Perinatal Depression:
The Most Common
Complication of Childbirth

Katherine L. Wisner, M.D., M.S.
Director, Women’
Women’s Behavioral HealthCARE
Professor of Psychiatry, Obstetrics and
Reproductive Sciences, Epidemiology and
Women’
Women’s Studies
Western Psychiatric Institute and Clinic
www.womensbehavioralhealth.org
Goals
1.
2.
3.
4.
5.
Define depression
Describe outcomes for depressed women
during pregnancy and after birth
Discuss a riskrisk-benefit model for treatment of
depression during pregnancy
Review outcomes associated with
antidepressant exposure during pregnancy
and lactation
Identify evidenceevidence-based and novel treatments
for childbearingchildbearing-related depression
1. Major Depression
92,000 of 4 million delivered women
exposed to SSRI per year
Over the last two weeks, most of the day nearly
every day, 5 symptoms (one must be mood or
interest):
1. *Depressed
*Depressed mood
2. *Diminished interest/pleasure
3. Weight loss/gain unrelated to dieting
4. Insomnia/hypersomnia
Insomnia/hypersomnia
5. Psychomotor agitation/retardation
6. Fatigue/loss of energy
7. Feelings of worthlessness/guilt
8. Diminished ability to concentrate
9. Recurrent thoughts of death
Kessler et al (1993) Journal of Affective Disorders
2. Outcomes: Stress and
Depression during Pregnancy

Maternal prenatal stress and depression associated
with low infant birth weight and prematurity (Wadhwa et
al, Am J Obstet Gynecol 169:858169:858-865)
865)

Association of maternal depression OR 2.5 (1.1(1.1-5.4),
and anxiety OR 3.2 (1.4(1.4-7.4) with preeclampsia (Kurki
et al 2000; Obstetrics and Gynecology)

Depression Recurrence
during Pregnancy
Significant association: uterine artery resistance index
and Spielberger state/trait anxiety scores (Teixeira et al

1999; British Medical Journal)

Maternal stress first trimester risk of birth defects,
esp Cranial Neural Crest (Hansen, Lancet 356:875356:875-880,
2000)

Recurrence risk for women who either maintained
or discontinued antidepressants proximal to
conception (Cohen et alal- JAMA. 2006;295:4992006;295:499-507)
Significantly more women who discontinued
(44/65, 68%) compared to women who maintained
(21/82, 26%) antidepressant treatment suffered
recurrent MDD.
Most recurrences emerged rapidly (50% in the first
trimester, and 90% by the end of second trimester).
1
Maternal Depression

You say that I’I’m depressed
I wonder if you understand
You’
You’ve never lived, I think
In this GodGod-forsaken land
I always fight to function
I’m fighting to survive
I’m trying desperately to remember
What it’
it’s like to feel alive
You say I’
I’m carrying life inside
How can that really be?
How could life possibly survive
In a nonnon-existent me?
Maternal Mental Illness

Depression and its Concomitants
Affect Multiple Domains of Perinatal
Health
Psychopathology in Children of Mothers
with Mood and Anxiety Disorders

Chronic postpartum depression affects
child development
Increased behavioral disturbances in
boys of depressed mothers (Murray, 1998)
Anxiety during pregnancy doubled the
risk for hyperactivity in 4 year old boys
Increased vulnerability to depression in 5
year old children of depressed mothers
Depression and its Concomitants
Affect Multiple Domains of Perinatal
Health

Choice of feeding methods for infant
Psychosocial relationships are crucial
for support after birth
Marital discord
Interactional partner for infant
Use of health services for infant
Loss of employment/health insurance
Affects maternal role gratification
Associated with negative cognitions and affect in
mother and infant
Increased likelihood that parent will be a less
capable social partner for child
Characterized by poor attachment, less stimulation
for infants, less responsiveness, less “dance”
dance”
Through social learning or modeling, children
acquire cognitions, behaviors, and affect that
resemble that displayed by their parents

Symptoms of Depression=physiological
dysregulation
Appetite Effects
Underweight, Overweight, Nutrition
Cognitive changes; attention to self and
infant safety
Prenatal care compliance
Use of other drugs/smoking
3. RiskRisk-Benefit DecisionDecision-Making for
Depression during Pregnancy:
A Framework

Wisner et al: RiskRisk-benefit decisiondecisionmaking for treatment of depression
during pregnancy. Am J Psych 157:
1933, 2000
Healthy outcomes for mother and baby
are the rule rather than the exception!
2
4. Available Prospective DataApplication to Model

Intrauterine fetal death -No evidence
Major birth defects - No evidence (But
what about paroxetine?
paroxetine? Not published,
retrospective, Swedish Registry, vs entire
populationpopulation- cardiac defect 2% vs 1%; U.S.
claims data, vs. other antidepressants,
cardiac 1.5% vs 1%; all malformations 4
% vs. 2%)
Data from GermanyGermany-paroxetine 3/88
(3.4%) anomalies; controls (4.5%);
RR=.76 (95% CI=.18CI=.18-2.53).

Analysis of gestational weight
gain
Cumulative weight (g)
13000
Maternal fat
Extravascular fluid
Blood
Breasts
Uterus
Amniotic fluid
Placenta
Fetus
9750
6500
3250
0
10
20
30
40
Weeks of gestation
Pregnancy ‘costs’ ~85,000 kcal
Modified from Hytten, 1991
Controlled prospective studies
Drugs=fluoxetine, tricyclics (TCA), and newer
SSRI (paroxetine
(paroxetine,, fluvoxamine,
fluvoxamine, sertraline) as
a group; venlafaxine,
venlafaxine, bupropion and
mirtazepine
Method=outcomes for drugdrug-exposed
compared to nonteratogennonteratogen-exposed controls
Growth Effects: SSRI use,
gestational weight gain and
neonatal low birth weight
Outcome Domains

Wisner et al, JAMA 282:1264282:1264-1269, 1999; ChunChun-FaiFaiChan et al: Am J Obset Gynecol 192:932192:932-936, 2005.

Chambers et al. , NEJM 1996
100 exposed early; 73 late (most through pregnancy)
Increased rate of premature birth for FLX
(14.3% late, 4.1% early, 5.9%, control)
For full term infants, birth weights, p=.04
3589 + 500 g (early)
3392 + 500 g (late)
3556 + 50 g (control)
Mean (SD) total maternal weight gain
• Exposed early: 37.4 (15.4) lb.
• Exposed late: 30.8 (15.4) lb., p=0.01
Institute of Medicine weight gain
recommendations (1990)
Recommended
total weight gain
(assuming 40 wk
gestation)
Recommended
rate of weight
gain in 2nd and 3rd
trimesters
Underweight
(BMI <19.8)
28 – 40 lb.
1.1 lb/week
Normal weight
(BMI 19.8 –
26.0)
25 – 35 lb.
0.9 lb/week
Overweight
(BMI 26.1 –
29.0)
15 – 25 lb.
0.66 lb/week
Obese
(BMI >29.0)
15 lb. lower limit
Determined on an
individual basis
Prepregnancy
BMI (kg/m2)
category
*for singleton gestations; BMI, body mass index (weight (kg) / height (m)2)
3
Antidepressant Use during
Pregnancy (ADUP) Study

Prepregnancy BMI X Depression Status
Naturalistic, longitudinal study (NIMHR01, Wisner PI)
3 groups of women and their offspring followed from
20 wk gestation to 24 months postpartum
1. Women who are being treated by their physicians
with antidepressants (SSRI) for MDD
2. Women with current MDD but without SSRI
exposure
3. Women with no lifetime history of MDD and no
SSRI exposure
4. MDD and SSRI (partial treatment responders)
Healthy
control
(n=109)
MDD +
No SSRI
(n=42)
No MDD,
SSRI +
(n=19)
MDD +,
SSRI +
(n=20)
Mean BMI
25.6
28.3
25.7
27.5
BMI category,%
Underweight
Normal weight
Overweight
Obese
1.8
60.6
17.4
20.2
7.1
33.3
21.4
38.1
5.3
52.6
26.3
15.8
5.0
35.0
30.0
30.0
37.6
59.5
42.1
60.0
Overweight
(BMI>
(BMI>25), %
Prepregnancy BMI Category by
Depression Status
Underweight
Overweight
Outcomes: Neurobehavioral
Normal weight
Obese

36%
2%
20%
6%

19%
59%
No differences in cognitive function, verbal
comprehension, expressive language,
mood, arousability,
arousability, activity levels
distractibility, behavior problems,
temperament (TCA, FLX)
Global outcomes, more detailed
developmental data are forthcoming
24%
34%
Non-depressed
Depressed
Specific Signs Reported to FDA AERS by
Frequency of Occurrence (N=57 Infants)
Neonatal Syndrome

EEG abnormalities
Jerkiness
Hyperreflexia
Respiratory Distress
Yellow= CNS Signs
Shivering
Hypothermia
Red = Neuro/muscular signs
High Pitched Cry
Hypotonia
Blue= GI / Respiratory/ Autonomic signs
Vomiting
Screaming
Trouble breathing
Crying
Posturing
Tachypnea
Seizures
Agitation
Tremor
Trouble feeding
Jitteriness
Hypertonia
Irritability
Poor neonatal adaptation in 31.5% of
infants in latelate-exposed group, 8.9% in
earlyearly-exposure group for fluoxetine
(Chambers et al, NEJM 335:1010335:1010-1015,
1996

Acute effects or withdrawal possible from
any antidepressant; typically these are
transientMoses-Kolko et al,
transient-about 2 weeks (Moses-
JAMA 293:2372293:2372-2382, 2005)
2005)

Restlessness, rigidity, tremor
0
10
20
30
40
Number of Infants with Specific Sign
50
4
Reported Neonatal SSRI
concentrations
Cord Blood
Withdrawal or Toxicity?
Infant Blood
2nd day of life
Infant Blood
2 weeks of
life
Reported Neonatal SSRI
concentrations
Paroxetine
Sertraline
Infant Blood
2nd day of life
↓
30%
Citalopram
↑
15%
↓
38%
↓
52%
↓
83%
Laine et al 2003
Do all SSRIs predispose to
neonatal complications?

Paroxetine
• Most common drug in the case literature
• High variability in onset time (birth–
(birth–5 days postpartum)
• Anticholinergic→
Anticholinergic→ cholinergic overdrive
Cord Blood
↓
60%
Fluoxetine +
Norfluoxetine

Fluoxetine
• 4-fold increase in relative to unexposed newborn
• Increased likelihood of respiratory disturbance
• Develops by 4 hours of life [half[half-life (7 days)]

Sertraline, citalopram, escitalopram,
escitalopram, fluvoxamine
• Make inferences based on pharmacology
Oberlander et al 2002
Persistent Pulmonary
Hypertension of the Newborn
Management: Toxicity
• Taper maternal drug 10 daysdays- 2 weeks prior to EDC
if risk of maternal illness doesn’
doesn’t outweigh risk of
complications
• Mild symptoms: Conservative management
strategies
Frequent small feeds /high calorie if needed
“Five S”
S” of infant calming (Karp): Swaddling,
Shhh,
Shhh, Soft Shaking, Sucking, Swinging
Maternal skin to infant skin contact
• Severe symptoms
What about drug management?

Chambers et al (NEJM 354:579354:579-587, 2006) increased risk of PPHN with SSRI treatment after
20 weeks gestation.
Odds of PPHN from late pregnancy compared to
early or no exposure was 6.1 (95% CI=2.2 -16.8).
Absolute risk = 6 -12/ 1000 births (0.6 to 1.2%);
14 SSRI exposed vs. 6 controls exposed
No increased risk of PPHN for nonserotonergic
drug exposure
No infant deaths is in this study
Case control studies -associations between
exposures and outcomes (esp
(esp for rare diseases).
5
5. Treatment Principles

Psychotherapy
Complex geneticsgenetics-environmental interaction
etiology creates multiple types of intervention
Treat until well, not just “better”
better”
If a single episode, treat for six months after
achieving wellness, longer for 2 episodes;
consider maintenance for 3 or more episodes
Patient choice, treatment availability and
resources are primary considerations

Omega-3 Fatty Acids
New Environmental Approaches

Aerobic Exercise (>
(> 30 minutes of moderate
intensity physical exercise, 3 to 5 days per
week) Dunn et al, Am J Prev Med 2005;28:12005;28:1-8, 2005
Nutritional status; Pregnancy and lactation
as a nutritional challenge. Bodnar and Wisner.
Biol Psych 58:67958:679-685, 2005.

Essential Fatty Acids for Depression
1-2 grams of EFA/day as in AHA
recommendations; Reviews: Freeman et al.
J Clin Psych 67, 2006; Parker
Parker et al, Am J Psych
163:969163:969-978, 2006
Bright Morning Light Therapy

Spinelli MG:
MG: Interpersonal
Psychotherapy for depressed
antepartum women: a pilot study.
study.
Am J Psych 154:1028154:1028-1030, 1997
IPT, an effective form of treatment
for depression, efficacy data for use
during pregnancy
Targets interpersonal distress and
effect on mood
•
•
•
•
•
•
Long chain PUFA
Plant or marine origin
Essential FA – must be derived from diet
Sources: flaxseed, hemp, canola, walnuts (a(alinolenic acid); fish (DHA and EPA)
Rec:
Rec: All adults eat fish > 2 X /week; Mood,
impulseimpulse-control, psychotic disorders 1g
EPA+DHA/day; Supplement may be useful for
persons with mood disorders 11-9 g/day; >3
monitored by physician; APA guideline/review
Freeman et al, J Clin Psych 67:195467:1954-1967, 2006.
Bright AM Light Treatment Pregnancy
Oren et al. Am J Psych 159:666159:666-669, 2002.
Bright Morning Light
Therapy, 10,000 lux
commercial UV blocked
box;
box; pregnancypregnancy-- Epperson et
al. J Clin Psych 65:42165:421-425, 2004;
Oren DA et al. Am J Psych 159:666159:666669, 2002. Golden et al: APA
review and metameta-analysisanalysis- Am J
Psych 162:656162:656-662, 2005

Data support efficacy in
nonnon-seasonal depression:
a nonnon-pharmacologic
somatic RX for
depression
6
More InformationPregnancy

Postpartum
Disorders
Developmental and Reproductive Toxicity:
www.toxnet.nlm.nih.gov (DART databasedatabase-free to
get information on any drug!)
Organization of Teratology Information Specialists
(OTIS) www.otispregnancy.org,
www.otispregnancy.org, (866) 626626-OTIS,
or (866) 626626-6847
MosesMoses-Kolko E et al. Neonatal signs after late in
utero exposure to serontonin reputake inhibitors:
Literature review and implications for clinical
applications. JAMA 2005;293:23722005;293:2372-2383.
Postpartum Psychosis is not
just really bad depression
Postpartum Depression is Not
The Baby Blues

Not a clinical disorder - 50% to 80% of new
mothers, not usually seen by physicians
Anxiety, mood lability,
lability, crying spells
Transient, no pervasive mood disturbance
Gone by day 10 postpartum!
Differentiate from depression by transience
and lowlow-level symptoms; be more
suspicious if she has a history of
depression
Epidemiology of Postpartum
Episodes

Onset in first few weeks postpost-birth;
delusions/hallucinations are bizarre,
cognitive difficulties prominent
Bipolar disorder! Mania or psychotic
depression; use ECT, mood stabilizers
Differentiate from obsessional thoughts
Very high risk for recurrence after later
births; prevention for patients who have
bipolar disorder is good management
Is there a good screening tool?
Edinburgh Postnatal Depression Scale (EPDS)

10 items selfself-report, feelings in previous 7 days
Responses: 0 (low risk) to 3 (high risk)
Developed for postpartum period
Easy to complete (< 3 minutes)
Validated in many populations
Good sensitivity and specificity
Available in 23 languages
Cox JL, et al. Br J Psychiatry 1987; 150:782150:782-86
7
Etiology: Is it my hormones?
EPDS 1010-item selfself-report:
Example questions

I have been able to laugh and see the funny side
of things
0=as much as I could
1=not quite so much now
2=definitely not so much now
3=not at all

I have looked forward with enjoyment to things
I have blamed myself unnecessarily when things
went wrong
The thought of harming myself has occurred to
me.
(Bloch, Am J Psych 2000;157:9242000;157:924-930)
930)

Induced hypogonadism,
hypogonadism, added supraphysiologic
doses of estradiol and progesterone for 8
weeks; withdrew steroids doubledouble-blind model
5/8 women with history of PPD developed
symptoms, 0/8 women with no history
Hormones interact with variable(s)
variable(s) to risk of
depression; but 25% of women who have had
PPD develop it after subsequent births (not all!)
Liability to depression: stressful life events,
genetic factors, prior history of major
depression, neuroticism (Kendler,
Kendler, Am J Psych
1993;150:11391993;150:1139-1148
We can Treat Postpartum
Depression: Psychotherapy

Psychotherapy/Pharmacology
O’Hara (Arch Gen Psych 2000;57:10392000;57:1039-1045)
Interpersonal Psychotherapy, a manualized
therapy, particular focus on role transition, 12
weeks
IPT>Wait list controls, who also responded when
treated
Measures of relationship with partners and
overall function improved

The only placeboplacebo-controlled randomized
clinical drug trial!
Appleby (British Medical Journal 314:932314:932936)
Six sessions psychotherapy (cognitive
behavioral counseling)> 1 session;
Fluoxetine 20mg/day>placebo
Six sessions and fluoxetine similar, not
additive
NTP vs. SERT Randomized
Controlled Trial, no Placebo
NIMH-funded Study
Wisner KL, Hanusa BH, Perel JM, Peindl
KS, Piontek CM, Findling RL, MosesMosesKolko EL. Postpartum depression: A
randomized trial of sertraline vs.
nortriptyline. J Clin Psychopharm 26:35326:353360, 2006.
Intake
S
I1
Continuation
Phase
(Weeks)
Acute Phase (Weeks)
1
2
3
4
5
6
7
8
12→
12→
16
20→
20→
24
A
A
A
A
P
A
P
A
P A
P A
S = Semistructured Screening Interview
I1 = Entry interview; Baseline measures
8 week acute phase parallel design,
6 month continuation phase,
no placebo
A = In-person Assessment
P = Phone Interview
8
Intent to Treat Analyses - Primary Symptom Outcomes at Weeks 4 and 8
Sertraline
Nortriptyline
55
54
%
Week 4
%
Remitted
15
27%
16
30%
Responded
25
46%
30
56%
Week 8
Remitted
25
46%
26
48%
Responded
31
56%
37
69%
Doses of Subjects who Achieved
Remission (wk 8) in NTP vs SERT Trial
SERT,
mg/day,
N=24
% remitted

Response and remission rates did not differ;
At 8 weeks, responders: SERT=56%,
NTP=69%: remitters SERT=46%, NTP=48%
Time to response and remission did not differ
Most women who remitted by week 8 had
response by week 4
Psychosocial functioning improved similarly
The total side effect burden of each drug was
similar
No clinical or demographic variables
differentiated responders
Medications similarly efficacious in women with
nonnon-postpartum depression
100
1 (4%)
12 (50%)
NTP, mg/day,
N=26,
% remitted
125 or 150
200
4 (17%)
7 (29%)
<100
100
125 or 150
15 (58%)
7 (27%)
4 (15%)
*Start with 25 mg of sertraline or 25 mg of nortriptyline;
half of usual starting dose of any antidepressant
Breastfeeding and
Antidepressants
Nortriptyline vs. Sertraline

<100

Data consist of mother and infant serum
levels; some test breastmilk
The most data are available for sertraline,
paroxetine,
paroxetine, fluoxetine; nortriptyline
Usually below limit of quantifiability for sertraline,
paroxetine,
paroxetine, nortriptyline
Adverse effects reported in breastfeeding infants
whose mothers were treated with doxepin,
doxepin,
fluoxetine, citalopram
Breastfeeding: Sertraline
Breastfeeding: Paroxetine
Maternal Dose Range 2525-200 mg/day
Maternal Dose Range 1010-50 mg/day
Author
(N)
Hendrick
(30)
Epperson
(11)
Stowe
(11)
Wisner
(8)
Infant
SERT, NSERT,
Age, wks ng/ml ng/ml
3-60
<1-8
<1-26
8-56
<2.5
<5
4-141
<1-3
<1-10
4-22
<2-3
<2-24
Author
(N)
Infant
Parox,
Age, wks ng/ml
4-42
<0.1
Misri
(24)
Stowe
4-55
(16)
Hendrick 3-26
(16)
<2
<1
9
Breastfeeding: Fluoxetine
Breastfeeding: Nortriptyline
Maternal Dose Range 1010-60 mg/day
Maternal Dose Range 5050-150 mg/day
Author
(N)
Lester
(1)
Brent
(1)
Hendrick
(20)
Infant
Fluox,
Age, wks ng/ml
6
340
NFluox,
ng/ml
208
Author
(N)
Infant
NTP,
Age, wks ng/ml
E-NTP- Z-NTPOH,
OH,
ng/ml
ng/ml
2
3
5-34
ND
61
<1-84
58
57
<1-265
Wisner
(19)
-1-24
<4-16
<1-252
<1-187
Kristenson NB-28
(13)
Breastfeeding and
Antidepressants

<4-17
More Information: Postpartum
Depression-Depression-- Websites
New! NIMHNIMH-funded site (SBIR, Medispin,
Medispin,
Inc) www.MedEdPPD.org (for physicians
and patients, two entries)
Postpartum Support International
www.postpartum.net
Center for Environmental Therapeutics,
www.cet.org,
www.cet.org, for light therapy information
Women’
Women’s Behavioral HealthCARE,
HealthCARE,
www.womensbehavioralhealth.org
Infants over 3 months of age are at low risk for
adverse effects due to maturation of hepatic
enzyme systems
All published data are from fullfull-term infants with
one exception (35 week infantinfant-NTP)
Short term intense behavioral and longlong-term
developmental studies are needed
Infant serum level monitoring not recommended
for healthy newborns (Weissman
(Weissman et al, 2004)

More Information:
Postpartum Depression
More Information:
Postpartum Depression

Weissman et al, Pooled analysis of antidepressant
levels in lactating mothers, breast milk, and nursing
infants. Am J Psych 161(6):1066161(6):1066-78, 2004
MosesMoses-Kolko E et al. Neonatal signs after late in
utero exposure to serontonin reputake inhibitors:
Literature review and implications for clinical
applications. JAMA 2005;293:23722005;293:2372-2383.
Wisner KL et al. Postpartum depression: A
randomized trial of sertraline vs. nortriptyline. J Clin
Psychopharm 26:35326:353-360, 2006.
<4-10

Miller LJ. Postpartum Depression.
JAMA 287:762287:762-765, 2002.
Dr. Miller’
Miller’s sites: www.hfs.illinois.gov/mch
www.psych.uic.edu/clinical/HRSA;
www.psych.uic.edu/clinical/HRSA; 11-800800-573573-6121
Wisner KL et al.. Clinical Practice: Postpartum
depression. NEJM 347:194347:194-199, 2002.
Wisner KL et al. A major public health problem:
Postpartum depression. JAMA 296:2616296:2616-2618, 2006.
MunkMunk-Olsen T. New Parents and Mental Disorders: A
PopulationPopulation-Based Register Study.
JAMA 2006;296:25822006;296:2582-2589
10
Mental Health
is Fundamental to
Health
David Satcher, M.D.
We must prioritize
the mental health
of the mothers of
our next generation!
11