Maternal-Fetal Dyad:  Risks and Benefits of Prescribing

Psychotropics During Pregnancy

Natalie Rasgon, M.D., Ph.D.Natalie Rasgon, M.D., Ph.D. ProfessorProfessor

Department of Psychiatry and Behavioral SciencesDepartment of Psychiatry and Behavioral SciencesDepartment of Obstetrics and GynecologyDepartment of Obstetrics and Gynecology

Stanford School of MedicineStanford School of MedicinePalo Alto, CaliforniaPalo Alto, California

Learning Objectives

To update knowledge about the epidemiology, risk factors and clinical course of perinatal mood disorders

To learn about controversies regarding treatment issues in women with perinatal mood disorders

Untreated Major Depression in Pregnancy

Major Depression associated with an increased incidence of preterm delivery compared to nondepressed patients in a large registry study

Major Depression during pregnancy has been associated with adverse obstetrical outcomes in small prospective studies but results differ in larger prospective studies (Chung et al, 2001; Andersson et

al, 2004) Major depression in pregnancy is clearly associated with an

increased risk for postpartum depression

(Oberlander et al, 2006)

Cohen, L. S. et al. JAMA 2006;295:499-507.

Relapse of Major Depression During Pregnancy

Depression in Pregnancy: Risk of Treatment vs No Treatment With Medications

Teratogenesis “Behavioral teratogenesis” Perinatal complications Miscarriage

Endocrine effects Mothers’ poor self

care ? Low birth weight ? Premature labor

Pharmacotherapy RisksPharmacotherapy Risks

Depression RisksDepression Risks

Effects of Antenatal Depression and Antidepressant Treatment on Gestational Age at Birth and Risk of Preterm Birth Prospective study of 93 women

Group 1: Depressed with antidepressantsGroup 2: Depressed without antidepressantsGroup 3: Controls

Study controlled for risk factors for prematurityResults: Antidepressant exposure associated with

1) Lower mean gestational age at birth (38.5 vs. 39.4 vs. 39.7 weeks) 2) Higher percentage of preterm deliveries

(14.3% vs. 0% vs. 5.32%) 3) Higher percentage of special care nursery admits

(20% vs. 9% vs. 0%)

Suri R. Am J Psychiatry 2007; 164: 1206-1213

Teratogenicity Time Table

Days Organ System Associated Defects

10-32 CNS Neural Tube

20-56 Cardiac Ebsteins Anomaly

42-63 Lips and palate Cleft lip and palate

24-56 Limbs

60-140 Craniofacial Craniofacial

Gestational Age Effects Effects of Selective Serotonin Reuptake Inhibitors

(SSRIs) on gestational age are dependant on the duration of in utero antidepressant exposure.

Longer exposure – more likely to decrease gestational age10

[10] Oberlander T, Warburton W, Misri S, Aghajanian J, Hertzman C.Effects of timing and duration of gestational exposure to serotoninreuptake inhibitors: population based study. Br J Psychiatry 2008;192:338–43.

Risks Associated With Pharmacotherapy During Pregnancy

Teratogenicity: gross evidence of organ dysgenesis (e.g., Ebstein’s anomaly with lithium)– Occurs 2-8 weeks after conception, but can extend into

2nd trimester (craniofacial) “Behavioral teratogenicity”: subtle functional disturbances (eg,

developmental delays, neurologic deficits)– Occurs throughout pregnancy

Perinatal complications: effect of drug on labor and delivery and immediate neonatal outcomes

Risks Associated with Antidepressant Use in Pregnancy

Antidepressants and Spontaneous Abortion (SA)– Variable findings in individual studies of differing antidepressants– Results of met analysis evaluating all published studies reported the

following risks for SA in 6 carefully evaluated cohort studies:• Nonexposed = 8.7% (7.5%-9/9%); N=1,534• Exposed= 12.4% (8.8%-14/1%); N=2,033• Relative Risk = 1.45• No difference between antidepressants (Nefazadone. Trazodone,

Venlafaxine, SSRIs)• Hemels et al, 2005; Ann Pharmacother 39: 803-9

937 women on antidepressants (AD) vs. 937 not on antidepressants (NAD)

338 women in the sample had h/o miscarriage Comparison SA in women with history of SA:

20% AD vs. 13% NAD (RR=1.63)

Unanswered questions:

• What is the contribution of depression?

• What comorbidities are associated with increased risk of SA ?(i.e. subclinical hypothyroidism? )

Einarson et al. J Obstet Gynaecol Can 2009; 31: 452-6.

Getting Closer…….

Paroxetine and Cardiac Congenital Malformations

Swedish Medical Birth Registry– 6,481 women delivered 6,555 infants exposed to SSRIs

during 1st trimester of pregnancy– No increased relative risk for any cardiac defect in SSRI

exposed infants compared to unmedicated total populationRR=.7 (78/6,555 vs. 11,367/873,876)

– Relative risk for any cardiac defect in Paroxetine subgroup compared to Sertraline or Fluoxetine or Citalopram: 1.63

– Paroxetine infants w/cardiac defect in select group (normal BMI) compared to general population RR = 2.63

(13/405 vs. 4.9/405)Kallen and Olausson, 2007 Birth Defects Re A Clin Mol Teratol

• Estimated to occur in 1% of births in general population

• Most common congenital heart defect

• Small defects are most common (80-90%)

• 30-50% small defects close spontaneously prior to 4 years old

• Small muscular defects are more likely to close than small membranous (80% vs. 35%)

• Risk factors include maternal alcohol use, valproic acid

Williams et al, 2004

National Birth Defects Prevention Study

9622 infants with major birth defects compared to 4092 control infants without defects

No significant associations found between maternal use of SSRIs overall in early pregnancy and congenital heart defects

Alwan S, et al. NEJM 2007; 356:2684-2692

Slone Epidemiology Center Birth Defects Study

Case control surveillance study of 9849 infants with and 5860 infants without birth defects

Overall SSRI use not associated with a significantly increased risk of omphalocele, craniosynostosis or heart defects

Significant associations found between specific SSRIs and specific defects

Louik C, et al. NEJM 2007; 356:2675-2683

Update: Conflicting FindingsUpdate: Conflicting Findings

Methods: MetanalysisSubjects: Unpublished cases from teratology services

(prospectively identified) and published database studies

Results: 2,061 unpublished cases cardiac deficit rate of infants exposed to Paroxetine: 1.5% 1,174 teratology register cases cardiac defect infants exposed to Paroxetine: 0.7%,

Bar-Oz et al. Clin Ther. 29:918-26, 2007

What Is Category Labeling?Key to FDA Use-in-Pregnancy Ratings

Controlled human studies have demonstrated no fetal risk

Animal studies indicate no fetal risk, but no human studies OR adverse effects in animals, but not in well-controlled human studies

No adequate human or animal studies OR adverse fetal effects in animal studies, but no available human data

Positive evidence of risk, but benefits outweigh risks

Contraindicated in pregnancy

InterpretationCategory

A

B

C

D

X

Prospective Studies of Antidepressants and Preterm Delivery

Author Medication Study Design N ResultsKulin et al, 1999 SSRIs SSRIs vs. MC 267 No difference

Einarson et al, 2001 Venlafaxine V vs. SSRI vs. NT 150/grp No differenceV vs. NT

Hendrick et al, 2003 SSRIs No controls 147 6.5% SSRI

Suri et al, 2004 FLX DEF vs. DE 59 No differenceVS. ND

Chun-Fai-Chen,2005 Buproprion B vs. NT 136 No differenceB vs. OADvs NT

Djuluk et al, 2006 Mirtazapine M vs. OA vs. NT 104 10% M vs. NT 2% p=. 04

Antidepressants and Preterm Delivery: Results of Large Birth Registry Studies

Author Registry N Results

Malm et al,

2005 Finnish Registry 1,782 SSRI NS

Oberlander et al,

2006 Canadian Health 1,451 S-ED p=.001

Care Registry 14,234 DE

92,192 NE

Relative Safety of Antidepressants in Pregnancy: Relative Safety of Antidepressants in Pregnancy: Neurobehavioral SequelaeNeurobehavioral Sequelae

StudyStudy NN MedMed ResultsResults

Nulman et al., 1997Nulman et al., 1997 808055558484

TCAsTCAsFLXFLXControlControl

IQ, Bayley, McCarthy similar up to age 7IQ, Bayley, McCarthy similar up to age 7

Mattson et al., 1999Mattson et al., 1999 66663030

FLXFLXControlControl

WPPS-RI no differencesWPPS-RI no differences

Nulman et al., 2002Nulman et al., 2002 464640403636

TCATCAFLXFLXControlControl

IQ, Bayley no differences between groups IQ, Bayley no differences between groups at 15-71 monthsat 15-71 monthsNumber of depressive episodes since Number of depressive episodes since delivery associated with lower language delivery associated with lower language developmentdevelopment

Casper et al., 2003Casper et al., 2003 13133131

ControlControlSSRIsSSRIs

Lower Bayley psychomotor developmental Lower Bayley psychomotor developmental indexes and motor quality in f/u (6-40 mo)indexes and motor quality in f/u (6-40 mo)

StudyStudy NN MeasuresMeasures ResultsResults

Misri et al.Misri et al.(2006)(2006)

13139914 14

SSRISSRISSRI + KlonopinSSRI + KlonopinControlsControls

No differences in ratings of No differences in ratings of internalizing behaviors between internalizing behaviors between groups (Child/Teacher Behavioral groups (Child/Teacher Behavioral Checklist) at 4 years oldChecklist) at 4 years oldMaternal depression associated Maternal depression associated with increased internalizing with increased internalizing behaviorsbehaviors

OberlanderOberlanderet al.et al.(2007)(2007)

22221414

SSRISSRIControlsControls

No difference in ratings of No difference in ratings of externalizing behaviors between externalizing behaviors between groups (CBCL) at 4 yearsgroups (CBCL) at 4 yearsMaternal stress, anxiety and Maternal stress, anxiety and depression associated with higher depression associated with higher scoresscores

Mattson et al. Teratology 1999; 59: 378-389; Nulman et al. N Engl J Med. 1997;336:258-262; Casper et al. J Pediatr. 2003; 142: 402-408 ; Nulman et al. Am J Psychiatry. 2002; 1889-1895; Misri et al., Am J Psychiatry. 163: 1026-1032, 2006; Oberlander et al. Arch Pediatr Adolesc Med. 161: 22-29, 2007

.

Relative Safety of Antidepressants in Pregnancy: Relative Safety of Antidepressants in Pregnancy: Neurobehavioral SequelaeNeurobehavioral Sequelae

Persistent Pulmonary Hypertension of the Newborn

Rare condition in the general population: estimated 1/1000 births

Cause: Unknown Possible Causes:

– Hypoxia and hypercarbia at birth (meconium aspiration, complicated deliveries)

– Increased medial muscle thickness of pulmonary arteries

– Vasoactive mediator abnormalities (nitrous oxide, leukotrienes, platelet activating factor)

Chambers, et al., NEJM 2006

Risk of Persistent Pulmonary Hypertension and SSRIs

Conflicting New Report:

Retrospective follow up study Infants exposed to SSRIs during last trimester of

pregnancy compared to unexposed infants No increased prevalence of PPHN (2.14/1000 vs.

2.7/1000

Andrade SE et al. Pharmacoepidemiol Drug Saf 18: 246-52, 2009

So, to treat or not to treat?

What is the Evidence for the Efficacy of Antidepressants in the Treatment of Antenatal Depression?

NONE!NONE!

To date: To date: • No randomized, placebo-controlled studies of No randomized, placebo-controlled studies of

antidepressant treatment in antenatal antidepressant treatment in antenatal depressiondepression

• No comparative studies of antidepressant No comparative studies of antidepressant treatment versus psychotherapy in antenatal treatment versus psychotherapy in antenatal depressiondepression

Coverdale JH, et al. The ethics of randomized placebo-controlled trials of antidepressants with pregnant women: a systematic review. Obstetrics & Gynecology. 112: 1361-1368, 2008.

Neonatal SSRI “Adaptation” Syndrome

Clinical characteristics:• Respiratory distress• Autonomic instability• Poor feeding• Neurologic symptoms: tremor, myoclonus, seizures

Neonatal adaptation syndrome occurs in 30% of neonates exposed to SSRIs in utero, leading to NICU and SCN admits

Etiology controversial: SSRI withdrawal or serotonergic toxicity? Self limited, supportive treatment

Retrospective cohort study of 76 mothers treated with SSRIs of Venlafaxine during third trimester

Results:

– 100% of premature infants presented neonatal adaptation symptoms compared to 69% of term infants

– Median length of stay in hospital was almost 4 times longer for preterm compared to term infants (14.5 vs. 3.7 days)

– 95% of premis demonstrated CNS symptoms (abnormal movements and agitation) vs. 30.9% of term (p=<.001)

– 66.7% of premis demonstrated respiratory symptoms vs. 25.5% of term (p=<.001)

Effects of Selective Serotonin Reuptake Inhibitors and Venlafaxine During Pregnancy in Term and Preterm Neonates

Ferreira et al., 2007 Pediatrics 119: 52-57

Buproprion and Pregnancy

United Healthcare Registry (2007)1213 infants exposed to Buproprion in first trimester compared with

other antidepressant exposure during the first trimester (4743 infants): Adjusted Odds Ratio for all congenital malformations was 0.95 (prevalence 23.1 per 1000 vs. 23.3 per 1000)

Cole et al. Pharmacoepidemiol Drug Saf 2007; 16:475-84

Prospective Study (2005)No significant differences between 136 women exposed to Buproprion and nonteratogen group or other antidepressant group in rate of major malformations, mean birth weight or mean gestational age at deliveryBuproprion associated with significantly more spontaneous abortions (20/136)

Chun-Fai et al. Am J Obstet Gynecol 200; 192: 932-6

Atypical and Typical Antipsychotics

Atypicals associated with gestational diabetes!!! Increased and decreased birthweight have both

been found in AAP exposed infants High potency typical antipsychotics appear to be

safe--no increased risk of congenital malformations, but risk of EPS

Atypical Antipsychotic Use During Pregnancy

Study by McKenna et al. (2005):– 151 pregnant women on an atypical antipsychotic, age-matched

with a control group– Followed through pregnancy and birth– No difference in rates of major malformations, complications

during labor, rates of hospitalization during pregnancy, neonatal complications, diabetes, or hypertension

– Higher rates of low birth weight among exposed women, although no difference in mean birth weight

– Exposed women less likely to take vitamins during pregnancy– No differences between drugs emerged

McKenna et al. McKenna et al. J Clin PsychiatryJ Clin Psychiatry 2005 2005

Risperidone and Pregnancy

Review of large data base of 713 infants exposed to

Risperidone in pregnancy revealed no increased risk of congenital malformations or spontaneous abortions

• Possible neonatal adaptation syndrome, including

jitteriness, poor feeding, tremor, somnolence

Coppola, D. et al. Drug Safety 30: 247-64, 2007

Atypical Antipsychotics in Late Pregnancy

50 women prospectively followed (52% BAD; 25%psychotic; 19% depressive) Note: not monotherapy in 75%

Maternal and umbilical samples at delivery Placental passage determined as umbilical cord:plasma ratio Obstetrical outcome measures: maternal reports and maternal

chart review Results:

Olzanzapine>Haldoperidol>Risperidone>Quietapine x=72.1% vs. 65.5% vs. 49.2% vs. 23.8% SD=42% SD= 40.3% SD= 33.9% SD=11% Trend for lower birth weight (30.85) in olanzapine exposed babies

(p=.06) Population norms=4-8% as well as NICU admits of 30.8% vs.population norms of 7-8%

Newport DJ et al. Am J Psychiatry 2007; 164:1214-20.

Teratogenicity, Perinatal Complications and Mood Stabilizers

Lithium (D)• Ebstein’s anomaly in general population 1/20,000• Reanalyzed rate in Lithium exposed infants is1/1000 or 2/1000 (.1-.05%) (Cohen, 1994)

• Counsel that risk is very low, but still 20-40 times the rate in general population

• Increased overall risk of congenital malformations4-12% lithium exposed infants vs. 2-4% nonexposed

• Perinatal complications include “floppy baby” syndrome, nephrogenic diabetes insipidus, thyroid dysfunction, polyhydramnios--rates unknown

Gentile, S. Bipolar Disord 8: 207-20, 2006Yonkers et al. American J Psychiatry, 2004

Teratogenicity, Perinatal Complications and Mood Stabilizers

Valproic Acid (D)

Rates of major malformations 6-20.3% Rates of neural tube defects 5-9%

Spina Bifeda is 50 X background rate

“Fetal Valproic Acid Syndrome:” irritability, jitteriness, poor feeding

Neurodevelopmental problems--lower IQ scores, autism

Supplement with Vit K and folate

Yonkers et al. American J Psychiatry, 2004

Vajda, 2005; Morrow, 2006

Carbamazepine (D)

Overall rates of major malformations 2.2-8.2%Rates of craniofacial defects 11%Rates of developmental delay as high as 20%Supplement Vit K and FolateOxcarbazepine is category C: produces no epoxide

metaolites, theoretically less teratogenic, but no confirmatory studies

Gentile, 2006

Lithium Management Guidelines

Fetal US and ECHO at 16-18 weeks Plasma volume and renal clearance increase during

pregnancy so higher doses may be needed Divided doses recommended to maintain stable

serum levels Decrease dosage prior to delivery due to increased

risk of lithium toxicity

Yonkers, 2004

Treatment with Lithium During Pregnancy

Levels in umbilical cord blood=maternal blood levels

Avoid toxicity at delivery by discontinuing the dose for approx. 48 hours

Neonatal toxicity is directly related to maternal blood levels

Newport et al., Am J Psychiatry, 2005

Treatment of Insomnia in Pregnancy

Zolpidem: Very limited safety data, but category B Trazadone: limited safety data: 58 infants prospectively

followed-no increased congenital malformation risk. Category C Einarson A. et al. Can J Psych 48:106-10, 2003

Diphenhydramine: Limited studies despite widespread use, Category B

Benzodiazepines: Category D– Largest study to date is 1,944 exposed infants from Swedish

Birth Registry• Cleft palate association not as strong as previously thought• ? Associated with low birth weight and preterm delivery• ? Associated with alimentary tract abnormities

• Wilkner BN et al. Pharmacoepidemiol Drug Safety 2007 16(1): 1203-10

Patient is contemplating pregnancy and is undergoing pharmacological treatment for depression.

Yonkers, et al, 2009

Patient with MDD pregnant not taking antidepressants

Yonkers, et al, 2009

Patient with MDD, pregnant currently on antidepressants.

Yonkers, et al, 2009