Stowe

The Beautiful Minds LuncheonFebruary 13th 2013

‘Women’s Mental Health: Pregnancy through the Postpartum Period'

Zachary N. Stowe, MDDirector, Women’s Mental Health Program

Professor of Psychiatry, Pediatrics, and Gynecology & Obstetrics

University of Arkansas for Medical Sciences

Arkansas Children’s Hospital Research Institute

Acknowledgments

“The Patients and their Families that gave their time, energy, blood, saliva, and long term commitment to furthering our understanding of the impact of neuropsychiatric illnesses during the perinatal period.”

UAMS Women’s Mental Health Program • Zachary N. Stowe, MD• Bettina Knight, RNResearch Coordinators/Assistants• Christian Lynch, MPH• Natalie Morris, BS• Elaine Rudkin, BSAdministration• Nadir Ellison• Jan Waldrip• Summer AlexanderInternal Collaborations• ACHRI

– Transgenerational Biorepository

• Pediatrics– Neurobehavioral Development– Pharmacokinetics/Pharmacogenomics

• Obstetrics and Gynecology– SARA Project– Pet Therapy– Exposure and Outcome

• Psychiatry– Perinatal Opiate Project– Infant/Child Neuroimaging

External CollaborationsEmory University• Stress in Pregnancy

– D. Jeffrey Newport, M.D.

• Anti-Epileptics Drugs in Pregnancy (26 site study)

– K. Meador, M.D.

University of North Carolina• Postpartum International Genetics

Consortium (19 Site Study)– David Rubinow, M.D.– Samantha Meltzer-Brody, MPH, M.D.

State University of New York (SUNY)• Genetics of Attention Deficit Disorder

– Stephen Faraone, PhD (SUNY)

*University of Wisconsin • Maternal Anxiety and Child Neuroendocrine

and Neuroimaging Outcomes– Ned Kalin, M.D.

Age at First Onset of Major Depression

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0-14 15-24 25-34 35-44 45-54 55-64

Age At First Onset (years)

Males

Females

Rat

e P

er 1

00

Weissman et al. JAMA. 1996;276:293.

United States ECA

• Differences in brain structure/function

• Reproductive-related hormonal fluctuations

• Effects of gender-specific socialization

• Lower social status• Ways of coping

Psychosocial Biological

Artifact

• Women more likely to report symptoms and seek treatment

• Possible diagnostic bias

1. Biegon A. J Neurosci 1982;2:199. 2. Adams PW. Lancet 1973;1:897. 3. Price JM Am J Clin Nutr. 1967;20:452. 4. Robinson DS. Schizophr Bull 1980;6:298 5. Hackmann E. Psychopharmacologia 1973;32:183 6. Ladisich W. Psychoneuroendocrinology 1977;2:257

Gonadal Steroids Affect CNS 5HT Activity

serotonin uptake and turnover5,6

Progesterone

Serotonin

Estrogen

5-HT1, 5-HT2 receptors1

• Modulates

tryptophan

hydroxylase2,3

MAO activity4

Mood and Anxiety Disorders Across

the Female Reproductive Cycle

Premenstrual depression/anxiety (eg, PMDD)

Depression/anxiety during pregnancy

Depression/anxiety during the postpartum period

Menarche MenopausePregnancy

Depression/anxiety associated with infertility, miscarriage, or perinatal loss

Depression/anxiety during the peri- / post-menopausal period

Maternal Mental Illness During Pregnancy and Postpartum Period

TreatmentMental Illness

Numerous Sources of Information and Opinions Influencing Treatment Planning

Patient

Obstetrician

Delivery Staff

Pediatrician

FACT:Everyone has an OPINION(whether they know anything or not)

Significant Other

Family Members Lactation Cons.

Nursery Staff

Clinician

Therapist

Internet

Pharmacist

Antenatal Depression: Prevalence

Kumar R, Robson RM. Br J Psychiatry 1984;144:35-47.O’Hara MW. Arch Gen Psychiatry 1986;43:569-573.Gotlib IH et al. J Consult Clin Psychol 1989;57:269-274.

Hobfoll SE et al. J Consult Clin Psychol 1995;63:445-453.Kelly R et al. Am J Psychiatry 2001;158:213-219.Evans J et al. BMJ 2001;323:257-260.

Suicidal / Homicidal Ideation

• Pregnancy

– Thoughts of Death and Dying in Pregnant Women with Mental Illness (Newport et al 2007) 16.9 – 33.1% positive depending on scale

utilized. Highest for self-report measures Risk Factors

– Current Depression– Co-morbid Anxiety Disorder– Unplanned Pregnancy

Survival Curve for Women with Major DepressionTaking Antidepressants Proximate to Conception

Cohen LS, et al. JAMA (2006) - Collaborative Study (RO1).

Proportion ofWomen Remaining

Euthymic

Weeks of Gestation

40363228242016128400.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0 Maintained Rx (n = 104)

Discounted Rx (n = 103)

Bipolar Disorder Relapse (n=89)

0

10

20

30

40

50

60

70

80

90

100

% o

f P

atie

nts

Rem

ain

ing

Sta

ble

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Weeks at Risk

Pregnant/Untreated

Pregnant/Treated

delivery

delivery

Viguera et al – AJP 2007

Scope of the Problem• > 4,000,000 deliveries in US annually

• > 50% inadvertent conception

• Maternal Age Increasing

– Longer time to develop illness prior to pregnancy

• Neuropsychiatric Illnesses in Pregnancy

– >500,000 women annually

– 8 health care databases: 6.6% of women prescribed Antidepressant at some point in pregnancy (Andrade et al 2007) e.g. >250,000 exposed annually

• Uniform support for Breast Feeding

Antenatal Maternal Depression: Acute Maternal & Neonatal Consequences

• Non-compliance with prenatal care

• Self medication with drugs, EtOH, and tobacco

– 10-12% use tobacco

– 14-15% use EtOH

– 3% use illicit drugs

• Not bonding with baby

• Effects on family

• Suicide

• Postpartum Depression

• Preterm labor

• Premature birth (<37 weeks)

• Low birth weight

• Small for gestational age, smaller head circumference

• Low APGAR scores

• Neonatal Complications

• Admission to NICU

• Fetal demise

Allister L, et al Neuropsychol 2001;20(3):639-651.Steer RA, et al J Clin Epidemiol 1992;45(10):1093-1099.Larsson C, et al Amer. Obstet Gynecol 2004;104:459-466.Chung TKH, et al Psychosom Med 2001;63:830-834.Rahman A, et al Arch Gen Psychiatry 2004;61:946-952.

Field T, et al Infant Beh Dev 2001;24:27-39.Hoffman S, Hatch MC. Health Psychol 2000;19(6):535-543.Orr ST, James SA, Prince CB. Am J Epidemiol 2002;156:797-802.Zuckerman B, et al Am J Obstet Gynecol 1989;160(5, Part 1):1107-1111.Berle JO, et al. Arch Women's Mental Health 2005; 8:181-189

Abrams, 1995Abrams, 1995 Poorer orientation skills (localizing sounds, tracking)Poorer orientation skills (localizing sounds, tracking) Decreased motor toneDecreased motor tone Lower activity levelsLower activity levels

Jones, 1998Jones, 1998 Lower vagal toneLower vagal tone

Estimate of respiratory sinus arrhythmiaEstimate of respiratory sinus arrhythmia Assoc’d with Assoc’d with ↓ ↓ performance on attention/learningperformance on attention/learning

Right EEG asymmetryRight EEG asymmetry

Lundy, 1999Lundy, 1999 Poorer orientation, reflex, excitability, and withdrawalPoorer orientation, reflex, excitability, and withdrawal

clusters on Brazelton Scaleclusters on Brazelton Scale

Depression During Pregnancy:Neonatal Neurobehavioral Sequelae

11Abrams SM et al. Abrams SM et al. Infant Mental Health JournalInfant Mental Health Journal. 1995;16:233 . 1995;16:233 22Jones NA et al. Jones NA et al. Infant Behavior & Development. Infant Behavior & Development. 1998;21:537 1998;21:537 33Lundy BL et al. Lundy BL et al. Infant Behavior & DevelopmentInfant Behavior & Development. 1999;22:119. 1999;22:119

11

22

33

The mothers’ HPA-axis modulates the fetal HPA axis

• Maternal cortisol level is a significant predictor of neonatal cortisol level

• Elevated cortisol levels in stressed mothers coincide with decreased expression of CBG

• While ACTH does not cross the placenta, maternal ACTH challenge produces ACTH-dependent signaling in the fetus

Field et al 2003; Weinstock 2005; Schwerin et al 2005

Emory Infant Stress StudyInfant Cortisol Response to Stress at 6 Months

N=171

Brennan P et al. J Am Acad Child Adolesc Psychiatry (2008)

MDD: F=4.91, p<.03Med: F=0.24, p<.63

19

WMHP Interfacing with PRI Programs

• Collection of comparable/similar measures in women during pregnancy and the postpartum period.

• Early Life Trauma Events

• Neuroimaging

• Center for Addiction Research

Maternal Abuse History, PTSD, and Infant Cortisol Reactivity

Lo

g A

UC

Rel

ativ

e to

Bas

elin

e

(Brand et al PNEC 2008)

Scanning 5 Year Old Children

Preliminary Pilot Data

Social vs. Non-social Activates pSTS

Biological movement

Incongruent vs. Congruent Activates precuneus, pCG, dmPFC

Involved in conflict processing

Happy vs. Neutral Activates occipital areas, fusiform

gyrus Face processing

Regression Analysis

• BA 46 (48, 35, 4)• Controlled for IQ and age• INS>CNS (cognitive conflict)

Perinatal Opiate Project

• Collaboration

– Obstetrics & Gynecology

– Pediatrics: NICU and New Born Nursery

– Brain Imaging Research Center

• Clinical Guideline Development and Research

– Buprenorphine Conversion

– Opiate Addiction/Abuse Treatment

– Maternal and Neonatal Pain Management

– Neonatal Outcome / Development

Emerging View of Infant Development

(genetics) (environment)

Impact of Stress/Glucocorticoids

Fetal ProgrammingEpidemiological Evidence

LOW BIRTH WEIGHT (LBW) . . .

• Adult Cardiovascular Disease (> 100 studies)

Barker DJP et al. Lancet 1989; 2:577-580

• Type 2 Diabetes Newsome CA et al. Diabet Med 2003; 20: 339-348

• Osteoporosis Dennison EM et al. Pediatr Res 2005; 57: 582-586

• Schizophrenia Wahlbeck K et al. Arch Gen Psychiatry 58: 48-52

• Depression Thompson C et al. Br J Psychiatry 2001; 179:

450-455 Gale CR et al. Br J Psychiatry 2004; 184: 28-33

27

FDA Pregnancy CategoriesCategory Interpretation

A Controlled studies show no risk: adequate, well-controlled studies in pregnant women have failed to demonstrate risk to the fetus

B No evidence of risk in humans: either animal findings show risk, but human findings do not; or, if no adequate human studies have been done, animal findings are negative

C Risk cannot be ruled out: human studies are lacking, and animal studies are either positive for fetal risk or lacking as well. However, potential benefits may justify the potential risk

D Positive evidence of risk: investigational or postmarketing data show risk to the fetus. Nevertheless, potential benefits may outweigh risks

X Contraindicated in pregnancy: studies in animals or humans, or investigational or postmarketing reports, have shown fetal risk that clearly outweighs any possible benefit to the patient

Perinatal Product Labeling

"Use in pregnancy is not recommended unless the potential benefits justify

the potential risks to the fetus."

"When manufacturers & official agencies warn against drug treatment during

pregnancy, their warnings serve to protect themselves and are of little use to clinically

responsible physicians.” Schou M. J Affect Disord 2001; 67: 21-32.

Pregnancy: Summary

• Mental Illness is a common problem

• Routine/Reflexive discontinuation of treatment carries significant risk of relapse

• Maternal Depression associated with adverse effects

• Role(s) of Maternal Depression in pregnancy in risk for later illnesses (programming) not yet delineated

• Concerns about medications have generated an enormous data base

0

10

20

30

40

50

60

70

Psychiatric Admissions in 2 Years Before and After Delivery

Pregnancy

–2 Years – 1 Year Childbirth +1 Year +2 Years

Kendell RE, et al. Br J Psychiatry 1987;150:662-673. Presented at the 1st Women's Mental Health Congress; March 27-31, 2001; Berlin, Germany.

Admissions/Mo

Sure Buffie,have somemore!

Let’s playBed-E-Bye I feel so

RELAXED

Mommy, I wantto take a nap!

Postpartum Mental Illness• Postpartum "blues"

– 50%-70% of adult women within 10-14 days

– Transient, considered nonpathologic

• Postpartum depression (PPD)

– 10% of adult women

– 2/3 have onset by 6 weeks postpartum

– Serious and disabling

• Postpartum psychosis (PPS)

– 1-2/1000 live births

– 70% are affective (bipolar D/O, depression)

– Medical emergencyNewport DJ, et al. J Clin Psychiatry 2002;63(suppl 7):31-44.

Postpartum Depression:Clinical Predictors

MDD = Major depressive disorder.O’Hara MW, et al. J Abnorm Psychol 1991;100:63-73.

Suicidal / Homicidal Ideation

• Postpartum

– Maternal psychiatric illness is leading cause of maternal mortality North American Australia Quebec

– Thoughts of harming infant Infanticide – rare Nursery rhymes

Maternal Depression during the Postpartum Period and Extended Follow Up

• Elevated Cortisol and Attention Deficits (Essex et al Biological Psychiatry 2002)

• Increased Violence in 10,11,12 years old (J. Affect. Disorders 2003)

• Maternal Depression in Pregnancy and Postpartum predicts higher rates of Conduct Disorder and Violent Behavior (Arch Gen Psych 2005)

Postpartum: Summary

• Mental Illness is a common problem

– Identification of at risk groups prior to delivery

• Desire to Breast Feed does not preclude treatment

– Antidepressants have largest data base in lactation than any other class of medication

• Long term adverse consequences for child if left untreated

UAMS Women’s Mental Health Program:A Good Start, a Solid Foundation, and a Bright Future

• Clinical Sites

– Psychiatric Research Institute

– University Women’s Clinic

– Telemedicine (18 sites to date)

• First Year:

– 2244 Total Visits

– 670 New Client Evaluations 609 Adult 61 Teen Pregnancies


“We treat our patients where we find them”

• Treatment Foundation

– “Harm Reduction”

– “Damage Control”

– Guideline Based Interventions ANGEL Guideline Revisions ACOG Practice Bulletin


• Research Protocols

– Stress in Pregnancy

– Transgenerational Biorepository A deficit in the majority of etiological

research is that the data is obtained after illness has onset.

• Training the next generation

– Resident Academic Track

– PGY V Fellow


• Expanding Clinical Services

– Additional telemedicine sites

– NW Arkansas

• Expanding Clinical Research

– Enrollment of Teen Pregnancy

– Non-English Speaking Clients

• Development of Inpatient Services Specifically for Women’s Mental Health

Questions?

THANKS !!

Postpartum Mental Illness

• Postpartum "blues"

– 50%-70% of adult women within 10-14 days

– Transient, considered nonpathologic

• Postpartum depression (PPD)

– 10% of adult women

– 2/3 have onset by 6 weeks postpartum

– Serious and disabling

• Postpartum psychosis (PPS)

– 1-2/1000 live births

– 70% are affective (bipolar D/O, depression)

– Medical emergency

D/O = disorder.

Newport DJ, et al. J Clin Psychiatry 2002;63(suppl 7):31-44.

Some Decisions are Worse than Others

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