Clinical Assistant Professor, NYU School of Medicine
Judy A. Greene, M.D.
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10.20.16 date of talk
Disclosures None
This presentation will include off-label use of medications in pregnancy and breastfeeding.
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To date, the FDA has not approved any psychotropics in pregnancy
Overview General Principals
Updates in Screening & Clinical services
Clinical Cases & Multiple Choice Questions
2016-2017 new updates SAGE-547 Stimulant use in pregnancy Marijuana use in pregnancy
Resources
Questions
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Restructured talk- those of you who have attended x past 4 years are now well versed in the risk/benefits of SSRIs in pregnancy, avoiding VPA in childbearing age pts, Today I’m going to focus on the changing landscape of perinatal mental heath in terms of screening, detection and tx New research from 2016-2017 Hot topics like MJ in pregnancy, melatonin Updates in the field over the past 1 year: uptick in media attention, new recommendations on screening for perinatal depression, growing body of literature High yield time for women to be stable; engage in treatment. Incredibly rewarding- work with women at this pivotal time
General Principles
Optimize non-pharmacological treatments
Mono-therapy when possible
Avoid newer medications Limited or no data on use during pregnancy and breastfeeding
Risk/benefit analysis No psychotropics are “safe” in pregnancy There is no “risk free” decision
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* Eg: preconception consultation: referred by psychiatrist, bipolar I- on 6 psychiatric meds:asenapine (Safris) lamictal, celexa, wellbutrin, klonopoin, trazodone -no currently in therapy * Polypharmacy- Increased risk of congenital heart disease has been reported w/exposure to mult antidepressants Concomitant use of antidepressants with benzos has been assoc with increased risk of congential heart disease when compared to use of either SSRI or benzo alone during preg (could represent competitive inhibition of hepatic metabolism leading to increased drug levels and increased neonatal risk) Risks of untreated illness on mother and child!!!
Unplanned pregnancy What percent of pregnancies in the US are unplanned annually?
A) 20%
B) 30%
C) 40%
D) 50%
www.bedsider.org
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Oops! Unplanned pregnancy = the rule, not the exception Eg: s/p postpartum psychosis with second child, s/p inpt admission, when asked at 3 months pp what form of contraception, long pause….. 50% preg in US; the rule not the exception; 80% teen pregnancies are unintended Clinicians angry at patients for becoming pregnant!
Documentation Before you provide the Rx, document in the medical record:
A) All prescribed and over the counter drug, environmental and substance exposures during pregnancy
B) Your plan to monitor symptoms and side effects across pregnancy
C) The risks of the medication and the risks of the psychiatric disorder(s) on pregnancy outcome
D) That you provided patient with relevant drug fact sheets in pregnancy eg: mothertobaby.org
“The plaintiffs failed to produce any reliable scientific evidence demonstrating that zoloft caused the injuries they alleged”
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Federal judge in Philadelphia dismissed >300 lawsuits alleging zoloft caused birth defects in children born to women on zoloft in pregnancy
New and Improved FDA Labeling
Published in December 2014
Implemented over the next three years (In effect: 6/2015) A, B, C, D, and X categories being phased out.
Three subsections Pregnancy General statement about background risk, fetal risk summary,
clinical considerations, data Information re: current registry
Lactation Information about amount of drug in breast milk and potential
effects on the breastfed child Females and Males of Reproductive Potential Information about pregnancy testing, contraception, and
infertility as it relates to the drug
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Pregnancy and Lactation subsections include 3 subheadings: Risk Summary, Clinical Considerations, and Data the new system will hopefully lead to more discussion between physician and patient about what is and is not known about the reproductive safety of a medication, versus a cursory reference to some previously assigned category label. Our group has shown that when it comes to making decisions about using medication during pregnancy, even when given the same information, women will make different decisions. This is critical since people make personal decisions about the use of these medications in collaboration with their doctors on a case-by-case basis, based on personal preference, available information, and clinical conditions across a spectrum of severity.
Perinatal Depression Screening
November 17, 2015
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Progress…. First Lady Chirlane Mccray; press release for perinatal depression screening at BHC; Initiative starting with all of the Health & Hospitals + Maimonides which account for ¼ deliveries in NYC. Raising awareness New programs are developing (Northwell perinatal mother-baby unit); Woodhull in Bklyn- psychiatrist in women’s health As of 2 weeks ago, Bellevue now has a NYCThrive social worker (full time) in Women’s health- devoted to perinatal depression screening.
US Preventive Services Task Force Recommendations
Siu AL. JAMA January 2016 Vol 315, 4
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These came after the ACOG recommendations for perinatal depression screening Panel gave the recommended screening a rating B, which means depression screening must be covered under the affordable care act. Recommendations do not specify which clinicians should screen (ob providers vs pediatricians vs both) or how often; or which screening tool to use
Mother-Infant Inpatient Unit
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20 bed unit Opened March 2016 2nd such facility in US (UNC Chapel Hill has similar inpt unit)
Preventable Tragedy? Postpartum mental illness?
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“monster mom” mother of 4 children, Daycare worker 1 month, 1 year, and 4 years Media’s portrayal of mental illness- Irresponsible journalism “Homicidal rage” when her 4 yo son dropped an egg on the floor; beat him with a broom Neighbor quoted in the article stating “she showed no remorse” and commented on her facial expression
Clinical Case #1 CC “My doctor told me I should go off my
antidepressant because the baby could be addicted”
31 yo married employed F with h/o recurrent MDD, OCD in partial remission presenting for preconception psychiatric consultation
Previously stable on escitalopram 30mg po daily, lorazepam 0.5mg po daily prn anxiety/insomnia
Tapered down to escitalopram 10mg po daily
No prior psychiatric hospitalizations, no h/o Suicide attempts
Clinical Case #1, cont. No etoh, tobacco, or illicits
Recent labs: CBC, Chem 7, LFTs, TSH wnl
PHQ9=22
Next steps regarding medication: A) Taper off escitalopram, initiate sertraline B) Taper off escitalopram, start weekly CBT C) Continue escitalopram at current dose D) Increase escitalopram dose to 30mg po daily; titrate to
remission of symptoms
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No SSRI is “safest” in pregnancy Use what has worked!!! Treat to remission of sx
www.mcpapformoms.org
www.mcpapformoms.org
SSRI Dose Changes in Pregnancy
The plasma concentrations of most SSRIs:
A) Do not change across pregnancy
B) Increase in the first trimester and then stabilize
C) Decrease across pregnancy, particularly in third trimester
D) Are elevated after birth and complicate breastfeeding by increasing infant irritability
Antidepressants in Pregnancy General Guidelines
For mild-moderate depression and/or anxiety: Consider non-pharmacological interventions
For moderate-severe depression and/or anxiety (suicidality, psychosis, poor weight gain, impaired self-care, inability to function): Continue or initiate antidepressant treatment
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Reiterates the APA-ACOG guidelines
Antidepressants in Pregnancy General Guidelines, cont.
Use the AD that has worked for the patient in the past
Monitor symptoms and side effects monthly throughout pregnancy
Dose might need to be increased as pregnancy progresses
Avoid multiple exposures when possible
No evidence for tapering prior to delivery (use lowest therapeutic dose)
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Duloxetine- 439 cases documented in the literature, malformation rate of approx 2.1% risk of spontaneous abortion was about 18% among women taking duloxetine. Reassuringly, the risk of pregnancy loss in women taking Cymbalta is not increased significantly over the 12%-15% risk of miscarriage seen in the general population. This is a complicated issue: it appears that having depression itself may impact the risk of miscarriage and more recent analyses have not documented an association between antidepressant exposure and spontaneous abortion. Mirtazapine- 300 cases documented in the literature; 2015 case series with 56 in utero exposures, no major malformations with 1TM exposure (n=26), 25% incidence of PNAS (poor neonatal adaptation syndrome); less likely to occur in breast fed babies exposed to remeron!
N Engl J Med 2014; 370(25): 2397-2407
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Published June 2014 Landmark study in the field. Large population based Cohort study; included 950,000 pregnant women enrolled in medicaid from 2000-2007 (about 65,000 SSRI 1st TM exposures!!!!) Compared risk of major cardiac defects among infants exposed to AD during 1TM compared to infants not exposed to AD Adjusted analysis and analyses that restricted the cohort to women with depression and that used propensity score adjustment to control for depression severity and other potential confounders. “most methodologically sophisticated study in the field to date and therefore has had a major impact in the field”
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6.8% of women used AD during the first trimester Associations btwn AD use and cardiac defects were attenuated with increasing levels of adjustment for confounding. *** Study found no sig association btwn paroxetine and right ventricular outflow tract obstruction or Between the use of sertraline and ventricular septal defects. Prior to the study; the jury was out: two studies showed a double or triple risk of R ventricular outflow tract obstruction associated with paroxetine use, and of ventricular septal defects with sertraline use. A meta-analysis estimated a 50% increase in the prevalence of cardiac defects overall with paroxetine use during the first trimester *this study the adjusted analysis restricted the cohort to women with a dx of depression to mitigate potential confounders *** women with anxiety disorders utilize more health care resources, including U/S, amniocentesis, and echocardiography of the infant; therefore-> higher rates of detection!!!! Detection bias!
Perinatal Insomnia Diphenhydramine
Unasom (doxylamine succinate)
Lorazepam 0.5mg -1mg prn
Ambien
Trazodone
Mirtazapine
Quetiapine
Anxiolytic and Hypnotics in Pregnancy
PLoS One. 2014 Jun 25;9(6):e100996.
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Older studies suggested increased risk of cleft lip and palate with benzo exposure in utero New study found no increase in overall risk of malformations among children exposed to benzos
Anxiolytics/Hypnotics cont. Singleton children born to women aged 15-45 years
between 1990-2010
UK primary care database
Absolute risks of major malformations calculated for children with 1TM exposure to anxiolytic and hypnotic drugs
Overall prevalence of malformations: 2.7% in 1,159 children exposed to diazepam 2.9% in 379 children exposed to temazepam 2.5% in 406 children exposed to zopiclone (stereoisomer,
eszopliclone available in US) 2.7% in 19,193 comparison group, mothers with dx MDD and
or anxiety but no 1TM drug exposure
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This study indicates no evidence for an increase in malformations in children exposed to benzodiazepines and non-benzodiazepine hypnotics in the first trimester of pregnancy. This data is reassuring when considering the reproductive safety of benzodiazepines as a class of medications; however, we would like to have more data on other benzodiazepines, such as clonazepam (Klonopin) and lorazepam (Ativan), which are used more commonly in the United States. Lunesta = eszopliclone Imovane= zopiclone
Postpartum Depression
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Alice Neel
SAGE-547 for Severe Postpartum Depression
SAGE-547 (injectable formulation of allopregnanolone) = potent positive allosteric modulator of GABAa receptors
Phase II, multicenter, placebo-controlled, double-blind trial, N=21 severe PPD Baseline score HAM-D >26 N=10 received active drug N=11 received placebo
Continuous IV infusion over 60 hour period Side effects: dizziness, sedation, somnolence (both
groups) Overall well tolerated; no women discontinued treatment
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“neuro-steroid” July 2016 results from Phase II study released All participants had inadequate response to AD trial IV SAGE-547 given over 60 hour period (48 hours, then dosage tapered over 12 hours to a maintenance dose to allow physiologic adjustment of decreasing allopregnanolone levels) (endogenous neurosteroid) Secondary endpoint: PHQ9 score at day 30 N= 10 received drug N=11 received placebo Well tolerated; sedation = most common se Adverse events about the same in both drug and placebo groups Limitations: IV infusion over 60 hours (expensive!!!), not compatible with breast feeding Additional studies 2017- cautious optimism
SAGE-547 for Severe Postpartum Depression
Results 7/10 women who received SAGE-547 achieved remission
from depression at 60 hours 1/11 women who received placebo achieved remission
(p=0.24)
PHQ-9 scores at day 30 SAGE-547 group score 0-4 (60%)
Limitations: Extremely small sample size, larger RCT needed IV infusion Not compatible with breastfeeding
SAGE Therapeutics press release July 2016, unpublished data
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Rapid response We won’t know until large trial which could take 2-4 years SAGE Therapeutics is developing a PO formulation of the drug
Perinatal Bipolar disorder
Clinical Case #2 “I’m pregnant; should I go off my Lithium?”
28 yo partnered F with history of bipolar I disorder stable on Lithium 900mg po QHS, unplanned pregnancy
PPhx: 2 prior psychiatric hospitalizations in setting of manic episodes; 1 prior suicide attempt
Prior medication trials: Valproic acid 1000mg po QHS Aripiprazole 10mg po daily -> akithisia Seroquel 300mg po QHS -> weight gain
Clinical Case #2, cont. No etoh, tobacco, or illicits
Next steps regarding medication : A) Discontinue Lithium due to risk of Epstein’s anomaly,
restart Lithium in 2nd Trimester B) Discontinue Lithium, initiate Atypical antipsychotic C) Continue Lithium at 900mg po QHS
Treating the Bipolar Pregnant Patient: General
Principles Bipolar I: Continue mood stabilizers and other
medications as needed to maintain stability throughout pregnancy
Mono-therapy when possible (avoid VPA)
Bipolar II: Attempt to taper off mood stabilizers prior to conception or during first trimester Monitor carefully for early relapse Optimize sleep hygiene, stress levels Resume mono-therapy during second trimester (or
earlier if necessary)
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Lamotrigine for bipolar II Atypical monotherapy *** preconception consultation, pt with bipolar I on lamictal, asenapine (Safris), celexa, wellbutrin, klonopin 2mg qid, trazodone 150mg daily!!!!!!????? 6 psychiatric meds
Bipolar Disorder in Pregnancy
Viguera et al. Am J Psychiatry 164:12, December 2007
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Prospective observational clinical cohort study, 89 F dx with bipolar I (61 or 70%) or II (28 or 30%) Subjects euthymic at conception: continued meds vs dc’d meds (Li, anticonvulsants, atypical antipsychotics) (6 months prior to conception or 12 weeks after conception) 58% women who d/c’d mood stabilizers relapsed during 1st TM! Overall risk of at least one recurrence in pregnancy was 71% Women who dc’d abpruptly or rapidly experienced a 50% risk of recurrence within 2 weeks! (proximate to conception defined as dc’ing meds 6 months prior to conception- 12 weeks after conception) Major clinical implication = women with severe and h/o freq relapses, recommend maintenance medication during pregnancy
Lithium 1TM exposure has 10-20 times greater relative risk of
cardiovascular malformations (Epstein’s anomaly*) Baseline risk 1/20,000 Absolute risk with exposure to Li = approx 1/1000
Pregnancy monitoring High-resolution U/S at 16-18 weeks of gestation to detect cardiac anomalies Fetal echocardiography TSH (every 3 months)
Dosage requirements change during pregnancy, labor, and delivery Monitor levels closely (monthly in 1TM, weekly in last month of pregnancy)
due to increase GFR in pregnancy Reduce dose prior to labor
Behavioral teratogenicity- none known
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Epstein’s anomaly- mortality rate of up to 50%; displacement of the tricuspid valve. Absolute risk is approx 1/1000 (0.1%)-1/2000 (0.05%) infants affected (compared to baseline frequency of 1/20,000) -5 yr f/u study of children exposed to Li during Glomerular filtration rate increases during pregnancy -> increased dosage 2nd and 3rd trimester of pregnancy (n=60) showed no sig behav probs (Schou 1976)
Lamotrigine Most registries find no increase in birth defects: Overall risk for major malformations 2.7%
Possible increased risk of oral clefts with 1TM exposure NA Antiepileptic Pregnancy Registry: 10x increased
incidence of oral clefts (1/1000 baseline risk) If true, absolute risk remains small (4.5/1000)
Behavioral teratogenicity- No increase in neurodevelopmental abnl found (Cummings et al. 2011)
Dosage adjustment may be necessary to maintain clinical response; Pre-pregnancy level (baseline) and monthly serum levels
Folic Acid 4mg/day
Clark et al. AJP 2013 Khan et al. Curr Psychiatry Rep 2016
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not replicated in other pregnancy registries Meta-analysis found no increased risk of malformations (2.9%) out of 564 pregnant women tx with lamictal, 5 cases of cleft palate, a prevalence of 0.9%; about 10 times higher than baseline prevalence of 0.1%) * Far safer than depakote and somewhat safer than Li, which causes a very low prevalence of a far more serious condition
Valproic Acid
6-10% risk of major congenital malformations
Cardiac defects associated w/1TM exposure
Craniofacial anomalies
2% risk of neural tube defects including spina bifida
Behavioral teratogenicity Lower IQs Poorer cognitive functioning Risk increases with dose and duration of exposure
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* Prenatal folic acid supplements did not prevent the occurrence of neural tube defects * WHAT FORM OF BIRTH CONTROL is your pt on VPA using? higher risk of additional educational needs among school aged children exposed to VPA in utero compared to those who were exposed to carbamazepine in utero and those not exposed to anticonvulsants (Adab et al 2001)
Atypical Antipsychotics in Pregnancy
Medicaid sample of 1,360,101 pregnant women with live-born infant
Atypical antipsychotic use during 1TM (n=9,258) Quetiapine n=4,221 Aripiprazole n=1,756 Risperidone n=1,566 Olanzapine n=1,394 Ziprasidone n= 697
Outcomes: major congenital malformations and cardiac malformations (during first 90 days after delivery)
Huybrechts et al JAMA Psychiatry August 2016
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Cohort included 9.258 women exposed to AP in 1TM compared to 570 (largest study to date)
Atypical Antipsychotics: Relative Risk for Congenital Malformations
Huybrechts et al JAMA Psychiatry August 2016
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First adjusted analysis: authors accounted for psychiatric and neurologic conditions, and the use of other psychotropic meds to adjust for possible confounding effects of the underlying disease and associated factors Second adjusted analysis: accounted for potential confounding variables including: medical illness (DM, htn, renal disease, obesity), other medications/number of prescription meds Adjusted for: psychiatric diagnosis, Obstetric morbidity index, etoh and/or drug use * After accounting for psychiatric conditions and other confounding variables, no increased risk for congenital malformations was found for typical or atypical antipsychotics, with a possible exception for risperdone.
Atypical Antipsychotics (SGAs)During Lactation
Systematic Review
Goal: Evaluate safety data on SGAs during lactation
Uguz, F. Jnl of Clinical Psychopharmacology June 2016
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Largest study to date No published reports of lurasidone, asenapine
Atypical Antipsychotics (SGAs)During Lactation
RID= Relative Infant Dose (weight adjusted infant dose relative to weight-adjusted maternal dose) Olanzapine RID= 1.59% Risperidone RID= 3.59% Aripiprazone RID- inconsistent values Quetiapine not detectable in breast milk if maternal dose
75mg/day or less
Conclusions: SGAs seem to be relatively safe in the exposed breastfed infants for short-term usage - limited data re: Aripiprazole, Ziprasidone, Clozaril
Additional studies re: long-term effects of SGAs on breastfed infants are needed
Uguz, F. Jnl of Clinical Psychopharmacology June 2016
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Aripiprazole- (long t1/2) may accumulate in infants due to immature hepatic and renal fx.
ADHD Medications in Pregnancy
Case-control study
Slone Epidemiology Center’s Birth Defects Study data
N=29,540 women who reported exposure to an ADHD medication in pregnancy
Overall prevalence of use increased from 0.2% to 1.3%
Adderall=most commonly used stimulant
Louik, C et al Pharmacoepidemiol Drug Safety Jan 2015
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Ego syntonic thoughts eg: “mother and baby are better off dead” r/o OCD
Stimulants in Pregnancy
Louik, C et al Pharmacoepidemiol Drug Safety Jan 2015
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Trends of the use of stimulants in pregnancy 30% pts are estimated to cont on stimulants from childhood throughout adulthood Id prevalence of use of ADHD meds
ADHD medications in pregnancy, cont.
Methylphenidate- not associated with increased risk of birth defects* N=382 exposures Congenital anomalies similar between exposed (3.2%)
and non-exposed (3.6%) Other adverse outcomes not assessed: PTB, LBW
Adderall
Vyvanse
Buproprion
*Diav-Citrin O et al. J. Clin Psychiatry 2016 May
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Ego syntonic thoughts eg: “mother and baby are better off dead” r/o OCD
Marijuana use in Pregnancy
Marijuana in Pregnancy 29 states and Washington DC have passed laws to legalize
medical MJ
Recreational MJ legalized in AL, CA, CO, ME, MA, NE, OR, WA, Washington DC
Prevalence of MJ use in pregnancy increased from 2.37%-3.85%
ACOG issued a committee opinion discouraging physicians from suggesting perinatal use of MJ.
Risks to fetus include: intrauterine growth restriction, low birth weight, stillbirth, cognitive delays and deficits, poor executive functioning
Brown Q. et al. Trends in MJ use among pregnant and non-pregnant reproduc aged women, 2002-2014 JAMA. 2016 Volkow, N et al The Risks of MJ use during pregnancy JAMA 2016
I’d like to end with a growing list of invaluable resources for patients and clinicians Educate/inform re: perinatal mood disorders and treatment options. Thank you very much for your attention
