maternal-fetal dyad : risks and benefits of prescribing psychotropics during pregnancy natalie...
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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