Mother May I? Managing Mental Illness During Pregnancy

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


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


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


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


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


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


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


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


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.


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


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.


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.


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


Absolute

risk

appears

small



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


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.


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


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.


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?


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


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.


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




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


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


# Studies Not Showing


12 4



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.


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.



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


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


Time to Depression Relapse for Medication

Reintroduction vs. No Reintroduction

Cohen LS et al. JAMA 2006;295(5):499-507.


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



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


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)


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


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.


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



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


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.


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



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.


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;



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.


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


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



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.



Antidepressant: "Stimulating" Treatments


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.



Antidepressant: Herbal Treatments


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.


Risk Factors for Postpartum Depression

• Previous major depressive episode

• Untreated depression during pregnancy

• Life stress

• Lack of social support

• Family history of postpartum depression



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



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.


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.



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.


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.


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.


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


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


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


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


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

Mother May I? Managing Mental Illness During Pregnancy

Documents

Transcript of Mother May I? Managing Mental Illness During Pregnancy