Post on 24-Mar-2020
The Course and Treatment of
Psychiatric Illness During
Pregnancy
Laura F. Petrillo, M.D.Center for Women’s Mental Health
Massachusetts General Hospital
www.womensmentalhealth.org
lpetrillo@mgh.harvard.edu
Major Depression During
Pregnancy
Are pregnant women protected
against relapse or new onset of major
depression?
Time to Relapse in Patients Who
Maintained or Discontinued Antidepressant
3
Cohen LS, et al. JAMA. 2006:295;499-507.
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 12 24 36
Gestational Age
Perc
enta
ge o
f P
atie
nts
Rem
ain
ing W
ell
Maintained (N = 82)
Discontinued (N = 65)
3
Relapse of Major Depression During
Pregnancy
No Relapse Relapse
Medication Status All 1st Trimester 2nd Trimester 3rd Trimester
All Women 115 (57.2) 86 (42.8) 44 (51.2) 31 (36.0) 11 (12.8)
Maintained 61 (74.4) 21 (25.6) 11 (52.4) 9 (45.0) 1 (4.8)
Increased 11 (55.0) 9 (45.0) 7 (77.8) 2 (22.2) --
Decreased 22 (64.7) 12 (35.3) 5 (41.7) 3 (25.0) 4 (33.3)
Discontinued 21 (32.3) 44 (67.7) 21 (47.7) 19 (43.2) 4 (9.1)
Cohen et al. JAMA. 2006.
Relapse of Bipolar Disorder During
Pregnancy
Viguera, et al , Am J Psychiatry, 2007
6
Identification and Treatment of
Antenatal Depression
• Routine screening for antenatal
depression has been uncommon but is
changing
• Identified antenatal depression is
typically untreated or incompletely
treated
• Prevalence of SSRI use during
pregnancy is 3-7%Andrade SE, et al. Am J Obstet Gynecol. 2008;198:194.e1-194.e5.
Marcus SM, Flynn HA. Int J Gynaecol Obstet. 2008;100:248-251.
6
Identification and Treatment of
Antenatal Depression:
Challenges
Challenges regarding management of perinatal
depression are not a function of difficulties in
screening.
Screening is easy; obstacles to treatment are
significant – what happens to identified cases?
Are identified patients treated to euthymia if they
even receive treatment?
8
Treatment of Depression During
Pregnancy: Lessons Learned and Future
Directions
• Focus of concern regarding known and
unknown risks of fetal exposure to
psychiatric medications is increasingly
balanced by data supporting risk of
exposure to disorder, stress and HPA-
axis dysregulation on fetoplacental unit
• Enhanced appreciation for impact of
disorder and chronic stress on long
term behavioral outcomes
9
Relative Impact of Antidepressant
Exposure vs. Depression in
Obstetrical and Neonatal Outcome• Some data support increased rates of
obstetrical complications and poor
neonatal outcome in depressed
pregnant women
• Increased effort to distinguish impact
of depression/anxiety from
medication exposure on obstetrical
and neonatal outcomeSteer RA et al. J Clin Epidemiol. 1992; Yonkers KA, et al. Obstet
Gynecol. 2009.; Warburton et al 2010
Impact of Maternal Depression on
Obstetrical Outcomes
*Center for Epidemiologic Studies Depression Scale
score in upper 10th percentile1 or Beck Depression
Inventory score >212.†<37 wks gestational age; ‡<2.5 kg; §<10th percentile.
0
5
10
15
20
25
30
%
Non-depressed
Depressed*
0
5
10
15
%
Non-depressed
Depressed*
N=3892N=13991
Preterm delivery†
Preterm delivery Low birth weight‡
Small for gestational age§
1. Orr ST, et al. Am J Epidemiol. 2002;156:797-802.
2. Steer RA, et al. J Clin Epidemiol. 1992;45:1093-1099.
11
Treatment of Depression During
Pregnancy: Take Home Message
• Absolute quantification of risk of
fetal exposure is impossible
• No treatment decision is perfect
• Decisions are made with more or
less complete data
Course of Anxiety Disorders
Across Pregnancy: Panic Disorder
• Some studies show increased risk of
new onset panic disorder in postpartum
women
• The course appears variable and
research to date suggests that some
women may be particularly vulnerable
to relapse during pregnancy
Cohen et al.,1994; Cohen LS,et al., 1996. George et al., 1987; Dannon et al., 2006;
Northcott and Stein MB. 1994; Wisner et al., 1996; Ross and McLean, 2006.
Perinatal Posttraumatic Stress
Disorder (PTSD)
• Prevalence among pregnant women -
2.3%-7.7%
• Estimated new onset PTSD - 3.2%
• Childbirth may qualify as traumatic
event in some cases
• PTSD related to childbirth events may
lead to sexual dysfunction, avoidance of
baby, fear of having more childrenRoss and McLean, 2006; Ayers and Pickering, 2001
Risks of Untreated Antenatal Anxiety
• May affect maternal weight gain
• May increase risk for prematurity, low
birth weight
• May increase the risk for substance
abuse
• Increases the risk for postpartum
depressionRoss and McLean, JCP 2006; Rambelli et al., 2009 Meshberg-
Cohen and Svikis, 2007; Meshberg-Cohen and Svikis 2007; Chen
et al., 2010; Lou et al., 1994; Lou et al., 1992; Acs et al., 2006.
15
SSRI Use During Pregnancy
• Recent findings and more data inform the pharmacologic treatment of depression during pregnancy
– Consistent conclusions that the absolute risk of SSRI exposure
in pregnancy is small1-3
– Case-control studies reveal inconsistent data regarding
teratogenic risk of individual SSRIs4-9
• Reproductive safety data on SSRIs exceed what is known about most other medicines used in pregnancy
1 Louik C, et al. N Engl J Med 2007; 2 Einarson TR, Einarson A. Pharmacoepidemiol Drug Saf 2005; 3 Einarson A, et al. Am J Psychiatry 2008; 4 Alwan S, et al. N Engl J Med 2007; 5 Greene MF. N Engl J Med 2007; 6 Hallberg P, Sjoblom V. J Clin Psychopharmacol 2005; 7Wogelius P, et al. Epidemiology 2006; 8 www.gsk.ca/english/docs-pdf/PAXIL_PregnancyDHCPL_E-V4.pdf Dear Healthcare Professional (3/17/08); 9 www.fda.gov/medwatch/safety/2005/Paxil_dearhcp_letter.pdf Dear Healthcare Professional (3/17/08)
15
16
Non-SSRIs During Pregnancy
• More limited reproductive safety data available for
SNRI’s compared to SSRIs, i.e.. venlafaxine,
duloxetine
• Data on bupropion includes growing number of
exposures supporting absence of increased risk for
malformation
http://www.gsk.com/media/paroxetine/ingenix_study.pdf
Chun-Fai-Chan B, Koren G, et al. Am J Obstet Gynecol, March 2005. 192(3).
Cole JA, Modell JG, Haight BR, et al Pharmacoepidemiol Drug Saf. 9 August 2006
Alwan et al , 2010
17
Antidepressant Use During
Pregnancy: Lessons Learned
• Safest antidepressant to use across
pregnancy is the medication that
affords euthymia
• Amount of data distinguishing
antidepressant compounds is very
sparse with respect to teratogenic
risk ** Hernández-Díaz S, et al. Pediatrics. 2007;120:e272-e282.
Kallen , August 2008 ; Pharmacoepidemiol Drug Safety
18
“Poor Neonatal Adaptation” and SSRI
Use During Pregnancy
• Consistent data: Late trimester exposure to
SSRIs is associated with transient irritability,
agitation, jitteriness, and tachypnea ( 25-30%)
Clinical implication: Should women be
treated with antidepressants late in
pregnancy and during labor and delivery
Levinson-Castiel R, et al. Arch Pediatr Adolesc Med. 2006;160:173-176.
Chambers CD, et al. N Engl J Med. 2006;354:579-587.
Chambers, BMJ, 2009
18
Antidepressants During Pregnancy:
Later Pregnancy Considerations
• Risk of persistent pulmonary hypertension of newborn (PPHN) with SSRIs?
• Inconsistent findings over the last 5 years
– FDA communication indicates that previous estimates reflect overestimation
– Other factors may play a role: race, high BMI, delivery by C-section
– If there is an association, risk extremely low
Chambers CD, et al. N Engl J Med. 2006;354:579-587.
Hernández-Díaz S, et al. Pediatrics. 2007;120:e272-e282.
20
Neonatal Distress Syndromes and PPHN:
Clinical Implications
• Data to support recommendations to lower
antidepressant proximate to delivery are
sparse
• Discontinuation of antidepressant during
peripartum period may increase risk for
puerperal illness
21
Antidepressant Treatment During
Pregnancy: Take Home Points
• Safest antidepressant is the medication
that affords euthymia
• Increased effort to distinguish impact of
depression/anxiety from medication
exposure on obstetrical and neonatal
outcome
• No antidepressant is absolutely
contraindicated
• Treatment across peripartum period may
attenuate risk for puerperal relapse of
mood
Risk of Major Depression in the
Postpartum Period
0
10
20
30
40
50
60
No History of
Depression
Past history
major depression
MDD during
pregnancy
Past history
postpartum
depression
Incid
en
ce (
%)
O’Hara MW, et al. J Abnorm Psychol. 1991;100:63-73.
Treatment Considerations for Women
with MDD in Pregnancy
• Depression during pregnancy is strongest predictor
of postpartum depression
• There are known and unknown risks associated with
antidepressant use during pregnancy
• Adverse effects of depression in pregnancy on
patient, infant and families
• Maternal euthymia is the most important
consideration
Benzodiazepine Use in Pregnancy
First trimester exposure may be associated with
increased risk for oral clefts but findings are
inconsistent
Late pregnancy exposure: possible withdrawal,
neonatal sedation, hypotonia, cyanosis
Avoidance in the first trimester, avoidance of
polypharmacy suggested
Dolovich et al, BMJ, 1998.
IPT=interpersonal psychotherapy; CBT=cognitive behavioral therapy.
1. Altshuler LL, et al. Am J Psychiatry. 1996;153:592-606.
2. Miller LJ. Hosp Community Psychiatry. 1994;45:444-450.
3. Wisner K. et al. Am J Psychiatr,y. 2000;157:1933-1940
4. Epperson J Clin Psych. 2004;65:421-5.
Treatment Options During
Pregnancy
• Treatment options
– Psychotherapy (IPT, CBT)
– Antidepressants
• No well-controlled studies in pregnancy
• However, available human data show no increased risk of teratogenesis or neurobehavioral sequelae
– Electroconvulsive therapy
– Light Therapy
Cohen LS, et al. JAMA. 1994;271:146-150. Steer RA, et al. J Clin Epidemiol. 1992;45:1093-1099; Orr ST, et al. Am J Prev Med. 1996;12:459-466; Suppes T, et al. Arch Gen Psychiatry. 1991;48:1082-1088; Faedda GL, et al. Arch Gen Psychiatry. 1993;50:448-55; Baldessarini RJ, et al.J Clin Psychiatry. 1996;57:441-448.
Pharmacologic Treatment of Pregnant Women
with Bipolar Disorder: Weighing Imperfect
Options
• Commonly employed antimanic agents are either known teratogens or have sparse available reproductive safety data
• Risks of untreated psychiatric illness
• Risk of discontinuing maintenance psychotropic medications
Altshuler LL, et al. Am J Psychiatry. 1996;153:592-606.
Cohen LS, Altshuler LL. Annual of drug therapy. Clin North Am.
1997.
Antipsychotic Use during
Pregnancy
Teratogenic risk
– Data support safety of typical
antipsychotics with respect to teratogenicity
– FDA Drug Safety Communication:
Antipsychotic drug labels updated on risk
of abnormal muscle movements and
withdrawal symptoms in newborns
“Antipsychotics in Pregnancy
Risky for Newborns”
• FDA updated labeling on pregnancy section for antipsychotics due to risk of abnormal muscle movements
• The new labeling standards are for older antipsychotic drugs as well as newer ones.
• Based on analysis of the FDA’s Adverse Event Reporting System
• Symptoms: agitation, increased or decreased muscle tone, tremor, sleepiness, respiratory depression, and difficulty in feeding
• ? additional exposures/medical issues
29
Atypical Antipsychotics: Unclear
Teratogenic Risk• Postmarketing surveillance data, case reports
• In 1 prospective study, 151 pregnancy outcomes
- Olanzapine, n = 60
- Risperidone, n = 49
- Quetiapine, n = 36
- Clozapine, n = 6
- No increased risk for major malformations
• Conclusions regarding reproductive safety not
possible with available data, although no signal of
teratogenicity is evident based on limited studies
1. Yaeger D, et al. Am J Psychiatry. 2006;163:2064-2070.
2. McKenna K, et al. J Clin psychiatry. 2005;66:444-449.
29
30
National Pregnancy Registry
for Atypical Antipsychotics
A NEW Research Study at the Massachusetts General
Hospital
Center for Women’s Mental Health
To determine the safety of atypical antipsychotics in
pregnancy for
women and their babies
Participation will involve 3 brief phone interviews over
approximately 8 months
Call Toll-Free:
1-866-961-2388
30
Atypical Antipsychotic Use
during Pregnancy
Consider medical sequelae and impact on pregnancy: weight gain, diabetes, hypertension
Obesity - gestational diabetes, preeclampsia, and c-section
Gestational diabetes – risk factor for diabetes mellitus when nonpregnant
Hypertension – small for gestational age, preterm delivery
0 12 24 36 48 60 720.0
0.2
0.4
0.6
0.8
1.0
Time Off Lithium (Months)
First YearOff Lithium
Time (Months)0 3 6 9 12
0.2
0.4
0.6
0.8
1.0
50% Recurrence
Proportion inRemission
Proportion Remainingin Remission
*Suppes et al. Arch Gen Psychiatry. 1992.
Lithium Use during Pregnancy:Relative Risks and Clinical Dilemmas
LV
RV
TV
RA
Ebstein’s AnomalyRelapse Following Discontinuation
of Lithium in Bipolar Patients*
1 Cohen LS, et al. JAMA. 1994;271:146-150.
Lithium and Pregnancy
• Revised risk based on meta-analysis 1/1000-1/2000 (.05%)1
• Relative risk 10-20 rate in general population (1/20,000)
• Relative vs. absolute risk
Absolute vs. Relative Risk
• Absolute risk– Risk stated without any context
– The probability of something occurring• The likelihood of someone developing lung cancer
• Relative risk or odds ratio – Comparison of different risk levels
– Ratio of incidence of disease in exposed individuals to the incidence of disease in non-exposed individuals
• The likelihood of developing lung cancer if you have ever smoked compared to a nonsmoker
Pregnancy Registries for
Anticonvulsants
• Central Registry of Antiepileptic Drugs and Pregnancy (EURAP)
• North American AED Pregnancy Registry
• U.K. Epilepsy and Pregnancy Registry
• Australian Pregnancy Registry
• Lamotrigine Pregnancy Registry
36
Summary of Findings Across
Pregnancy AED Registries• Valproic acid (VPA) is associated with the highest risk for all
major malformations
– Risk estimates around 10% and higher1
– Risk appears to be dose-dependent (>1000 mg/d); may
be with LTG2,3
– Folic acid supplementation may not be protective
against VPA-associated neural tube defects
• Risk is highest with anticonvulsant polytherapy4,5
• Carbamazepine (CBZ) and LTG are associated with lower
risk than VPA1. Wyszynski DF, et al. Neurology. 2005;64:961-965.
2. Morrow J, et al. J Neurol Neurosurg Psychiatry. 2006;77:193-198.
3. Cunnington M, et al. Epilepsia. 2007;48:1207-1210.
4. Meador KJ, et al. Neurology. 2006;67:407-412.
5. Holmes LB, et al. Arch Neurol. 2004; 61:673-678.
36
37
Lamotrigine (LTG) Monotherapy
Exposure: Risk for Oral Clefts
• Overall risk for major malformations with LTG
approximately 2.7% across several studies1,2
• North American Antiepileptic Pregnancy Registry
showed an increased incidence of a specific
malformation
− Oral clefts: 8.9/1000 vs baseline 0.37/10003
• Finding not corroborated in other registries; further
data needed
• Absolute risk remains small
1. Cunnington M, et al. Neurology. 2005;64:955-960.
2. Meador KJ, et al. Neurology. 2006;67:407-412.
3. Holmes LB, et al. Abstract presented at the 46th Annual Meeting of the Teratology Society. June 24-29, 2006; Tucson, Arizona.
37
Neurobehavioral Teratogenicity
and Valproic Acid
Emerging data suggests that valproic acid
may be associated with cognitive and
developmental adverse effects.
Neurobehavioral risk with LTG unknown
Adab N, et al. J Neurol Neurosurg Psychiatry. 2004;75:1575-1583.
Adab N, et al. J Neurol Neurosurg Psychiatry. 2001;70:15-21.
Vinten J, et al. Neurology. 2005;64:949-954.
Gaily E, et al. Neurology. 2004;62:28-32.
Meader, et al. N Engl J Med. 2009
Cognitive Function in 3 year olds
Following Fetal Exposure to AED’s
IQ Scores of Children Who Were Exposed to Antiepileptic
Drugs In Utero, According to Drug and Dose
Meader, et al. N Engl J Med. 2009
40
• Teratogenic risk and neurobehavioral toxicity of
valproate make its use in reproductive age women
contraindicated
• Risk of PCOS associated with valproate use in
reproductive age women in combination with
neural tube defect risk and behavioral
teratogenicity support this conclusion
Pharmacologic Treatment of Bipolar
Disorder During Pregnancy : Take
Home Messages
Gabapentin
• Lack of data
• One study: 223 women who used gabapentin
in first trimester and 223 controls
• Main indications were pain and epilepsy
• Findings: Increased rates of preterm births
and low birth weight but no increased risk for
birth defects
• More research is needed
Fujii, et al, Neurology, 2013
Clinical Implications
• Pre-pregnancy consultation
• Risk of anomalies discussed with
patient in relation to background risk
and specific drug(s)
• Discuss risks of untreated condition to both
mother and fetus
• Discuss types of prenatal testing available
• Defer pregnancy until disease
control optimal
Treatment of Bipolar Disorder in
Pregnancy:
Mild to Moderate Bipolar Disorder• Gradual taper and discontinuation of antimanic
prophylaxis (lithium, sodium valproate) prior to pregnancy ?
• Discontinuation of mood stabilizer after pregnancy is documented? problematic with sodium valproate
• Reintroduce mood stabilizer as needed or during second trimester
Pharmacologic Treatment of Bipolar
Illness during Pregnancy (continued)
Lithium may be the safest alternative for women
dependent on mood stabilizers
Lithium nonresponders
Consider lamotrigine monotherapy
Consider lamotrigine and typical antipsychotic
Use of atypicals across pregnancy?
Little role for monotherapy with
typical antipsychotics
Severe Bipolar Disorder
During Pregnancy:
Treatment OptionsConsider continuation of mood stabilizer across
pregnancy in women with highly recurrent illness
Frequency of use of atypical antipsychotics demands
better data to inform use during pregnancy
Absolute small risk may be acceptable versus risk of
bipolar relapse during pregnancy and implications for
puerperal relapse of the illness
45
ECT During Pregnancy
• Treatment of choice when expeditious
management is imperative
• Use in delusional depression, mania
• External fetal monitoring,
ultrasonography
• Comprehensive treatment team
Anderson, EL & Reti, IM. Psychosom Med, 2007.
47
www.womensmentalhealth.org
For Further Information
References
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• http://pregnancyregistry.gsk.com/documents/bup_report_final_2008.pdf
50
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