulmonary hypertension of the newborn (PPHN). The largest and most well-known study by Chambers et al. found a 6-fold increased risk of PPHN with late pregnancy SSRI exposure. However, subsequent larger studies like one using Nordic health registers found a lower 2-fold increased risk. Overall, the risk of PPHN remains low at around 3 per 1000 births, and the health issues from untreated maternal depression may outweigh this risk. The document concludes that health professionals should continue discussing treatment options with patients until more research

1. SAFETY OF
ANTIDEPRESSANT USE
DURING PREGNANCY
Daniel Huisman
PharmD Candidate
UIC College of Pharmacy
April 26, 2012

2. Objectives
 Describe the epidemiology, risk factors, symptoms, and
consequences 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 SSRI
exposure in newborns regarding the development of
PPHN
 Apply evaluation to a patient case

3. Introduction
 In July 2006, the U.S. Food and Drug
Administration issued a warning regarding a
potential link between selective serotonin-
reuptake inhibitors (SSRIs) and persistent
pulmonary hypertension of the newborn
(PPHN) based on a study published in the
New England Journal of Medicine that showed
a 6-fold increased risk.

4. Introduction
 In December 2011, after review of additional
studies, the FDA revised its initial warnings,
recommending physicians continue
antidepressant therapy in pregnant women
due to a variety of health issues caused by
untreated maternal depression.

5. Introduction
 In January 2012, the British Medical Journal
published a study warning pregnant women
that they can significantly increase the risk of
their infants developing PPHN if they take
certain SSRIs.

6. Patient Case
BV is a 27 y/o AAF presenting to clinic with plans of becoming
pregnant in the near future. BV has concerns of continuing her
antidepressant therapy and wants to discuss her options for treatment
during pregnancy.
HPI:
BV has had 7-8 episodes of depression in the past several years. The
most recent episode was less than a year ago, and she failed therapy
with fluoxetine. During these episodes, BV experienced loss of
appetite, disconnect from family, panic attacks, and drug/alcohol
abuse.

7. Patient Case
PMH:
Major depressive disorder (2003)
History of panic attacks

8. Patient Case
SH:
(-) tobacco – quit smoking 3 months ago
(+) EtOH – occasionally
(+) illicits – marijuana socially
not married; lives with boyfriend of 2 years
Allergies/ADRs: NKDA
Medications:
Sertraline 50mg – 1 tab PO qdaily
Multivitamin Centrum – 1 tab PO qdaily
Oxycodone 10mg – 1 tab PO q4h prn back pain

9. Maternal Depression
Affects approximately 10-20% mothers-to-be
and new mothers (up to 12 months
postpartum)
- 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 beginning
during and lasting up to 6 months after
pregnancy
 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 - Consequences
Affects 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 rupturing
of 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 Reuptake
Inhibitors (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 of
serotonin
 Weak affect on norepinephrine and dopamine
reuptake
 Varying affinity for muscarinic, GABA,
benzodiazepine, alpha1, alpha2, beta-
adrenergic, dopaminergic, histaminergic
receptors

17. SSRIs – Safety in Pregnancy
Category C:
Citalopram
Escitalopram
Fluoxetine
Sertraline
Fluvoxamine
Category D:
Paroxetine
 Cardiac malformations (primarily ventricular and atrial septal
defects

18. Persistent Pulmonary Hypertension of
the Newborn (PPHN)
Overview
 Occurs when pulmonary vascular resistance remains elevated after birth
 Results in right-to-left extrapulmonary shunting of blood through fetal
circulatory pathways
 Leads to inadequte pulmonary perfusion  severe hypoxemia, respiratory
distress, and acidosis that may not respond to conventional respiratory
support
Epidemiology
 Incidence – 1-2 per 1000 births
 Prevalence of resulting neurologic disability – 15-60%
 Mortality – nearly 40%

19. SSRIs and PPHN
Hypothesized that SSRIs accumulate in the lungs where they increase
pulmonary vascular resistance due to their vasoconstrictive properties.
In addition, higher circulating levels of serotonin in the fetal lung may
result in proliferation of pulmonary smooth-muscle characteristic of
PPHN due to the neurotransmitter’s mitogenic and comitogenic
properties. SSRIs also inhibit the synthesis of nitric oxide, a
vasodilator
important to regulating vascular tone in utero and postnatal life.

20. Selective Serotonin Reuptake Inhibitors and
Risk of Persistent Pulmonary Hypertension of
the Newborn
Chambers 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 pregnancy
Study Design
 Retrospective, case-control study
Methods
 Subjects from 97 institutions in four major metropolitan areas were identified between
1998 and 2003
 Admission/discharge records and NICU logbooks reviewed for PPHN patients
 Weekly telephone calls made to community hospitals with PPHN patients that might not
have 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, atrial
septal 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 controls
within six months of delivery
 Demographic characteristics
 Medical/obstetrical history
 Habits and occupations
 Use of all medications (including OTC) from the period of two months before
conception 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 last
menstrual period until delivery

25. Chambers et al.
Results
637 enrolled – 377 diagnoses matched w/ 836 controls
Frequency of death up to interview
- 3% in PPHN group vs. 0% in control group
Crude
 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)

26. Chambers et al.
Conclusions
 Findings may be consistent with transient complications
in 20-30% of newborns with late exposure found in other
studies
 tachypnea, failure to cry, cyanosis, etc.
 Exposure to non-SSRI antidepressants not associated
with PPHN
 Exposure to SSRI in first half of pregnancy not
associated with PPHN
 BMI, smoking, diabetes, NSAID use in late pregnancy
did not attenuate association
 6-fold increased risk in developing PPHN with late
exposure to SSRIs

27. Chambers et al.
Limitations
 Retrospective design
 Inaccurate recall
 Other medications?
 Small amount of PPHN diagnoses in infants
with late exposure to SSRIs
 Difficult to analyze specific dosing/drug

28. Selective serotonin reuptake inhibitors during
pregnancy and risk of persistent pulmonary
hypertension in the newborn: population based
cohort study from the five Nordic countries
Kieler et al.
BMJ 2012;344:d8012

29. Kieler et al.
Objective
Assess whether the use of SSRIs during
pregnancy increases the risk of PPHN, and
whether such an effect might differ between
specific SSRIs
Study Design
Multinational, population based cohort study

30. Kieler et al.
Methods
Obtained 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

31. Kieler et al.
Exposures
SSRIs
 Fluoxetine, citalopram, paroxetine, sertraline, escitalopram
Other antidepressants (subanalysis)
 Clomipramine, venlafaxine, imipramine, amitriptyline, duloxetine, dosulepine,
milnacipran, trazodone, nefazodone, moklobemide
Ever use
 Three months before start of pregnancy until delivery
Late pregnancy
 140 days after start of pregnancy until delivery
Early pregnancy
 Three months before start of pregnancy until pregnancy length of 55 days

32. Kieler et al.
 Participants
 Identified those born after 33 weeks between
1997 and 2006 in Denmark, Finland, Iceland,
Norway, and Sweden
 Exclusions
 meconium aspiration
 most common cause of PPHN

33. Kieler et al.
Results
1,618,255 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

36. Kieler et al.
Conclusions
 Use of SSRI after 20 weeks gestation is associated with
a risk for developing PPHN of 3 per 1000 liveborn
infants
 Specific SSRIs have similar increased risks of PPHN
 suggests class effect
 Incidence of PPHN most likely not associated with disease
state alone

37. Kieler et al.
Strengths
 Large study
 Used information from health registers (avoid inaccurate recall)
 Multinational, population based
Limitations
 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

38. Additional Studies
Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertension
of the newborn.
Kallen B, Olausson PO
Pharmacoepidemiol 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 not
with 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 groups
Antidepressant 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

39. 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 maternal
depression
 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 discuss
treatment options until further research is conducted

40. Back to the patient case…
Is it appropriate to use an SSRI in this
patient if she becomes pregnant?
Yes. There is inadequate evidence available to
support avoiding SSRI use in pregnancy due to an
association with PPHN. Risks vs. benefits of
treatment should be discussed in detail with the
patient.

41. 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 care
and monitoring for suicidal and risk-taking behaviors
 Counseling
 If patient desires to discontinue SSRI, strongly
suggest discussion with doctor first about risks vs.
benefits and tapering

42. 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 for
health 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 persistent
pulmonary 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 hypertension
of 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 persistent
pulmonary 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 hypertension
of 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 of
delivery and not with maternal use of selective serotonin reuptake inhibitors. Am J Perinatol. 2011 Jan;28(1):19-24. Epub
2010 Jul 6.