mother may i? managing mental illness during pregnancy
TRANSCRIPT
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Mother May I? Managing Mental
Illness During Pregnancy: Focus on Antidepressants
page 275 in syllabus
Sponsored by the Neuroscience Education Institute
Additionally sponsored by Fairleigh Dickinson University School of Psychology
This activity is supported by educational grants from: Lilly USA, LLC; Otsuka America Pharmaceutical, Inc.; Pamlab, L.L.C.; Sunovion Pharmaceuticals Inc.;
Takeda Pharmaceuticals International, Inc., U.S. Region and Lundbeck Pharmaceutical Services, LLC; Teva Pharmaceutical Industries Ltd. with additional support from: Assurex Health, Inc.; JayMac Pharmaceuticals, LLC; Neuronetics, Inc.. For further information concerning Lilly grant funding, visit www.lillygrantoffice.com.
Ronnie Gorman Swift, MD
Professor and Associate Chairman, Department of Psychiatry and
Behavioral Sciences, New York Medical College, Valhalla
Chief of Psychiatry and Associate Medical Director,
Metropolitan Hospital Center, New York, NY
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Learning Objectives
• Evaluate the potential risks of using antidepressants
during pregnancy and postpartum
• Compare the risk–benefit analyses of specific
antidepressants for the developing fetus and the
breastfeeding infant
• Identify risk factors for the emergence of depressive
symptoms during pregnancy and postpartum
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
I feel competent managing patients with depression
throughout a pregnancy and postpartum, or who are
breastfeeding.
1. 1 (strongly disagree)
2. 2
3. 3
4. 4
5. 5 (strongly agree)
Pre-Poll Question
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The labels for antidepressants (SSRIs in particular)
include several warning statements about possible
adverse effects of use during pregnancy. Which of the
following has the most evidence suggesting an increased
risk with antidepressant use during pregnancy?
1. First trimester cardiac malformations
2. Persistent pulmonary hypertension of the newborn
(PPHN)
3. Postnatal adaptation syndrome (PNAS)
4. Long-term neurodevelopmental abnormalities
Pretest Question 1
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
A 26-year-old woman with a history of major depression has been
maintained on an SSRI for the last 2 years. She has just learned
that she is pregnant and is concerned that the antidepressant may
harm her baby. For most patients, the evidence to date suggests
which risk–benefit analysis for the use of antidepressants during
pregnancy and breastfeeding?
1. Antidepressants can be continued during pregnancy and
breastfeeding
2. Antidepressants can be continued during pregnancy but should
be discontinued during breastfeeding
3. Antidepressants should be discontinued during pregnancy but
can be reinstated during breastfeeding
4. Antidepressants should not be used during pregnancy or
breastfeeding
Pretest Question 2
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Major Depression During Pregnancy
and Postpartum
Gaynes N et al. Evidence Report/Technology Assessment No. 119. AHRQ Publication No 5-E006-2.
Rockville, MD: Agency for Healthcare Research and Quality; 2005.
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
20%
Period Prevalence Incidence
Conception to birth
Birth to 3 months postpartum
Copyright © 2013 Neuroscience Education Institute. All rights reserved. Copyright © 2013 Neuroscience Education Institute. All rights reserved.
ANTIDEPRESSANT USE
DURING PREGNANCY
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
FDA Use-in-Pregnancy Ratings
A B C D X
Controlled
studies show
no risk
No evidence
of risk in
humans
Risk cannot
be ruled out
Positive
evidence of
risk
Contra-
indicated
A B C D X
OK to use
I don't know I don't know I don't know Contra-
indicated
What They Really Mean
A B C D X
0 8 66 16 6
# of Psychotropics With Rating
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Antidepressant Use During Pregnancy
Has Been Associated With:
Yonkers KA et al. Obstet Gynecol 2011;117:961-77;
Pedersen LH et al. Pediatrics 2010;125;e600-8; Field. Int J Neurosci 2010;120:163-7.
Cardiac defect
Minor physical malformation
Major physical malformation
Miscarriage
First Trimester
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
First Trimester
• 3% of infants in the US are born with a major birth defect
• Each specific type of major birth defect is rare
• Risk of congenital heart defects in general population is 0.82 per 1000 births
• Why might antidepressants increase the risk of some birth defects?
– Serotonin is important during early embryonic development of the neural tube, branchial arches, and heart
Byatt N et al. Acta Psychiatr Scand 2013;127:94-114.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Paroxetine Warning in FDA Label
Epidemiological studies have shown
that infants exposed to paroxetine
in the first trimester of pregnancy
have an increased risk
of congenital malformations,
particularly cardiovascular malformations
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Weighing the Evidence for First Trimester Teratogenicity: Studies
Increased Risk (# Studies) No Increased Risk (# Studies)
bupropion 2 2
citalopram 4 4
duloxetine 1 0
escitalopram 0 4
fluoxetine 4 7
fluvoxamine 0 4
mirtazapine 0 2
paroxetine 8 7
sertraline 3 6
trazodone 0 2
venlafaxine 1 3
Varying methodology across studies. Causality and magnitude of risk unclear.
Byatt N et al. Acta Psychiatr Scand 2013;127:94-114; Hoog SL et al. Int J Med Sci 2013;10(4):413-9;
Polen KND et al. Birth Defects Res Part A: Clin Mol Teratol 2013;97(1):28-35.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Weighing the Evidence for First
Trimester Teratogenicity: Meta-analyses # Meta-analyses Finding
Increased Risk
Major Cardiac
# Meta-analyses Finding
No Increased Risk
Major Cardiac
citalopram 0 0 1 1
fluoxetine 1 1 2 1
paroxetine 2 4 3 1
sertraline 0 0 1 1
SSRI (class) 1 0 1 1
Newer AD (class) 0 0 1 0
AD (class) 0 1 1 0
Myles N et al. Aust N Z J Psychiatry 2013;Epub ahead of print; Addis A, Koren G. Psychol Med
2000;30(1):89-94; Bar-Oz B et al. Clin Ther 2007;29(5):918-26; O'Brien L et al. J Obstet Gynaecol Canada
2008;30(8):696-701; Wurst KE et al. Birth Defects Res Part A: Clin Mol Teratol 2010;88(3):159-70; Einarson
TR et al. J Popul Ther Clin Pharmacol 2012;19(2):w334-48; Nikfar S et al. DARU J Pharm Sci 2013;20(1):75;
Einarson TR, Einarson A. Pharmacoepidemiol Drug Safety 2005;14:823-7; Grigoriadis S et al. J Clin
Psychiatry 2013;74(4):e296-308; Riggin L et al. J Obstet Gynaecol Canada 2013;35(4):362-9.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Increased Risk of Major Malformations
With Antidepressants: Summary
• Paroxetine
– Increased risk of major and cardiac
malformations in several studies
– Not seen in large database assessments
• Bupropion
– Limited data; possible increased risk of
congenital heart defects
• SSRIs
– Findings are inconsistently observed
• Other newer antidepressants
– Very limited data
Byatt N et al. Acta Psychiatr Scand 2013;127:94-114.
Absolute
risk
appears
small
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Antidepressant Use During Pregnancy
Has Been Associated With:
Yonkers KA et al. Obstet Gynecol 2011;117:961-77; Gentile S, Galbally M. J Affective Disord
2011;128(1-2):1-9; Pedersen LH et al. Pediatrics 2010;125;e600-8; Field. Int J Neurosci
2010;120:163-7.
Persistent pulmonary hypertension
Postnatal adaptation syndrome
Preterm birth
Low birth weight
Small for gestational age
Long-term neurodevelopmental effects?
Third Trimester
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Persistent Pulmonary Hypertension of
the Newborn (PPHN)
• At birth, the lung replaces the placenta as the primary site of gas change
• rapid drop in pulmonary vascular resistance and thus an increase in pulmonary blood flow
• PPHN can occur when this cardiopulmonary transition does not occur (1–2 cases per 1000 births)
• Presents within 12 hours of birth as cyanosis and mild respiratory distress
• Can progress to respiratory failure, requiring intubation and mechanical ventilation; fatal in 10–20% of cases
Neonatal Inhaled Nitric Oxide Study Group. J Pediatr 2000;136:611-7; Davidson D et al. Pediatrics
1998;101:325-34; Greenough A, Khetriwal B. Paediatr Respir Rev 2005;6:111-6.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
FDA Class Statement:
PPHN
• Infants exposed to SSRIs in pregnancy may have an increased risk of persistent pulmonary hypertension of the newborn (PPHN); PPHN occurs in 1–2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality
• Several recent epidemiological studies suggest a positive statistical association between SSRI use in pregnancy and PPHN
• Other studies do not show a significant statistical association
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Weighing the Evidence
for Increased Risk of PPHN
# Studies Showing Increased
Risk of Exposure
Early Late
# Studies Not Showing
Increased Risk of Exposure
Early Late
fluoxetine 0 1 0 0
SSRI 1 2 2 3
antidepressant 1 3 1 1
Chambers CD et al. N Engl J Med 1996;335:1010-5; Chambers CD et al. N Engl J Med
2006;354:579-87; Kallen B, Olausson PO. Pharmcoepidemiol Drug Saf 2008;17(8):801-6; Andrade
SE et al. Pharmacoepidemiol Drug Safety 2009;18:246-52; Wichman CL et al. Mayo Clin Proc
2009;84:23-7; Wilson KL et al. Am J Perinatol 2011;28:19-24; Reis M, Kallen B. Psychol Med
2010;40:1723-33; Kieler H et al. BMJ 2011;344:d8012.
Varying methodologies. Studies did not assess duration of exposure.
Most studies were underpowered.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Increased Risk of PPHN With SSRIs:
Summary
• Unclear if SSRIs are linked to an increased risk of
PPHN
• Possible that any risk is indirect via increased risk of
preterm birth
• If there is an increased risk, what does that mean?
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
PPHN and Antidepressants:
Understanding the Risk
Chambers CD et al. N Engl J Med 2006;354:579-87.
Variable Definite
PPHN
(N=377)
Matched
Control
(N=836)
Adjusted
Odds Ratio
(95% CI)
P-value
No AD during
pregnancy
357 (94.7%) 799 (95.6%) 1.0
AD before wk 20 6 (1.6%) 26 (3.1%) 0.6 (0.2–1.5) 0.28
AD after wk 20 14 (3.7%) 11 (1.3%) 3.2 (1.3–7.4) 0.008
No SSRI during
pregnancy
361 (95.8%) 812 (97.1%) 1.0
SSRI before wk 20 2 (0.5%) 18 (2.2%) 0.3 (0.1–1.2) 0.08
SSRI after wk 20 14 (3.7%) 6 (0.7%) 6.1 (2.2–16.8) 0.001
Study With Highest Relative Risk With AD Use
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
PPHN and Antidepressants: Understanding the Risk
What does the relative risk mean?
Variable Definite
PPHN
(N=377)
Matched
Control
(N=836)
Adjusted
Odds Ratio
(95% CI)
P-value
SSRI after wk 20 14 (3.7%) 6 (0.7%) 6.1 (2.2–16.8) 0.001
In other words:
Population risk:
1–2 per 1000
Absolute risk w/ SSRI:
6–12 per 1000
Rate of no PPHN in population:
~99%
Rate of no PPHN w/ SSRI:
~99%
Chambers CD et al. N Engl J Med 2006;354:579-87.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Postnatal Adaptation Syndrome (PNAS)
• 20–30% of infants exposed to SSRIs in late
pregnancy exhibit symptoms such as irritability,
abnormal crying, tremor, lethargy, hypoactivity,
decreased feeding, tachypnea, and respiratory
distress
• Termed PNAS; also called neonatal behavioral
syndrome or poor neonatal adaptation syndrome
• Usually develops within days of birth and
resolves within days or weeks
Byatt N et al. Acta Psychiatr Scand 2013;127:94-114.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
FDA Class Statement:
Postnatal Adaptation Syndrome
• Neonates exposed to SSRIs or SNRIs late in the third
trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube
feeding; such complications can arise immediately upon
delivery
• Reported clinical findings have included respiratory
distress, cyanosis, apnea, seizures, temperature
instability, feeding difficulty, vomiting, hypoglycemia,
hypotonia, hypertonia, hyperreflexia, tremor, jitteriness,
irritability, and constant crying
• These features are consistent with either a direct toxic
effect of SSRIs and SNRIs or possibly a drug
discontinuation syndrome
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Weighing the Evidence for Risk of PNAS
• Some conflicting evidence
– Varying methodologies
• Overall, data suggest that PNAS can occur in
neonates exposed to SSRIs or SNRIs
• Most often reported after exposure to
paroxetine, fluoxetine, or venlafaxine
# Studies Showing
Increased Risk of Exposure
# Studies Not Showing
Increased Risk of Exposure
12 4
Byatt N et al. Acta Psychiatr Scand 2013;127:94-114.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
PNAS: Why and How It May Occur
• All SSRIs cross the placenta and thus may increase serotonin in the developing fetus
• Suggested causes of PNAS
– Serotonin toxicity (symptoms resemble serotonin syndrome)
– Discontinuation syndrome (symptoms resemble adult serotonin discontinuation syndrome)
• Severity and duration of PNAS are affected by:
– Antidepressant dose, timing, duration of exposure, and pharmacokinetics
– Genetic predisposition?
Sie SD et al. Arch Dis Child: Fetal Neonatal Ed 2012;97:F472-6.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Long-term Neurodevelopmental
Outcomes
• Very limited data
• No studies found detrimental effects on cognitive development
• Two studies found possible effects on motor development
• Studies that exist are reassuring but have limitations
– Most did not follow children through school-age
– Most did not control for maternal IQ
– Most did not measure maternal treatment adherence
Gentile S, Galbally M. J Affective Disord 2011;128:1-9.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
FDA Class Statement:
AD Discontinuation and Depression Relapse
• Physicians should also note the results of a
prospective longitudinal study of 201 pregnant
women with a history of major depression who were
either on antidepressants or had received
antidepressants less than 12 weeks prior to their last
menstrual period and were in remission
• Women who discontinued antidepressant
medication during pregnancy showed a significant
increase in relapse of their major depression
compared to those women who remained on
antidepressant medication throughout pregnancy
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Time to Depression Relapse for Medication
Maintenance vs. Discontinuation
Cohen LS et al. JAMA 2006;295(5):499-507.
5-fold increased risk of relapse for discontinuation vs. maintenance
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Time to Depression Relapse for Medication
Reintroduction vs. No Reintroduction
Cohen LS et al. JAMA 2006;295(5):499-507.
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Risks of Untreated Depression
During Pregnancy
• Miscarriage
• Inadequate maternal
weight gain
• Poor self-care
• Substance use
• Preeclampsia
• Postpartum depression
• Cesarean delivery
• Impaired fetoplacental
function
• Preterm birth
• Low birth weight
• Small for gestational age
• Fetal distress
• Neonatal care unit
admittance
Byatt N et al. Acta Psychiatr Scand 2013;127:94-114.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Risk–Benefit Analysis:
Depression vs. Antidepressants No randomized controlled trials comparing risk of depression vs. antidepressants
Persistent pulmonary
hypertension?
Postpartum depression
Miscarriage
Preterm birth
Low birth weight
Small for gestational age
Long-term
neurodevelopmental
abnormalities?
Inadequate maternal
weight gain
Poor maternal self-care
Substance use
Preeclampsia
Cesarean delivery
Impaired fetoplacental
function
Fetal distress
Neonatal care unit
admittance Postnatal adaptation
syndrome
Cardiac defect
Major malformation
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Treated vs. Untreated Depression: Propensity Score Matching
Outcome Differences
SE-D – DE DE – Nonexposed
Difference P-value Difference P-value
C-section1 0.03 0.01 0.01 <0.001
Birth weight, g -32 0.05 -24 <0.001
Gestational age, wk -0.35 <.001 -0.06 <.001
Preterm birth1 0.02 <0.001 0.006 0.007
Birth weight <10th percentile2 0.005 0.51 0.007 0.005
Length of hospital stay, d 0.43 0.007 0.12 0.006
Hospital stay >3 d3 0.05 <0.001 0.01 <0.001
Respiratory distress1,3 0.063 <0.001 0.004 0.07
Feeding problems1 0.015 0.002 0.003 0.02
Jaundice1 0.019 0.01 -0.004 0.08
Convulsions1 0.0005 0.64 -0.0002 0.49
1Incidence. 2For gestational age. 3Also significant for subgroup born vaginally.
SE-D: depressed, treated w/ SSRI. DE: depressed, not treated w/ medication.
Oberlander TF et al. Arch Gen Psychiatry 2006;63:898-906.
Gestational age, wk: 38.8 (SE-D) vs. 39.1 (DE) vs. 39.2 (Nonexposed)
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Outcome Differences, SE-D – DE
Unmatched Propensity score matched
Difference P-value Difference P-value
C-section1 0.03 0.01 -0.009 0.69
Birth weight, g -32 0.05 10 0.72
Gestational age, wk -0.35 <0.001 -0.14 0.18
Preterm birth1 0.02 <0.001 0.007 0.61
Birth weight <10th percentile2 0.005 0.51 0.033 0.02
Length of hospital stay, d 0.43 0.007 0.055 0.83
Hospital stay >3 d 0.05 <0.001 0.037 0.07
Respiratory distress1,3 0.063 <0.001 0.044 0.006
Feeding problems1 0.015 0.002 0.011 0.28
Jaundice1 0.019 0.01 0.01 0.45
Convulsions1 0.0005 0.64 0.00077 0.30
1Incidence. 2For gestational age. 3Also significant for subgroup born vaginally.
SE-D: depressed, treated w/ SSRI. DE: depressed, not treated w/ medication.
Oberlander TF et al. Arch Gen Psychiatry 2006;63:898-906.
Treated vs. Untreated Depression: Propensity Score Matching
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Treated vs. Untreated Depression:
Prospective Data
• Study 1: increased risk of lower gestational age and preterm birth with prenatal antidepressant use but not with untreated depression
– Natural design; N=90; treated vs. untreated vs. control; comparable levels of depression in both treated and untreated groups
• Study 2: increased risk of preterm birth for both prenatal antidepressant use and untreated depression
– Natural design; N=238; treated vs. untreated vs. control; lower depression levels in treated group
Suri R et al. Am J Psychiatry 2007;164:1206-13;
Wisner KL et al. Am J Psychiatry 2009;166:557-66.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Why Is it So Hard to Interpret
Study Results?
• Different methodologies, each with limitations
– Retrospective case-control: recall bias, high
nonresponse rate
– Prospective interview: small sample size
– Drug registry: unclear if patients actually took the drug
as prescribed
• Untreated disorder as a confounding factor
– Carries risks as well
– Severity may be related to medication use
– Drugs may be used for different disorders
Byatt N et al. Acta Psychiatr Scand 2013;127:94-114.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Antidepressants During Pregnancy:
Summary
• Possible small absolute risk of major
malformations
• Possible small absolute risk of PPHN
• 20–30% rate of PNAS in exposed infants
• Unclear long-term neurodevelopmental effects
• Possible increased risk of lower gestational age
(clinical significance?) and preterm birth
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Preconception Planning for Patients on
an Antidepressant: Guidelines Moderate to severe symptoms?
No Yes Consider period of stability before
attempting to conceive
Started antidepressant <6 months ago?
No Yes Consider period of stability before
attempting to conceive
Recurrent episodes of MDD?
No Yes Previously responded to psychotherapy?
Patient may be eligible for a trial off
medication with referral for
psychotherapy, unless she wants to
continue
No Yes
Consider continuation unless
patient wants to discontinue
Yonkers KA et al. Obstet Gynecol 2009;114:703-13.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Untreated Pregnant Patients With a
Current MDE: Guidelines
Patient willing to consider
pharmacotherapy?
No Yes Treated with psychotherapy in the past?
Patient may be eligible for psychotherapy
alone No Yes
Failed to respond to psychotherapy?
No Yes
Consider treatment with an
antidepressant, assuming patient
assessment and history do not reveal
evidence of bipolar disorder
Yonkers KA et al. Obstet Gynecol 2009;114:703-13.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Pregnant Patients on an Antidepressant:
Guidelines Patient considering discontinuing pharmacotherapy?
No Yes
Continue antidepressant; monitor Treated with psychotherapy in the past?
No Yes
Does the patient have current
moderate to severe symptoms?
Failed to respond or relapsed with
psychotherapy in the past?
No Yes No Yes
Previously relapsed after
stopping antidepressant?
Consider psychotherapy;
reevaluate medication need
Continue antidepressant;
monitor
No Yes
Consider taper;
monitor Yonkers KA et al. Obstet Gynecol 2009;114:703-13.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
FDA Use-in-Pregnancy Categories for
Antidepressants (for What They're Worth)
B C D
maprotiline
amitriptyline
amoxapine
bupropion
citalopram
clomipramine
desipramine
desvenlafaxine
doxepin
duloxetine
escitalopram
fluoxetine
fluvoxamine
isocarboxazid
milnacipran
mirtazapine
nefazodone
phenelzine
protriptyline
selegiline
sertraline
tranylcypromine
trazodone
trimipramine
venlafaxine
vilazodone
imipramine
nortriptyline
paroxetine
Preferred / Most Data:
fluoxetine (not during
lactation)
sertraline
paroxetine
citalopram
Sie SD et al. Arch Dis Child: Fetal Neonatal Ed 2012;97:F472-6;
Byatt N et al. Acta Psychiatr Scand 2013;127:94-114.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Depression Treatment Guidelines
• SSRIs are generally considered first-line in pregnancy
• Strongly consider an antidepressant that the woman is currently responding to or has responded to in the past to avoid unnecessary exposures during pregnancy
• Use lowest possible dose, but avoid undertreatment (could lead to dual exposure of drug and depression)
• Maximize non-medication evidence-based treatments
• Avoid polypharmacy unless it is clearly indicated
• Tapering antidepressants in the third trimester has not been shown to decrease the incidence of postnatal adaptation syndrome or improve infant outcomes*
Byatt N et al. Acta Psychiatr Scand 2013;127:94-114;
*Warburton W et al. Acta Psychiatr Scand 2010;121(6):471-9.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Shared Decision Making
• Provide the patient with the information needed
to make an informed decision
• Involve the family (father, grandparents)
• Ensure proper communication with other care
providers
• Confirm that the patient has a support system
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If a Patient Chooses to Discontinue Her
Antidepressant: General Management
• Advise to resume antidepressant treatment
shortly after delivery in order to mitigate the risk
of postpartum depression
• Advise to report the onset of any depression-
related symptoms
• Schedule follow-up appointment
• Communicate with the OBGYN
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
If a Patient Chooses to Discontinue Her
Antidepressant: "Stimulating" Treatments
Treatment Evidence in Pregnancy or Postpartum
Psychotherapy 1 positive randomized trial with IPT in postpartum depression1
1 positive open-label trial of partner-assisted IPT in perinatal and
postpartum depression2
Exercise 1 positive randomized study (N=80) in pregnant women with no
history of depression3
Bright light
therapy
1 positive small open-label trial in perinatal depression4
1 positive small randomized trial in perinatal depression5
1 negative small randomized trial in perinatal depression6
1. O'Hara MW et al. Arch Gen Psychiatry 2000;57:1039-45.
2. Brandon AR et al. Arch Womens Ment Health 2012;15(6):469-80.
3. Robledo-Colonia AF et al. J Physiother 2012;58(1):9-15.
4. Oren DA et al. Am J Psychiatry 2002;159:666-9.
5. Epperson CN et al. J Clin Psychiatry 2004;65:421-5.
6. Wirz-Justice A et al. J Clin Psychiatry 2011;72(7):986-93.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
If a Patient Chooses to Discontinue Her
Antidepressant: "Stimulating" Treatments
Treatment Evidence in Pregnancy or Postpartum
rTMS Positive published case reports1
1 positive small open-label trial2
ECT Positive published case reports3-5
Acupuncture 1 positive randomized trial (N=150) in perinatal depression7
1 small negative trial in postpartum depression8
1. Richards EM, Payne JL. CNS Spectrums 2013;Epub ahead of print.
2. Kim DR et al. J Womens Health (Larchmont) 2011;20(2):255-61.
3. O'Reardon JP et al. J ECT 2011;27:e23-6.
4. Anderson EL, Reti M. Psychosom Med 2009;71(2):235-42.
5. Gahr M et al. Pharmacopsychiatry 2012;45(2):79-80.
6. Bulut M et al. J ECT 2013;29(2):e19-20.
7. Manber R et al. Obstet Gynecol 2010;115(3):511-20.
8. Chung KE et al. J Affective Disord 2012;142(1-3):115-21.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
If a Patient Chooses to Discontinue Her
Antidepressant: Herbal Treatments
Treatment Evidence in Pregnancy or Postpartum
Omega-3 1 positive small double-blind trial in perinatal depression1
3 negative double-blind trials (N=118) in perinatal depression2-4
Folate Prospective chart review (N=6809) was negative for perinatal
depression but positive for postpartum depression at 21 months5
Thyroid
hormone
Not studied; subset of patients may have abnormal thyroid levels
Vitamin D Not studied; low vitamin D levels have been associated with
perinatal depression6
1. Su KP et al. J Clin Psychiatry 2008;69(4):644-51.
2. Mozurkewich EL et al. Am J Obstet Gynecol 2013;208(4):313.e1-9.
3. Freeman MP et al. J Affective Disord 2008;110(1-2):142-8.
4. Rees AM et al. Aust N Z J Psychiatry 2008;42(3):199-205.
5. Lewis SJ et al. Eur J Clin Nutr 2012;66(1):97-103.
6. Cassidy-Bushrow AE et al. J Womens Health (Larchmont) 2012;21(11):1189-95.
Copyright © 2013 Neuroscience Education Institute. All rights reserved. Copyright © 2013 Neuroscience Education Institute. All rights reserved.
ANTIDEPRESSANT USE
POSTPARTUM
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Risk Factors for Postpartum Depression
• Previous major depressive episode
• Untreated depression during pregnancy
• Life stress
• Lack of social support
• Family history of postpartum depression
Yonkers KA et al. Obstet Gynecol 2011;117:961-77.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Risks of Postpartum Depression
• Disruption of
maternal–infant
bonding
• Self-harm
• Harm to infant
• Difficult temperament
• Attachment insecurity
• Cognitive delay
• Developmental delay
• Behavioral problems
• Difficulty with social
interaction
Byatt N et al. Acta Psychiatr Scand 2013;127:94-114.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Drug Exposure in Breast Milk
• Exposure can vary between women and within
the same woman at different times
– Drug characteristics (lipid solubility, dose,
metabolism)
– Genetic influence (enzyme activity of mother/child)
– Timing of feeding vs. medication ingestion
Yonkers KA et al. Obstet Gynecol 2011;117:961-77;
Sie SD et al. Arch Dis Child: Fetal Neonatal Ed 2012;97:F472-6.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Antidepressants and Lactation Drug (~Descending
Order of Available Data)
Relative Infant
Dose (%)*
Relative Infant Plasma
Concentration (%)**
fluoxetine 6.5–11 up to 80
sertraline 0.5–3 --
paroxetine 0.5–3 --
citalopram 3–10 up to 10
fluvoxamine <2 --
venlafaxine 6–9 up to 30
escitalopram 3–6 <4
mirtazapine 0.5–3 <1
bupropion 2 --
duloxetine <1 --
desvenlafaxine 5.5–8.1 --
Sie SD et al. Arch Dis Child: Fetal Neonatal Ed 2012;97:F472-6; Chad L et al. Can Fam Physician
2013;59:633-4; Berle JO, Spiqset O. Curr Womens Health Rev 2011;7(1):28-34.
*Infant dose (mg/kg/d) divided by maternal dose (mg/kg/d). Value <10% is considered negligible.
**Infant plasma concentration divided by maternal plasma concentration OR by what is considered a low
therapeutic adult concentration.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Antidepressant Use During Pregnancy
and Lactation
ACOG Practice Bulletin. Obstet Gynecol 2008;111(4):1001-20.
L1
(safest)
L2
(safer)
L3
(moderately
safe)
L4
(possibly
hazardous)
L5
(contra-
indicated)
amitriptyline
amoxapine
clomipramine
desipramine
fluvoxamine
imipramine
nortriptyline
paroxetine
sertraline
trazodone
bupropion
citalopram
escitalopram
fluoxetine*
maprotiline
mirtazapine
venlafaxine
nefazodone doxepin
*Neonates only; L2 in older infants.
Categories were not identified for desvenlafaxine, duloxetine, isocarboxazid,
milnacipran, phenelzine, protriptyline, selegiline, tranylcypromine, or trimipramine.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Breastfeeding Treatment Guidelines
Generally preferred
• Sertraline and paroxetine
– Most data
– Negligible relative infant
doses/concentrations
Generally not preferred
• Fluoxetine, venlafaxine,
and citalopram
– Highest infant plasma
concentrations (flu, ven)
– Case reports of possible
adverse effects (flu, cit)
After 3–6 months of age, the capacity to metabolize drugs is
matured, and measurable infant plasma levels are not expected
(Metabolic capacity takes longer to mature in preterm infants)
Sie SD et al. Arch Dis Child: Fetal Neonatal Ed 2012;97:F472-6; Chad L et al. Can Fam Physician
2013;59:633-4; Berle JO, Spiqset O. Curr Womens Health Rev 2011;7(1):28-34.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Breastfeeding Treatment Guidelines
(cont.)
• Generally not necessary to recommend that women needing antidepressants abstain from breastfeeding
• Although some agents are less preferred, they can be considered in women who took them during pregnancy or have had previous effectiveness with them
• Often recommended to take the medication immediately after breastfeeding and prior to the infant's sleep time in order to minimize exposure to peak drug concentrations
– Likely only reduces infant drug intake to a small extent
• No benefit of "pump and dump"
• Infants should be monitored for adverse effects, such as sedation, irritability, or change in sleep/feeding pattern
Berle JO, Spiqset O. Curr Womens Health Rev 2011;7(1):28-34.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
If a Patient Does Not Want to Take
Medication While Breastfeeding
• "Breast is best"; however, the risks of untreated
postpartum depression may well outweigh the
benefits of breastfeeding
• Can consider nonpharmacological treatment
• If nonpharmacological treatment is unavailable
or considered insufficient, encourage bottle
feeding over treatment discontinuation
• Support the mother in her decision and monitor
her carefully
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Summary
• Existing data suggest that the benefits of
antidepressant treatment during pregnancy and
postpartum may outweigh the risks
• Breastfeeding does not need to be discontinued if
antidepressants are used postpartum
• Whether or not to treat with antidepressants should
be a shared decision between a clinician and an
informed patient
• Ultimately, the decision belongs to the patient;
support her as an ally and offer alternative treatment
suggestions if needed
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
I feel competent managing patients with depression
throughout a pregnancy and postpartum, or who
are breastfeeding.
1. 1 (strongly disagree)
2. 2
3. 3
4. 4
5. 5 (strongly agree)
Post-Poll Question
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
The labels for antidepressants (SSRIs in particular)
include several warning statements about possible
adverse effects of use during pregnancy. Which of the
following has the most evidence suggesting an
increased risk with antidepressant use during
pregnancy?
1. First trimester cardiac malformations
2. Persistent pulmonary hypertension of the newborn
(PPHN)
3. Postnatal adaptation syndrome (PNAS)
4. Long-term neurodevelopmental abnormalities
Posttest Question 1
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
A 26-year-old woman with a history of major depression has been
maintained on an SSRI for the last 2 years. She has just learned
that she is pregnant and is concerned that the antidepressant may
harm her baby. For most patients, the evidence to date suggests
which risk–benefit analysis for the use of antidepressants during
pregnancy and breastfeeding?
1. Antidepressants can be continued during pregnancy and
breastfeeding
2. Antidepressants can be continued during pregnancy but should
be discontinued during breastfeeding
3. Antidepressants should be discontinued during pregnancy but
can be reinstated during breastfeeding
4. Antidepressants should not be used during pregnancy or
breastfeeding
Posttest Question 2