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

• Acs N, Banhidy F, Horvath-Puho E, Czeizel AE. Maternal panic disorder and congenital abnormalities: a population-based case-control study. Birth Defects Res A Clin Mol Teratol 2006;76:253-61.

• Adab N, Jacoby A, Smith D, Chadwick D. Additional educational needs in children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2001;70:15-21.

• Adab N, Kini U, Vinten J, Ayres J, Baker G, Clayton-Smith J, et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004;75:1575-83.

• Altshuler LL, Cohen L, Szuba MP, Burt VK, Gitlin M, Mintz J. Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry 1996;153:592-606.

• Alwan S, Reefhuis J, Botto LD, Rasmussen SA, Correa A, Friedman JM. Maternal use of bupropion and risk for congenital heart defects. American journal of obstetrics and gynecology 2010;203:52 e1-6.

• Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. The New England Journal of Medicine 2007;356:2684-92.

• Anderson EL, Reti IM. ECT in pregnancy: a review of the literature from 1941 to 2007. Psychosom Med 2009;71:235-42.

• Andrade SE, Raebel MA, Brown J, Lane K, Livingston J, Boudreau D, et al. Use of antidepressant medications during pregnancy: a multisite study. American journal of obstetrics and gynecology 2008;198:194 e1-5.

• Ayers S, Pickering AD. Do women get posttraumatic stress disorder as a result of childbirth? A prospective study of incidence. Birth 2001;28:111-8.

• Baldessarini R, Tondo L, Faedda G, Floris G, Suppes T, Rudas N. Effects of rate of discontinuing lithium maintenance treatment in bipolar disorders. J Clin Psychiatry 1996;57:441-8.

• Chambers C. Selective serotonin reuptake inhibitors and congenital malformations. BMJ 2009;339:b3525.• Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, et al. Selective serotonin-reuptake inhibitors and risk of

persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354:579-87.• Chen Y, Lin H, Lee H. Pregnancy outcomes among women with panic disorder - do panic attacks during pregnancy matter? J Affect Disord

2010;120:258-62.• Chun-Fai-Chan B, Koren G, Fayez I, Kalra S, Voyer-Lavigne S, Boshier A, et al. Pregnancy outcome of women exposed to bupropion

during pregnancy: a prospective comparative study. American journal of obstetrics and gynecology 2005;192:932-6.• Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Remnick AM, Loughead A, Vitonis

AF, Stowe ZN. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA.2006; 295(5):499-507.

• Cohen LS, Friedman JM, Jefferson JW, Johnson EM, Weiner ML. A reevaluation of risk of in utero exposure to lithium. JAMA 1994;271:146-50.

• Cohen LS, Sichel DA, Dimmock JA, Rosenbaum JF. Impact of pregnancy on panic disorder: a case series. J Clin Psychiatry 1994;55:284-8.• Cohen LS, Sichel DA, Faraone SV, Robertson LM, Dimmock JA, Rosenbaum JF. Course of panic disorder during pregnancy and the

puerperium: a preliminary study. Biological psychiatry 1996;39:950-4.• Cole JA, Modell JG, Haight BR, Cosmatos IS, Stoler JM, Walker AM. Bupropion in pregnancy and the prevalence of congenital

malformations. Pharmacoepidemiol Drug Saf 2007;16:474-84.

References (Cont.)

• Corral M, Wardrop AA, Zhang H, Grewal AK, Patton S. Morning light therapy for postpartum depression. Arch Womens Ment Health 2007;10:221-4.

• Cunnington M, Ferber S, Quartey G. Effect of Dose on the Frequency of Major Birth Defects Following Fetal Exposure to Lamotrigine Monotherapy in an International Observational Study. Epilepsia 2007.

• Cunnington M, Tennis P. International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology 2005;64:955-60.

• Dannon PN, Iancu I, Lowengrub K, Grunhaus L, Kotler M. Recurrence of panic disorder during pregnancy: a 7-year naturalistic follow-up study. Clin Neuropharmacol 2006;29:132-7.

• Dolovich L, Antonio A, Vaillancourt JR, Power JB, Koren G, Einarson T. Benziodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies. Bmj 1998;317:839-43.

• following gestational exposure to venlafaxine: a multicenter prospective controlled study. Am J Psychiatry 2001;158:1728-30.

• Einarson A, Pistelli A, DeSantis M, Malm H, Paulus WD, Panchaud A, et al. Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy. Am J Psychiatry 2008;165:749-52.

• Einarson TR, Einarson A. Newer antidepressants in pregnancy and rates of major malformations: a meta-analysis of prospective comparative studies. Pharmacoepidemiol Drug Saf 2005;14:823-7.

• Epperson CN, Terman M, Terman JS, Hanusa BH, Oren DA, Peindl KS, et al. Randomized clinical trial of bright light therapy for antepartum depression: preliminary findings. J Clin Psychiatry 2004;65:421-5.

• J, Francomb H, Oke S, Golding J. Cohort study of depressed mood during pregnancy and after childbirth. BMJ 2001; 323:257-60.

• Faedda GL, Tondo L, Baldessarini RJ, Suppes T, Tohen M. Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. Archives of General Psychiatry 1993;50:448-55.

• Fujii H, Goel A, Bernard N, Pistelli A, Yates LM, Stephens S, Han JY, Matsui D, Etwell F, Einarson TR, Koren G, Einarson A. Pregnancy outcomes following gabapentin use: results of a prospective comparative cohort study. Neurology 2013;80:1565-70.

• Gaily E, Kantola-Sorsa E, Hiilesmaa V, Isoaho M, Matila R, Kotila M, et al. Normal intelligence in children with prenatal exposure to carbamazepine. Neurology 2004;62:28-32.

• George DT, Ladenheim JA, Nutt DJ. Effect of pregnancy on panic attacks. Am J Psychiatry 1987;144:1078-9.

• Greene MF. Teratogenicity of SSRIs--serious concern or much ado about little? N Engl J Med 2007;356:2732-3.

• Hallberg P, Sjoblom V. The use of selective serotonin reuptake inhibitors during pregnancy and breast-feeding: a review and clinical aspects. J Clin Psychopharmacol 2005;25:59-73.

• Hernandez-Diaz S, Smith CR, Wyszynski DF, Holmes LB. Risk of major malformations among infants exposed to carbamazepine during pregnancy. Birth Defects Research (Part A) 2007;79:357.

• Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Mitchell AA. Risk factors for persistent pulmonary hypertension of the newborn. Pediatrics 2007;120:e272-82.

• Holmes LB, Wyszynski DF, Baldwin EJ, Habecker E, Glassman LH, Smith C. Increased risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy. In: 46th Annual Meeting of the Teratology Society. Tucson, AZ; June 2006.

• Holmes LB, Wyszynski DF, Lieberman E. The AED (antiepileptic drug) pregnancy registry: a 6-year experience. Archives of Neurology 2004;61:673-8.

• http://pregnancyregistry.gsk.com/documents/bup_report_final_2008.pdf

50

References (Cont.)

• http://www.fda.gov/Drugs/DrugSafety/ucm243903.htm 2011

• Kallen B, Olausson PO. Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf 2008;17:801-6.

• Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med 2006;160:173-6.

• Lou HC, Hansen D, Nordentoft M, Pryds O, Jensen F, Nim J, et al. Prenatal stressors of human life affect fetal brain development. Dev Med Child Neurol 1994;36:826-32.

• Lou HC, Nordentoft M, Jensen F, Pryds O, Nim J, Hemmingsen R. Psychosocial stress and severe prematurity. Lancet 1992;340:54.

• Louik C, Kerr S, Mitchell AA. First-trimester exposure to bupropion and risk of cardiac malformations. Pharmacoepidemiol Drug Saf. 2014.

• Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA. First-trimester use of selective serotonin reuptake inhibitors and the risk of birth defects. The New England Journal of Medicine 2007;356:2675-83.

• Marcus SM, Flynn HA, Blow FC, Barry KL. Depressive symptoms among pregnant women screened in obstetrics settings. J Womens Health. 2003; 12(4):373-80.

• McKenna K, Koren G, Tetelbaum M, Wilton L, Shakir S, Diav-Citrin O, et al. Pregnancy Outcome of Women Using Atypical Antipsychotic Drugs: A Prospective Comparative Study. J Clin Psychiatry 2005;66:444-9.

• Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360:1597-605.

• Meador KJ, Baker GA, Finnell RH, Kalayjian LA, Liporace JD, Loring DW, et al. In utero antiepileptic drug exposure: fetal death and malformations. Neurology 2006;67:407-12.

• Meshberg-Cohen S, Svikis D. Panic disorder, trait anxiety, and alcohol use in pregnant and nonpregnant women. Compr Psychiatry 2007;48:504-10.

• Miller LJ. Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry. 1994; 45(5):444-50.

• Morrow J, Russell A, Guthrie E, Parsons L, Robertson I, Waddell R, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006;77:193-8.

• Northcott CJ, Stein MB. Panic disorder in pregnancy. J Clin Psychiatry 1994;55:539-42.

• O’Hara MW, Schlechte JA, Lewis DA, Varner MW. Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables. J Abnorm Psychol. 1991; 100(1):63-73.

• Miller LJ. Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry. 1994; 45(5):444-50.

• Morrow J, Russell A, Guthrie E, Parsons L, Robertson I, Waddell R, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006;77:193-8.

• Northcott CJ, Stein MB. Panic disorder in pregnancy. J Clin Psychiatry 1994;55:539-42.

• O’Hara MW, Schlechte JA, Lewis DA, Varner MW. Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables. J Abnorm Psychol. 1991; 100(1):63-73.

51

References (Cont.)

• Orr S, Miller C. Maternal depressive symptoms and the risk of poor pregnancy outcome. Review of the literature and preliminary findings. Epidemiologic Reviews 1995;17:165-71.

• Rambelli C, Montagnani MS, Oppo A, Banti S, Borri C, Cortopassi C, et al. Panic disorder as a risk factor for post-partum depression: Results from the Perinatal Depression-Research & Screening Unit (PND-ReScU) study. J Affect Disord 2010;122:139-43.

• Ross LE, McLean LM. Anxiety disorders during pregnancy and the postpartum period: A systematic review. J Clin Psychiatry 2006;67:1285-98.

• Steer RA, Scholl TO, Hediger ML, Fischer RL. Self-reported depression and negative pregnancy outcomes. J Clin Epidemiol 1992;45:1093-9.

• Suppes T, Baldessarini RJ, Faedda GL, Tohen M. Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry 1991;48:1082-8.

• Viguera AC, Nonacs R, Cohen LS, Tondo L, Murray A, Baldessarini RJ. Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. Am J Psychiatry. 2000;157(2):179-84.

• Viguera AC, Whitfield T, Baldessarini RJ, Newport DJ, Stowe Z, Reminick A, et al. Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry 2007;164:1817-24.

• Vinten J, Adab N, Kini U, Gorry J, Gregg J, Baker GA. Neuropsychological effects of exposure to anticonvulsant medication in utero. Neurology 2005;64:949-54.

• Warburton W, Hertzman C, Oberlander TF. A register study of the impact of stopping third trimester selective serotonin reuptake inhibitor exposure on neonatal health. Acta Psychiatr Scand 2010;121:471-9.

• Wisner KL, Peindl KS, Hanusa BH. Effects of childbearing on the natural history of panic disorder with comorbid mood disorder. J Affect Disord 1996;41:173-80.

• Wisner KL, Zarin DA, Holmboe ES, Appelbaum PS, Gelenberg AJ, Leonard HL, Frank E. Risk-benefit decision making for treatment ofdepression during pregnancy. Am J Psychiatry 2000; 157:1933-1940.

• Wogelius P, Norgaard M, Gislum M, Pedersen L, Munk E, Mortensen PB, et al. Maternal Use of Selective Serotonin Reuptake Inhibitors and Risk of Congenital Malformations. Epidemiology 2006;17:701-4.

• www.fda.gov/medwatch/safety/2005/Paxil_dearhcp_letter.pdf Dear Healthcare Professional (3/17/08)

• www.gsk.ca/english/docs-pdf/PAXIL_PregnancyDHCPL_E-V4.pdf Dear Healthcare Professional (3/17/08);

• Wyszynski D, Nambisan M, Surve T, Alsdorf R, Smith C, Holmes L, et al. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005;64:291-5.

• Yaeger D, Smith HG, Altshuler LL. Atypical antipsychotics in the treatment of schizophrenia during pregnancy and the postpartum. Am J Psychiatry 2006;163:2064-70.

• Yonkers KA, Wisner KL, Stewart DE, Oberlander TF, Dell DL, Stotland N, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;114:703-13