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
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.
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
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
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
24.
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
34.
35.
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.