Depression in Pregnancy and the Post-Partum

Ali Al-Ibrahim MFM Fellow

Myth Busters

Pregnancy is a time of emotional well-being Category B is a safe category in pregnancy There is a specific algorithm for the treatment of pregnant patients It is best to stop psychotropic medications prior to conception It is best to taper psychotropic medications prior to delivery

MDD in pregnancy

10-16% of women have major depression during pregnancy Associated with problems for both mother and fetus When emerges in pregnancy, is frequently overlooked Pregnancy is neither protective, nor exacerbating for depressive disorders Under-recognized and under-treated in primary care settings

Cohen L, Nonacs R (editors): Mood and Anxiety Disorders During Pregnancy and Postpartum (Review of Psychiatry Series, Vol 24, Number 4). Washington, DC, APPI, 2005

PERCENTAGE OF MOTHERS WITH SEVERE DEPRESSION WHO DID NOT TALK TO DOCTOR OR COUNSELOR

100 90 80 70 60 50 40 30 20 10 0

100 79.9 72.2 57.5 78.3 73.1

White

African American

Hispanics

Asian

Pacific Islander

Native American

Antidepressant Use in Pregnancy

Recent studies estimate up to 9% of pregnant women may take an SSRI during pregnancy Several studies have also shown an increase in antidepressant use SSRIs accounted for the largest increase

A Multisite Retrospective Study

118,935 deliveries 2001-2005, 6.6% women took antidepressants Antidepressant use increased from 2% deliveries in 1996 to 7.6% deliveries in 2005 SSRI use increased from 1.5% in 1996 to 6.4% in 2004
Andrade S et al. Use of antidepressant medications during pregnancy: a multisite study. American Journal of Obstetrics and Gynecology. Feb. 2008

Why is this important?

All women of childbearing years are potentially pregnant until proven otherwise Approximately 50% pregnancies are unplanned 10-16% women have major depression during pregnancy Risk benefit analysis ideally prior to conception, every medication change!

Weighing the Risks and Benefits

Risk of untreated mental illness Risk of relapse of psychiatric illness Effects of psychiatric illness on the fetus Teratogenicity of psychotropic medications Long term behavioral effects Incomplete reproductive safety data for medications

Risk of Untreated Psychiatric Illness in Pregnancy

Maternal Depression may cause:

Preterm birth, low birth-weight, smaller head circumference, and lower Apgar scores

Contribute to poor self-care, inattention to prenatal care Women are more likely to smoke, use alcohol or illicit drugs Children of depressed mothers are more likely to have behavioral problems, delays in cognitive, motor and emotional development Risk for suicide

Nonacs R, Viguera A, Cohen L. Psychiatric Aspects of Pregnancy. Womens Mental Health, a Comprehensive Textbook. Ed. Susan Kornstein and Anita Clayton. New York, NY, 2002.

Anxiety and Stress in Pregnancy

Lead to poor outcomes Increase cortisol and adrenocorticotropic hormone levels May be associated with preeclampsia May reduce uteroplacental blood-flow Antenatal anxiety predicts postpartum anxiety and depression

Cohen L, Nonacs R (editors): Mood and Anxiety Disorders During Pregnancy and Postpartum (Review of Psychiatry Series, Vol. 24, Number 4). Washington, DC, APPI, 2005 Heron J, O;Connor T et al. The course of anxiety and depression through pregnancy and the postpartum in a community sample. J. Affect. Disord 80:65-73,2004.

Depression Relapse in Pregnancy: Cohen et al. 2006:

43% of the women experienced relapse during pregnancy 26% who maintained medication relapsed

68% who discontinued medication relapsed

Cohen L, Altshuler L, Harlow B et al. Relapse of Major Depression During Pregnancy in Women Who Maintain or Discontinue Antidepressant Treatment. JAMA Vol 295 (5),: 499-507, 2006.

Risks Associated with Medications in Pregnancy

Pregnancy loss or miscarriage Organ malformation or teratogenesis Neonatal toxicity or withdrawal syndromes Long-term neurobehavioral sequelae

Organogenesis

Weighing and Presenting the Evidence

There is no such thing as ZERO risk There is no specific algorithm The goal is to minimize fetal medication exposure, and maximize mental health Even experts vary on interpretation of the current evidence!

SSRIs in Pregnancy

No major teratogenic risk associated with SSRI use Possible increase in cardiac defects with first trimester exposure to paroxetine Adverse perinatal outcomes: conflicting data Persistent pulmonary hypertension Possible increase in spontaneous abortion No significant developmental delay in children

Cohen L. Treatment of Bipolar Disorder During Pregnancy. J. Clinical Psychiatry 68 (9), 2007: 4-9.

Late 3 trimester exposure

rd

Neonatal Behavioral Syndrome Symptoms include:

Jitteriness Tachypnea Tremulousness Hypertonia Restlessness

Difficult to differentiate reported adverse outcomes related to:

Antidepressant exposure Antidepressant withdrawal Maternal depression and anxiety

SSRIs and Persistent Pulmonary Hypertension

Cohort Study: SSRIs in late pregnancy may be a risk factor for PPHN (Chambers et al 1996) Case-Control Study: (Chambers et al 2006)
14 infants were exposed to an SSRI after the 20th week of gestation Retrospective design Absolute risk: 7/1000 women Based on this study, in April 2006 the FDA required a label change to include SSRIs increasing the risk for PPHN

Chambers C, Hernandez-Diaz S, Van-Marter L et al. Selective Serotonin-Reuptake Inhibitors and Risk of Persistent Pulmonary Hypertension of the Newborn. N Engl J Med. Vol 354:6 579-587, February 9, 2006.

Paxil and Cardiac Defects

Multiple studies show no increased risk of cardiac defects with Paxil or other antidepressants Meta-analysis (Koren et al. 2007)

Increased risk for cardiac malformation Women using antidepressants had higher numbers of echocardiograms, amniocentesis and ultrasounds Women on paroxetine used the drug for anxiety and panic

1,174 unpublished cases and 2,061 cases from published database studies T, Koren rate of cardiovascular defect falls within the Bar-Oz, Einarson The G et al. Clinical Therapeutics. 2007: 29: 918-926. normal rate April, 2008 Einarson A, Pistelli A, Koren G. AJP. 1008: 1-4.in the general population

Epidemiologic Study (Koren et al. 2008)

CATEGORY INTERPRETATION
A B

FDA Categories

Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities to the fetus in any trimester of pregnancy. Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women. OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.

Animal studies have shown an adverse effect and there are no adequate and wellcontrolled studies in pregnant women. OR No animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women. Adequate well-controlled or observational studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective.

Adequate well-controlled or observational studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities or risks.

The use of the product is contraindicated in women who are or may become pregnant.

Other Antidepressants

Venlafaxine Trazodone Mirtazapine Duloxetine Bupropion MAOI inhibitors are avoided in pregnancy

Tricyclic Antidepressants

No major risk for malformations Desipramine and nortriptyline preferred - less anticholinergic activity Perinatal syndromes described in infants

Anticholinergic effects are transient (bowel obstruction, urinary retention)

Withdrawal Syndrome No long-term neurobehavioral effects

Medication Reduction or Discontinuation Prior To Delivery

Adverse effects on the fetus:

Hypotonia Neonatal withdrawal syndromes Neonatal apnea Temperature dysregulation

But rare, temporary, treatable, and reversible Higher risk of relapse in pregnancy and post-partum

Other Treatment Options

Cognitive Behavioral Therapy Interpersonal Therapy Group Therapy Light Therapy

Electroconvulsive Therapy

Safety well documented over 50 years Organ Dysgenesis

Occasional reports of malformations but no direct causal link to ECT

Intrauterine Growth Defects/Neonatal Toxicity

None Few case reports - developmental delays or MR No direct causal link to ECT

Neurobehavioral Teratogenicity

Recommendations for Antidepressant Treatment in Pregnant Women

Psychotherapy is first line for mildmoderate depression Psychotherapy + antidepressant recommended for moderate to severe depression Individualized risk-benefit analysis No hx of antidepressant treatment: SSRI antidepressant considered first-line Successful history of antidepressant treatment: data should be reviewed with Altshuler L, Cohen, L, Moline M et al. Treatment of Depression in Women: A Summary of the Expert Consensus Guidelines. Journal of Psychiatric Press: 185-208, May, 2001. mom, and considered first line

Recommendations continued

Altshuler L, Cohen, L, Moline M et al. Treatment of Depression in Women: A Summary of the Expert Consensus Guidelines. Journal of Psychiatric Press: 185-208, May, 2001

ECT for psychotic depression Review all risks and benefits of treatment Moms should be monitored carefully for increased depression, mania or psychosis Dosages may need to be adjusted Goal is monotherapy and minimal effective dosage

Postpartum Depression versus Postpartum Blues

Disorder Incidenc Time Clinical e Course Features (%) 75-85 10
1st PP week- 2 weeks 1st pp month Mood instability, tearfulness, anxiety, insomnia

Postpartum Blues Postpartum Depression Postpartum Psychosis

0.1-0.2 1st pp month

Depressed mood, guilt, fear of harm coming to baby, obsessional features Disorientation, confusion, delusions, hallucinations, rapid

Risk Factors for Postpartum Depression

Previous history of MDD- 24% risk Depression during pregnancy- 35% Previous postpartum depression-50% Stressful life events Marital dissatisfaction Demographic variables may be weak contributors Hormonal fluctuations

Burt, V. Hendrick, V. Clinical manual of Womens Mental Health. Arlington, VA 2005.

Recommendations for Screening

Edinburgh Postnatal Depression Scale PP Depression Scale Responsiveness of mom and baby Sleep patterns Weight loss or gain Assess for fears of infant harm

Treatment of Postpartum Depression in Breastfeeding Women

Mild to moderate depression: first line is PSYCHOTHERAPY Moderate to severe depression: antidepressant + psychotherapy Clinical point:
No medication is FDA approved for breastfeeding No antidepressant has proven safer or more effective than another

Antidepressants and Lactation

American Academy of Pediatrics national immunization survey 2002:

More than two-thirds of breast-feeding mothers with depression are likely to start breastfeeding

The risk benefit assessment for breast feeding women should include:

Known risk to the baby of untreated depression Efficacy of antidepressant medication Pearlstein, Teri. Perinatal Depression: Treatment options and Dilemmas. Journal of Psychiatry and for PPD Neurosciences; 33(4):302-18, 2007.

Individualized Risk Benefit Analysis Plan

Risk of Untreated PPD Benefits of Treatment Previous Tx Of Depression

Risk of Antidepressant Treatment Target Symptoms

Risk of Breastfeeding

Infant Serum Levels

Maternal Wishes

SSRIs and Lactation

Paroxetine and Sertraline- 1st line

Less than 10% maternal level Exceeded 10% maternal level (22% cases) Exceeded 10% maternal level (17% cases) Few case reports

Fluoxetine

Citalopram

Escitalopram and Fluvoxamine

Academy of Breastfeeding Medicine Protocol Committee Clinical Protocol #18: Use of Antidepressants in Nursing Mothers. Breastfeeding Medicine. VOl 3. (1), 2008.

Tricyclics, Heterocyclics, and Lactation

Nortriptyline- undetectable in infant serum

Growing evidence that other tricyclics appear to be safe

Doxepin- cautioned due to hypotonia, poor feeding Mirtazapine- no adverse effects reported Bupropion SNRIs Trazodone- infant levels less than 10% MAOI inhibitors- discontinue

Menon, S. Psychotropic Medication during Pregnancy and Lactation. Arch. Gynecol. Obstet. 277: 1-13, 2008.

Complementary and Alternative Medications for Perinatal Depression

Omega-3-fatty acids: general data support use in pregnancy and postpartum S-adenosyl-methionine: Some efficacy in reducing depression Folate: some evidence to support augmentation for depression St. Johns Wort- some evidence of efficacy- possible drug interactions

Freeman, M. Complementary and Alternative Medicine for Perinatal Depression. Journal of Affective Disorders, 2008.

CAM continued

Bright light therapy: evidence supports potential use in perinatal and postpartum Acupuncture: caution advised in pregnant women Massage: some efficacy in pregnancy Exercise: appears to have antidepressant effects

Recommendations for Antidepressant Treatment in Lactating Women

Individualized risk-benefit analysis Psychotherapy

Mild to moderate depression Moderate to severe depression Paroxetine or Sertraline

Psychotherapy + antidepressant

No prior antidepressant:

Prior successful antidepressant treatment

Academy of Breastfeeding Medicine Protocol Committee Clinical Protocol #18: Use of Antidepressants in Nursing Mothers. Breastfeeding Medicine. VOl 3. (1), 2008.

Discuss data with mom; consider as first

Recommendations Continued

Review all risks and benefits of treatment Monitor carefully for increased depression, mania, or psychosis Evaluate infants prior to and after starting a new medication Strategies to decrease infant exposure: not evidence-based

Altshuler L, Cohen, L, Moline M et al. Treatment of Depression in Women: A Summary of the Expert Consensus Guidelines. Journal of Psychiatric Press: 185-208, May, 2001

Conclusions

Every female patient of childbearing years is potentially pregnant! Ideally, decisions about psychotropic medications should be made prior to conception Consider non-pharmacologic

Conclusions

Risk-benefit analysis Minimize medication number and dose Document, document, document! In all cases, optimizing the mothers health and ability to parent should be considered crucial for the developing child

Thanks for coming!! Questions?

ABM Clinical Protocol #18: Use of Antidepressants in Nursing Mothers. Breastfeeding Medicine. Andrade S et al.2008. VOl 3. (1), Use of antidepressant medications during pregnancy: a multisite study. American Journal of Obstetrics and Gynecology.
Feb. 2008 Altshuler et al. Pharmacological Management of psychiatric illness in pregnancy: dilemmas and guidelines. Am J. Psychiatry 1996; 153: 592-606. Bar-Oz B. Einarson T, Einarson A. et al. Paroxetine and Congenital Malformations: Meta-Analysis and Considerations of Potential Confounding Factors. Clinical Therapeutics, Vol 29(5)918-926, 2007. Bupropion Pregnancy Registry Interim Report September 1997 through 31 August 2007 Issued: December 2007 Glaxo Smith Kline Burt, V. Hendrick, V. Clinical manual of Womens Mental Health. Arlington, VA 2005. CDC: Births: Preliminary Data 2006; National Vital Statistics Report. Volume 57, Number 7, December 2007. Chambers C, Johnson K, Dick, L et al. Birth Outcomes in Pregnant Women Taking Fluoxetine. N Engl J Med 335:1010-1015, 1996. Chambers C, Hernandez-Diaz S, Van-Marter L et al. Selective Serotonin-Reuptake Inhibitors and Risk of Persistent Pulmonary Hypertension of the Newborn. N Engl J Med. Vol 354:6 579-587, February 9, 2006. Cohen L. Treatment of Bipolar Disorder During Pregnancy. J. Clinical Psychiatry 68 (9), 2007: 4-9. Cohen L, Nonacs R (editors): Mood and Anxiety Disorders During Pregnancy and Postpartum (Review of Psychiatry Series, Vol 24, Number 4). Washington, DC, APPI, 2005 Cohen L, Altshuler L, Harlow B et al. Relapse of Major Depression During Pregnancy in Women Who Maintain or Discontinue Antidepressant Treatment. JAMA Vol 295 (5),: 499-507, 2006. Einarson A, Pistelli A, DeSantis M. et al. Evaluation of the Risk of Congenital cardiovascular Defects Associated with Use of Paroxetine During Pregnancy. Am J Psychiatry in advance- April 1, 2008. Finer, L and Henshaw K. Disparities in Rates of Unintended Pregnancy in the United States, 1994 and 2001. Perspectives on Sexual and Reproductive Health. Vol 38 (2), 90-96, 2006.

References

Freeman M. Antenatal Depression: Navigating the Treatment Dilemmas. Am J Psychiatry Vol 164(8)1162-1165, 2007. Gentile S. Prophylactic Treatment of Bipolar Disorder in Pregnancy and Breastfeeding: Focus on Emerging Mood Stabilizers. Bipolar Disorders. 8:207-220, 2006. Heron J, O;Connor T et al. The course of anxiety and depression through pregnancy and the postpartum in a community sample. J. Affect. Disord 80:65-73,2004. Koren, G. Medication Safety in Pregnancy and Breastfeeding. 2007 Menon, S. Psychotropic Medication during Pregnancy and Lactation. Arch. Gynecol. Obstet. 277: 1-13, 2008. Newport D, Stowe Z et al. Psychiatric Disorders in Pregnancy. Neurologic Clinics Vol 22: 863-893, 2004. Newport D, Viguera A, Nemeroff C et al. Atypical Antipsychotic Administration During Late Pregnancy: Placental Passage and Obstetrical Outcome. Am J Psychiatry, 164:8, 1214-1220 August 2007. Nonacs R, Viguera A, Cohen L. Psychiatric Aspects of Pregnancy. Womens Mental Health, a Comprehensive Textbook. Ed. Susan Kornstein and Anita Clayton. New York, NY, 2002. U.S. Food and Drug Administration. FDA Public Health Advisory,Paroxetine. Available at: http://www.fda.gov/cer/drug/advisory/paroxetine200512.htm. Accessed April 7, 2008 Viguera A, Stowe Z, Cohen C et al. Risk of Recurrence in Women with Bipolar Disorder During Pregnancy: Prospective Study of Mood Stabilizer Discontinuation. Am J Psychiatry. 164:12 December 2007, 1817-1824. Yaeger D., Smith H., Altshuler L. Atypical Antipsychotics in the Treatment of Schizophrenia During Pregnancy and the Postpartum. Am J Psychiatry 163:12, 2064-2070, 2006. Yonkers K, Wisner K, Stowe Z et al. Management of Bipolar Disorder During Pregnancy and the Postpartum Period. Am J Psychiatry Vol 161: 608-620, 2004.