course and treatment of psychiatric disorder during...
TRANSCRIPT
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Lee S. Cohen, MD
Director, Ammon-Pinizzotto Center for Women’s Mental Health Massachusetts General Hospital
Edmund and Carroll Carpenter Professor of Psychiatry
Harvard Medical School
Course and Treatment of Psychiatric Disorder During Pregnancy: Lessons Learned over Two Decades
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My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose: 12-Month Disclosure Research Support for the National Pregnancy Registry for Atypical Antipsychotics: Alkermes Biopharamaceuticals; Bristol-Myers Squibb/Otsuka Pharmaceuticals; Forest/Actavis Pharmaceuticals; Ortho-McNeil Janssen Pharmaceuticals; Sunovion Pharmaceuticals, Inc. Other research support: Cephalon, Inc.; JayMac Pharmaceuticals; National Institute on Aging; National Institutes of Health; National Institute of Mental Health; Takeda/Lundbeck Pharmaceuticals Advisory/Consulting: None Honoraria: None Royalty/patent, other income: None
Disclosures
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Are pregnant women protected against relapse or new onset of major depression?
Major Depression During Pregnancy
O’Hara et al. J Abnorm Psychol. 1990 Evans et al. BMJ. 2001 Yonkers et al. Epidemiology 2011 Roca et al. J Affective Disorders 2013
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Time to Relapse in Patients Who Maintained or Discontinued Antidepressant
Cohen LS, et al. JAMA. 2006
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Gestational Age
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Maintained (N = 82)
Discontinued (N = 65)
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Relapse of Bipolar Disorder During Pregnancy
Viguera et al. Am J Psychiatry 2007
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For Further Information:
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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%
SSRI = selective serotonin reuptake inhibitor
Andrade SE, et al. Am J Obstet Gynecol. 2008 Marcus SM, Flynn HA. Int J Gynaecol Obstet. 2008
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Psychotropic Drug Use in Pregnancy
• Medications used when risk to mother and fetus from disorder outweighs risks of pharmacotherapy
• Optimum risk/benefit decision for psychiatrically ill pregnant women
• Patients with similar illness histories make different decisions regarding treatment during pregnancy
• No decision is risk-free
• Collaborative, patient-centered approach required
Henshaw Fam Plann Perspect. 1998
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Treatment of Depression During Pregnancy: Lessons Learned and New 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
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Relative Impact of AD Exposure vs. Depression in Obstetrical and Neonatal Outcome
• Some data support increased rates of obstetrical complications and poor neonatal outcome in depressed or anxious pregnant women
– Increased risk of preterm birth
– Lower birth weight (LBW)
– Small for gestational age (SGA)
• Depression and anxiety often comorbid
• Increased effort to distinguish impact of illness from medication exposure on obstetrical and neonatal outcome
Steer RA et al. J Clin Epidemiol. 1992 Wisner Am J Psychiatry 2009 Yonkers KA, et al. Obstet Gynecol. 2009 Warburton et al 2010
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Maternal Depression in Pregnancy: Obstetric Outcome
Preterm=<37 weeks estimated gestational age; LBW=low birth weight (<2.5 kg); SGA=small for gestational age (<10th percentile); CES-D=Center for Epidemiologic Studies-Depression; BDI=Beck Depression Inventory.
Steer et al, 1992 (N=389) Orr and Miller, 1995 (N=186)
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Preterm LBW SGA P
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Orr S, Miller C. Epidemiol Rev. Steer RA, et al. J Clin Epidemiol. 1992
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A Meta-analysis of Depression During Pregnancy and the Risk of Preterm Birth, Low Birth Weight, and Intrauterine Growth Restriction
Grote et al. Arch Gen Psychiatry. 2010
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The Problem of Confounding
• Analyses of outcomes typically do not control for depression (or its severity)
• Recent efforts to control for depression in analyses of malformation risk attenuate risks for drug exposure
Palmsten and Hernandez-Diaz Epidemiology 2012. Huybrechts et al. NEJM 2014.
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• Newborns of women with depression at 26 weeks gestation demonstrate altered microscructure in right amygdala compared to those born to women without depression during pregnancy
• Dysregulation of HPA-axis during pregnancy may increase risk of onset of depression in older children
Untreated Psychiatric Disorders During Pregnancy: Effects on Fetal Brain and HPA-Axis
Pearson et al. JAMA Psychiatry 2013 Van den Bergh Neuropsychopharmacology 2008
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Rifkin-Graboi et al. Biol Psychiatry 2013.
Figure 1. The top and bottom rows, respectively, show the brain using the color map of diffusion tensor imaging and T2-weighted magnetic resonance imaging from one infant of our sample. The axial, coronal, and sagittal slices are respectively illustrated from left to right. The red contour indicates the amygdala on diffusion tensor imaging and T2-weighted magnetic resonance imaging.
Untreated Psychiatric Disorders During Pregnancy: Effects on Fetal Brain and HPA-Axis
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What is the Safest Antidepressant for Women of Childbearing Age?
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Treatment of Depression During Pregnancy: Lessons Learned (cont.)
• All pregnancies have an underlying risk for major fetal malformations or pregnancy loss regardless of fetal exposure to medications or maternal illness
• There are more safety and efficacy data on the use of SSRIs during pregnancy than any other drug class
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Phasing Out: FDA Pregnancy Categories
• Category A: – Well controlled studies in human pregnancy show no increased risk to
the fetus
• Category B: – Animal studies show no increased risk to the fetus OR
– Animal studies show an increased risk to the fetus but well controlled human studies do not.
• Category C:
– Animal studies show an increased risk to the fetus and there are no well controlled studies in human pregnancy OR
– There aren’t any animal studies or well controlled human studies.
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http://womensmentalhealth.org/posts/fda-finalizes-guidelines-pregnancy-lactation-labeling-information/
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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
– Consistent pattern of malformations with SSRI exposure is lacking
– 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); Grigoriadis et al. J Clin Psychiatry 2013.
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• Do more data help?
• Extensive data on risks of psychotropic drug use during pregnancy can complicate interpretation of clinical implications/ relevance (varying methodologies, disparate data sources)
• Selectivity of studies described or highlighted in reviews and media (convention and social) complicate clinical decision making
Fetal Exposure to Psychotropics: More and More Data
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• Most recent studies/analyses demonstrate either modest increase in relative risk or absence of risk
SSRI Use and Risk for Cardiovascular Malformations
Grigoriadis et al. J Clin Psychiatry 2013. Huybrechts et al. NEJM 2014.
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• Recent analysis of 949,504 pregnant women enrolled in Medicaid
– 3 months prior to pregnancy to 1 month following pregnancy
• 6.8% use of SSRIs during first trimester
• Risk for cardiac defects attenuated with increasing levels of adjustment for confounding
Risk of Cardiovascular Malformation Following SSRI Exposure
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• No evidence of increased risk for major malformations or cardiovascular malformations in children of pregnant women exposed to SSRIs
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Cardiovascular Malformation and Fetal SSRI Exposure
Huybrechts et al. NEJM 2014.
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Non-SSRIs During Pregnancy
• More limited reproductive safety data available for SNRI’s compared to SSRIs, i.e. venlafaxine, duloxetine (new registry in 2009, limited data)
• Data on bupropion includes growing number of exposures supporting absence of increased risk for malformation, overall and ? cardiac (Alwan et al. 2010)
• Should bupropion be used more frequently during pregnancy?
http://www.gsk.com/media/paroxetine/ingenix_study.pdf
Chun-Fai-Chan B et al. Am J Obstet Gynecol 2005
Cole JA et al. Pharmacoepidemiol Drug Saf. 2006
Alwan et al. Am J Obstet Gynecol. 2010
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Non-SSRIs During Pregnancy
• Bupropion
• Prospective studies have not demonstrated overall increased risk of malformations, compared to control groups exposed to other ADs or non-exposed controls
• Retrospective case control study from birth defect registry suggested small but increased risk of cardiovascular left outflow defects
• Absolute risk was approximately 2 out of 1000 pregnancies
• Recent case control study: increased risk for VSD, no risk for other cardiac malformations
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http://pregnancyregistry.gsk.com/documents/bup_report_final_2008.pdf; Chun-Fai-Chan et al. Am J Obstet Gynecol. 2005; Cole et al. Pharmacoepidemiol Drug Saf. 2007; Alwan et al. Am J Obstet Gynecol. 2010. Louik et al. Pharmacoepidemiol. Drug Saf. 2014.
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Non-SSRIs During Pregnancy
• Other Non-SSRI Antidepressants:
• SNRIs:
• Limited reproductive safety data available for SNRIs, i.e. venlafaxine, duloxetine
• Mirtazapine:
• Small prospective study does not suggest increased rate of malformations
Einarson et al. American Journal of Psychiatry 2001 Einarson et al. J Clin Psychiatry 2012 Djulus et al. J Clin Psychiatry 2006.
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“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%)
• Overall studies do not adequately control for maternal mental health condition, adequate blinding of exposure in neonatal assessments
• Clinical implication: Should women be treated with antidepressants late in pregnancy and during labor and delivery (Warburton et al. 2010)
• Are any subgroups of newborns vulnerable to enduring symptoms beyond the first days of life ?
Levinson-Castiel R, et al. Arch Pediatr Adolesc Med. 2006 Chambers CD, et al. N Engl J Med. 2006 Chambers, BMJ, 2009 CWMH Blog, July 27 2005: http://womensmentalhealth.org/posts/neonatal-symptoms-after-in-utero-exposure-to-ssris/
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Chambers CD, et al. N Engl J Med. 2006 Hernández-Díaz S, et al. Pediatrics. 2007
Risk for PPHN Associated with Late Trimester Exposure to Antidepressant
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Antidepressants During Pregnancy: Later Pregnancy Considerations
www.womensmentalhealth.org Grigoriadis et al. BMJ 2014
• Risk of persistent pulmonary hypertension of newborn (PPHN) with SSRIs?
• INCONSISTENT FINDINGS
– Initial report showed SSRIs increased risk by 6-fold (Chambers 2006; approximately 1%)
– Lower risk (0.15%) seen by Källén and Olausson, 2008 No association seen by others (Andrade et al, 2009; Wichman et al, 2007; Wilson et al, 2010)
– Other factors may play a role: race, high BMI, delivery by C-section
– If there is an association, risk extremely low
– Revised FDA communication (2012) noting earlier overestimation of risk (http://www.fda.gov/drugs/drugsafety/ucm283375.htm)
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Antidepressant Use Late in Pregnancy and Risk of PPHN
• Large Medicaid Database – 3.8 million pregnancies
– 128 950 women (3.4%) filled at least 1 prescription for antidepressants last 90 days of pregnancy; 2.7% used an SSRI and 0.7% used a non-SSRI
– Overall, 7630 infants not exposed to antidepressants were diagnosed with PPHN (20.8; 95%CI, 20.4-21.3 per 10 000 births) compared with 322 infants exposed to SSRIs (31.5; 95%CI, 28.3-35.2 per 10 000 births), and 78 infants exposed to non-SSRIs (29.1; 95%CI, 23.3-36.4 per 10 000 births)
• Absolute Risks:
– With SSRI: 31.5/10,000= 0.3%
– No antidepressant: 20.8/10,000 = 0.2%
• Associations between antidepressant use and PPHN were attenuated with increasing levels of confounding adjustment
Huybrechts et al., JAMA 2015
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Neonatal Distress Syndromes and PPHN: Lessons Learned and Clinical Implications
• Data to support recommendations to lower AD proximate to delivery are sparse; discontinuation of AD during peripartum period may increase risk for puerperal illness
Hernandez-Diaz et al. Pediatrics 2007
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Are SSRIs associated with an increased risk of autism or other child psychopathology?
Studies have been inconsistent – some show low risk, some show no risk • Croen et al., 2011: Case-control study. N= 298 children with & randomly selected control children
– Prenatal exposure to SSRI was reported for 20 case children (6.7%) and 50 controls (3.3%) – 2-fold increased risk of ASD associated SSRI in year before delivery; strongest effect in first trimester (adjusted OR, 3.8)
• Rai et al., 2013: Population based nested case-control study, Sweden, 2001-07. – 4429 cases of autism spectrum disorder; 43,277 matched controls in the full sample (1679 cases of autism
spectrum disorder and 16,845 controls with data on maternal antidepressant use nested within cohort (n=589,114)
– A history of maternal (adjusted odds ratio 1.49, 95% CI 1.08 to 2.08) but not paternal depression was associated with increased risk of ASD
– Subsample with available data on meds, association confined to women reporting antidepressant use during pregnancy (OR 3.34, 1.50 to 7.47, P=0.003, SSRI or non SSRI)
– All associations were higher in cases of autism without intellectual disability – If causal, SSRI use during pregnancy explained 0.6% of the cases of autism spectrum disorder.
No association: • Hviid et al., 2013: Danish population registry study: linked information on maternal use of SSRIs
before and during pregnancy, autism spectrum disorders, confounders – 3892 cases of autism spectrum disorder, N= 52 cases of women with SSRI use
• Clements et al., 2014: N=1377 w ASD matched controls, AD exposure not associated with ASD after controlling for maternal depression- No risk
• Malm et al., 2016: Finnish population national register cohort study looked at SSRI exposed, exposed to illness but not SSRI, exposed to SSRIs only before pregnancy, and unexposed – No association with autism but association with ADHD was noted
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SSRIs and Risk for Autism Spectrum Disorders
Clements et al. Molecular Psychiatry 2014
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What are the Long-term Neurobehavioral Effects of Prenatal Exposure to an Antidepressant?
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*Mean ± SD. †Children were tested between 16 and 86 months of age (mean, 33 ± 14). Bayley and McCarthy scores are typical for this age. Normal range for both tests is 100 ± 1 SD. Lower scores mean lower cognitive function. Mean Reynell score in normal children of this age is 0 ± 1 (range of possible scores, –3 to +3).
Neurodevelopment of Children
Results of Neurobehavioral Tests in Infants According to Whether They Were Exposed In Utero to Antidepressants*
Tests†
TCAs (N = 80)
Fluoxetine (N = 55)
Controls (N = 84)
Bayley Mental Development Index
118 ± 17 117 ± 17 115 ± 14
McCarthy General Cognitive Index
117 ± 10 114 ± 16 114 ± 13
Reynell Verbal Comprehension Scale
1.3 ± 0.8 1.2 ± 1.2 1.1 ± 0.9
Reynell Expressive Language Scale
0.3 ± 0.9 -0.2 ± 1.0 0.1 ± 1.0
Nulman I et al. N Engl J Med. 1997
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Antidepressants During Pregnancy: Long-term Data
Recent review by Suri et al., J Clin Psychiatry 2014: • 13 prospective studies have assessed neurobehavioral infant outcome after in
utero antidepressant exposure
• N=721 children with antidepressant exposure and N=380 children without exposure
• The longest follow-up has been 4 to 5 years
• The majority do not suggest major long term adverse effects of prenatal antidepressant exposure on infant/child neurobehavioral development; no significant differences in neurobehavior/development
• Generally encouraging but sample sizes have been small, and there are reports of possible subtle effects on gross motor function and language development, as well as the potential for longer-term consequences following poor neonatal adaptation
• Most studies do not assess for nor quantify the severity of depressive symptoms in mothers across pregnancy
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Treatment of Depression During Pregnancy: Lessons Learned
• Treatment decisions are complex (maternal and fetal benefits and risks)
• Absolute quantification of risk associated with fetal exposure to medication or maternal disease is impossible
• No treatment decision is “perfect” – Each treatment decision should try to optimize pregnancy outcomes
for the mother and her child
– Consider the risks of untreated disease and the risks of medication treatment
Kallen Obstet Gynecol Int. 2012 Palmsten and Hernandez-Diaz Epidemiology 2012
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APA/ACOG Joint Recommendations
● Psychotherapy: First-line for mild to moderate MDD ● Lifestyle components: Nutrition, weight management, prenatal
care, childbirth education; treatment for substance abuse ● Document all exposures dating back to conception ● Women trying to conceive who have histories of MDD:
– Encourage period of euthymia – Sustained remission: may consider tapering and discontinuing – More recently depressed or with symptoms: consider remaining on
medication, optimizing medication
● Pregnant women with severe MDD: Medication is first-line ● Pregnant women on antidepressants during pregnancy: take
into account patient preferences, previous course of illness ● Medication selection should be based on known safety
information
MDD, major depressive disorder. Yonkers KA et al. Obstet Gynecol. 2009;114(3):703-713.
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Antidepressant Use During Pregnancy: Lessons Learned
• Safest AD to use across pregnancy is the medication that affords euthymia
• Amount of data distinguishing AD compounds is very sparse with respect to teratogenic risk
Hernández-Díaz S, et al. Pediatrics. 2007 Kallen Pharmacoepidemiol Drug Safety 2008
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Summary of treatment considerations for women with MDD in pregnancy (cont.)
• Depression during pregnancy is strongest predictor of
postpartum depression
• There are known and unknown risks associated with
AD use during pregnancy
• Adverse effects of depression in pregnancy on
patient, infant and families
• Nothing trumps maternal euthymia
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Treatment of Bipolar Disorder During Pregnancy
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Cohen LS, et al. JAMA. 1994 Steer RA, et al. J Clin Epidemiol. 1992 Orr ST, et al. Am J Prev Med. 1996 Suppes T, et al. Arch Gen Psychiatry. 1991 Faedda GL, et al. Arch Gen Psychiatry. 1993 Baldessarini RJ, et al. Clin Psychiatry. 1996
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
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Antipsychotic Use During Pregnancy
Typical or “first generation” antipsychotics
• Significant experience available with older “typical” antipsychotics
• Meta-analysis – small but higher risk of congenital malformations after first trimester exposure to low potency agents compared to the general population – High potency are preferred: i.e., haloperidol, perphenazpine, trifluoroperizine,
thiothixine
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FDA Drug Safety Communication: Antipsychotic drug labels updated on use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns
Safety Announcement http://www.fda.gov/Drugs/DrugSafety/ucm243903.htm
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Atypical Antipsychotics in Pregnancy
• Newer antipsychotics: Abilify (aripiprazole) Seroquel (quetiapine)
Clozaril (clozapine) Zyprexa (olanzapine)
Geodon (ziprasidone) Saphris (asenapine)
Invega (paliperidone) Fanapt (iloperidone)
Risperdal (risperidone) Latuda (lurasidone)
• Risk of teratogenicity remains unknown
• Sparse data for best known atypicals in pregnancy
• No human data for newest agents
• Studies thus far complicated by: • High rates of polypharmacy
• Heterogeneous diagnosis
• Lifestyle factors of known risk to pregnancy among cases compared to healthy non-exposed control groups
• No signal of teratogenicity is evident based on limited studies
Yaeger D et al. Am J Psychiatry 2006; McKenna K et al. J Clin Psychiatry 2005; Sadowski A et al. BMJ Open Access 2013; Haberman F et al. J Clin Psychopharmacology 2013.
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Atypical Antipsychotics in Pregnancy
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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
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• Prospective study
• As of May 20th, 2016:
– 704 enrolled
– 312 1st trimester exposures enrolled w/ evaluable data at time of analysis
– Risk ratio = 2.27 (0.26, 20.15)
• Preliminary conclusions: atypical antipsychotics are not major teratogens but more data are needed to narrow the confidence interval
Presented at ASCP, Cohen et al., 2016
National Pregnancy Registry for Atypical Antipsychotics: Preliminary Findings
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Secondary aim: Evaluate neonatal outcomes of
infants with prenatal exposure to atypical
antipsychotics relative to unexposed infants
Secondary aim: Evaluate maternal health
outcomes of mother’s exposed to atypical
antipsychotics during pregnancy compared to
unexposed mothers
Potentially eligible women call our toll free number: 1-866-961-2388
Baseline interview as soon as possible after consent (~30 min)
Phone screen conducted, and if eligible, verbal consent is obtained
Second interview at 7 mo. gestation (~10 min) Medical record release forms sent to subjects after 7 mo. interview
Final interview at 2-3 mo. postpartum (~15 min)
Study Design
Primary aim: Prospectively evaluate rates of
major malformations among infants
exposed to atypical antipsychotics in utero
relative to unexposed infants
Secondary aim: Evaluate obstetrical
outcomes associated with use of atypical
antipsychotics in utero relative to unexposed
infants
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Lithium: A Known Teratogen
• 1970s Lithium Baby Registry—risk for specific cardiovascular malformation high; Ebstein’s anomaly
• Revised risk based on meta-analysis: 1/1000 to 1/2000 (0.05%)
• Relative risk for Ebstein’s anomaly is 10 to 20 times the rate in general population (1/20,000)
• Absolute risk vs. relative risk: Absolute risk is low or flat after adjusting for anomalies which resolved spontaneously
• Limited data regarding long-term neurodevelopmental outcomes
• Clearance is increased in late pregnancy
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Cohen et al. JAMA 1994
Diav-Citrin et al. American Journal Psychiatry 2014
www.mghcme.org *Suppes et al. Arch Gen Psychiatry. 1992.
Lithium Use During Pregnancy: Relative Risks and Clinical Dilemmas
LV
RV
TV
RA
Ebstein’s Anomaly Relapse Following Discontinuation
of Lithium in Bipolar Patients*
0 12 24 36 48 60 72 0.0
0.2
0.4
0.6
0.8
1.0
Time Off Lithium (Months)
First Year Off Lithium
Time (Months) 0 3 6 9 12
0.2
0.4
0.6
0.8
1.0
50% Recurrence
Proportion in Remission
Proportion Remaining in Remission
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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
− Specifically with VPA
• Carbamazepine (CBZ) and LTG are associated with lower risk than VPA
1. Wyszynski DF, et al. Neurology. 2005 2. Morrow J, et al. J Neurol Neurosurg Psychiatry. 2006 3. Cunnington M, et al. Epilepsia. 2007 4. Meador KJ, et al. Neurology. 2006 5. Holmes LB, et al. Arch Neurol. 2004
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Lamotrigine (LTG) Monotherapy Exposure: Increased 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 2. Meador KJ, et al. Neurology. 2006 3. Holmes LB, et al. Abstract presented at the 46th Annual Meeting of the Teratology Society. June 24-29, 2006; Tucson, Arizona.
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Lamotrigine: North American AED Pregnancy Registry
• 2008:
– N=792 with lamotrigine monotherapy; limited to those with medical records
– 16/684 (2.3%) – major malformations
– 5/684 (7.3/1000, or 0.73%)- oral clefts – 10-fold increase from external reference (0.7/1000)
– From other registries: 4/1623 (2.5/1000)
Holmes et al., Neurology 2008
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Lamotrigine: North American AED Pregnancy Registry
• 2012:
– N=1562 with lamotrigine monotherapy
– 31/1562 (2.0%) – major malformations
– 7/1562 (0.45%; CI 0.20-0.88) - oral clefts
– External reference - 0.11%
Holmes et al., Neurology 2008
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Neurobehavioral Teratogenicity and Anticonvulsants: Is there a Differential Risk?
• Data from several studies suggest VPA exposure is associated with increased risk for adverse cognitive and neurodevelopmental effects compared with other anticonvulsants
• Neurobehavioral risk with LTG unknown
Adab N, et al. J Neurol Neurosurg Psychiatry. 2004 Adab N, et al. J Neurol Neurosurg Psychiatry. 2001 Vinten J, et al. Neurology. 2005 Gaily E, et al. Neurology. 2004 Meader, et al. N Engl J Med. 2009
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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
Meador et al. N Engl J Med. 2009
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Cognitive Function in 6 year olds Following Fetal Exposure to AED’s
Child IQ at 6 years, by exposure to maternal antiepileptic drug use and periconceptional folate
Meador, et al. Lancet Neurol. 2013
Mean (95% CIs) are shown for folate (solid lines) and no folate (dashed lines).
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• 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
Treatment of Bipolar Disorder During Pregnancy: Lessons Learned
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Treatment of Bipolar Illness During Pregnancy: What is a Reasonable Strategy?
Cohen LS, J Clin Psychiatry 2007 (suppl 9).
• Lithium and lamotrigine have well characterized reproductive safety profiles, low absolute risks
• Lithium may be the best characterized and reasonable alternative for women who require an anti-manic agent but its use is declining
• Lamotrigine appears reasonable for the prevention of depressive episodes
• Atypical antipsychotics have growing body of data and do not at this time appear to be major teratogens
• More human pregnancy data available for older medications in the class
• May be reasonable to continue during pregnancy, particularly if patient has had good response, psychotic symptoms, is a lithium non-responder, or atypical was critical in affording euthymia
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Treatment of Bipolar Disorder during Pregnancy: Lessons Learned
• Polytherapy of bipolar disorder during pregnancy is the rule
• Frequency of use of atypical antipsychotics demands better data to inform use of these agents during pregnancy
• Absolute small risk may be acceptable versus risk of bipolar relapse during pregnancy and implications for puerperal relapse of the illness
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Postpartum Prophylaxis in Bipolar Women
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12
Cu
mu
lati
ve s
urv
ival
Prophylaxis (N=14)
No prophylaxis (N=13)
Time (weeks)
Significant difference between groups (Peto-Peto-Wilcoxen 2 = 6.966, df = 1, p<0.01)
Cohen LS, Sichel DA, et al. Am J Psychiatry. 1995.
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Altshuler, Cohen et al. Am J Psychiatry. 1996. Dolovich, et al. BMJ. 1998.
Benzodiazepines
• Methodological issues have confounded reports: dose, duration, class of BZD, other drug exposures, recall bias
• Risk of oral clefts following first trimester exposure (0-0.6%)
• Review of 12 studies (2001-2011): Most studies show no increase in malformations, no consistent pattern of defects
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ECT During Pregnancy
• Treatment of choice when expeditious management is imperative
• Use in delusional depression, mania
• External fetal monitoring, ultrasonography
• Comprehensive treatment team
68
www.mghcme.org
VA Reproductive Mental Health Initiative: Partnership with MGH
• Enhance Reproductive Mental Health care delivery in VA
• Collaboration between mental health, reproductive health, pharmacy benefits management, primary care, and MGH
• Preconception counseling and safe prescribing are key components
• Develop curriculum for providers addressing reproductive mental health across the lifecycle
www.mghcme.org
Reproductive Mental Health in Women Veterans: An Urgent Need
Dear Dr. Cohen: I am just back from a tour in Iraq and am finally settled back in my home with my husband and 3 year old daughter. I am being treated for PTSD and anxiety with venlafaxine and a little bit of Seroquel at night to help me sleep. We would like to grow our family but I am worried about what happens to my PTSD symptoms during pregnancy and what do I do about the medicines. My doctor told me to ask you.
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Cohen et al. Psychosomatics 1989
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www.womensmentalhealth.org
For Further Information:
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