Wisconsin Public Psychiatry Network Teleconference · Sequelae of maternal depression ... Treatment...
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Wisconsin Public Psychiatry Network Teleconference (WPPNT) • This teleconference is brought to you by the Wisconsin Department of Health Services (DHS), Division of Care and Treatment Services, Bureau of Prevention Treatment and Recovery and the University of Wisconsin-Madison, Department of Psychiatry. • Use of information contained in this presentation may require express authority from a third party. • 2019, Charlotte Ladd, Reproduced with permission. 1
Transcript of Wisconsin Public Psychiatry Network Teleconference · Sequelae of maternal depression ... Treatment...
Wisconsin Public Psychiatry Network Teleconference
(WPPNT)
• This teleconference is brought to you by the Wisconsin Department of Health Services (DHS), Division of Care and Treatment Services, Bureau of Prevention Treatment and Recovery and the University of Wisconsin-Madison, Department of Psychiatry.
• Use of information contained in this presentation may require express
authority from a third party.
• 2019, Charlotte Ladd, Reproduced with permission.
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WPPNT Reminders
Call 877-820-7831 before 11:00 a.m. Enter passcode 107633#, when prompted. Questions may be asked, if time allows. To ask a question, press *6 on your phone to un-
mute yourself. *6 to remote. The link to the evaluation for today’s presentation
is on the WPPNT webpage, under todays date: https://www.dhs.wisconsin.gov/wppnt/2018.htm
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TREATING PERIPARTUM MENTAL ILLNESS
Charlotte Ladd, MD, PhD
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Good afternoon, thanks for coming. This talk is the second in a three part series. Dr. Jeffrey Newport began the series a few weeks ago by reviewing the challenges of perinatal research, including confounding factors, sampling bias, and lack of placebo controlled studies. I’m going to fill you on the nuts and bolts of treating pregnant and postpartum women, particularly with respect to medication, and Roseanne Clark will finish the series in the fall by reviewing therapeutic techniques for postpartum depression.
Perinatal Psychiatry = Preventative Psychiatry Perinatal Medication = Controversy, Fear Knowledge leads to Rational Decision Making
Perinatal Psychiatry 4
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So as a medical student, I felt very good about my decision to focus on perinatal psychiatry, which I viewed as a form of preventative psychiatry. What I was naïve about then was the enormous controversy that was about to erupt regarding use of antidepressants and other psychotropic medications in pregnancy. So I spent a great deal of time familiarizing myself with the available data in order to be able to discuss the potential risks and benefits of pharmacologic treatment with my patients.
Prenatal Programming (Wadhwa) 5
Pregnancy and Family Planning
“The field of perinatal psychiatry faces the challenge of trying to understand whether more adverse outcomes occur in women who take antidepressants but remain euthymic or in women who do not take antidepressants but remain depressed in pregnancy.”
Rita Suri and Lori Altshuler (2009) “No
Decision is Without Risk” J Clin Psychiatry 70(9): 1319-1320.
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Perinatal Psychiatry
“Too often, a pregnancy in the context of ongoing psychiatric treatment is experienced by the patient and her health care providers as a surprising event that can derail treatment, and care is often driven by fear rather than rational decision-making using evidence-based medicine.”
“The best model…is that of a collaborative decision-making partnership, which includes the patient’s preferences and values at the forefront, treatment options tailored to the situation, maximization of nonmedication options, and the rational use of medications.” Marlene Freeman (2009) J Clin Psychiatry 70(9): 1311-1312
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In an essay entitled “No decision is without risk” these authors go on to say that…
Overview
Risks of maternal perinatal mental illness Risks of antenatal pharmacologic treatment Postpartum treatment Case Review Resources
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Dr. Fritz, who organized this series, was hoping that we could include some translational research information. So, I will begin with a brief overview of how maternal behavior influences epigenetics. Then I’ll talk about prenatal depression and anxiety, which are the best predictors of postpartum depression and the most controversial to treat. I’ll first review the epidemiology and risks of maternal depression and then discuss the known risks of antidepressants in pregnancy. We’ll then talk about treatment guidelines and optimizing outcomes. Then I will talk a little about treating prenatal bipolar disorder and psychosis, postpartum depression, anxiety, and psychosis, and review what we know about medications in lactation. Finally, I will provide a few resources that you might find helpful to keep in your office for future reference.
Risks of prenatal depression to the fetus
Increased substance use and poorer prenatal care Poorer birth and neonatal outcomes:
Increased Preterm delivery Low birth weight, SGA Neonatal irritability and hypoactivity (Field T, review) Elevated cortisol and lower vagal tone in newborn Developmental delay at 18 months (Deave T)
Prenatal depression is the single best predictor of postpartum depression
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When considering the risks of prenatal depression, one must acknowledge the tendency for depressed individuals to take poor care of themselves; this leads to increased rates of substance abuse and poorer prenatal care among depressed women. Depression also leads to worse obstetrical and neonatal outcomes, whether by itself or confounded by poorer self care: these include… Finally, prepartum depression is the ..
Sequelae of maternal depression
Increased externalizing behaviors in preschool (Essex) Increased internalizing behaviors in middle childhood Increased depression and cardiovascular disease in
adulthood Chronicity of depression is the most robust risk factor Less than half the psychiatric risk to the offspring associated
with maternal depression can be accounted for by psychosocial factors (Barker ED, Br J Psychiatry 2012, 200:124-129)
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The effects of maternal depression are long lasting in humans. Marilyn Essex has investigated the effects of maternal depression on offspring in a longitudinal cohort in Wisconsin that began when the mothers were pregnant. In preschool, children of depressed moms exhibit increased externalizing behaviors, by middle childhood, this vulnerability morphs into internalizing behaviors, and in adulthood, offpring of depressed mothers are more likely themselves to be diagnosed with depression and cardiovascular disease. In these studies, it is the chronicity of depression that carries the most risk
Transmission of Risk
Lower TNFα in women whose depression was treated successfully with medication in pregnancy vs untreated women or nonresponders (Miller 2018)
MDD is associated with higher CRF and cortisol levels which cross placenta and may alter neurodevelopment (Wadhwa)
42 CpG sites with significantly different DNA methylation levels in neonates exposed to non-medicated depression or anxiety relative to controls (Non 2014)
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Thus, investigators such as Robert Sapolsky and Wadwha have hypothesized that
Transmission of Risk
Maternal depression can alter the course of the newborn’s behavioral, endocrinologic, and psychological development in manner that may be phenomenologically adaptive to a species under environmental stress but maladaptive to the individual (Wadwha, Sapolsky)
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Maternal Depression Pharmacotherapy
Fetal Health
Prenatal Care
Substances Nutrition
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Maternal health
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Balancing Maternal and Fetal Health
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So when considering using antidepressants in pregnancy, you have to balance the effects of mom’s depression vs medication on the developing fetus. If you chose to use antidepressant medication, aim toward remission, so that then the fetus is exposed only to medication, not to both medication and maternal depression.
Resolved depression Pharmacotherapy
Fetal Health
Prenatal Care
Substances Nutrition -
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Maternal health
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Balancing Maternal and Fetal Health
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Because as a mother’s mood improves, the impact of depression on her child lessens, she is less likely to use substances, and she is more likely to seek prenatal care. If she reaches a euthymic state, then the impact of these three risks subsides, and she is left with the risks of medication, which we will discuss now.
Data: strengths and limitations Pharmacokinetics Birth outcomes Neurobehavioral outcomes
SSRIs in Pregnancy 15
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Antidepressants are among the best studied medications in pregnancy. First I will briefly talk about the strengths and limitations of this research (since Dr. Newport covered this area well three weeks ago), then I’ll talk about the pharmacokinetics of antidepressant passage into the placenta, birth outcomes associated with antidepressants, and neurobehavioral outcomes in children exposed to antidepressants in utero
Data: strengths and limitations
SSRIs are among the best studied drugs in pregnancy
Considerable data on TCAs, haloperidone Less data on newer antidepressants,
antipsychotics Few controlled efficacy studies Existing studies are often confounded by
maternal illness, substance use, age, poor prenatal care, and sampling bias
Limited long term follow up studies
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For ethical reasons, there are as yet no controlled efficacy studies of antidepressants in pregnancy Therefore, existing studies are … Long term follow up studies are limited by the relative “newness” of serotonergic antidepressants, the oldest being prozac which was introduced in the late 1980s
Pharmacokinetics: SSRIs
There is extensive passage of antidepressants into amniotic fluid: the fetus is essentially bathed in medication in utero
Rat studies suggest that the serotonin transporter is saturated in the fetal developing brain at doses of SSRIs equivalent to 10 mg paroxetine
Conversely, passage into breast milk is orders of magnitude less than placental passage “a drop in the bucket” compared to in utero exposure Sertraline and paroxetine are virtually undetectable in infant serum
after breast feeding Lowest effective doses are encouraged but don’t undertreat!
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Antidepressants pass freely into the placenta… Conversely,
Birth outcomes: SSRIs
Loss of pregnancy*: Increased risk of spontaneous abortion Increased risk of miscarriage (12.4% vs. 8.7%, RR=1.45)
Gestational age*: Preterm delivery rate is higher with SSRI, TCA, or SNRI
exposure in some studies but not others Growth effects*:
Decreased birth weight Increased incidence of SGA (0.033 difference)
*confounded to some degree by substance use, poor prenatal care, and maternal illness
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Antidepressant exposure has been associated with significant differences in birth outcomes, including increased risk of spontaneous abortion and miscarraige, decreased gestational age, and decreased birth weight. Usually the reductions in birth age and weight are minor, on the order of a few days or a few ounces. Only some studies have found an increased rate of preterm delivery with antidepressants. Much of the data is confounded by substance use, poor prenatal care, and maternal illness. However, these differences are important to acknowledge and discuss with patients who are considering taking an antidepressant in pregnancy
Poor Neonatal Adaptation Syndrome (PNAS)
Transient, self-limited, usually mild Hours to days after birth 15-30% with SSRIs, SNRIs, mirtazapine, TCAs
Tachypnea, hypoglycemia, irritability, weak cry, convulsions No adverse effects 2 years later (Oberlander 2004) Most common with paroxetine and fluoxetine (Moses-
Kolko, 2005) Less common with breast feeding (Smit 2015) Treatment is supportive Most data is cross-sectional and unblinded
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At birth, up to 30% of infants exposed to serotonergic antidepressants exhibit “poor neonatal adaptation,” a transient syndrome characterized by irritability, tachypnea, hypoglycemia, and convulsions. Since tricyclic antidepressants are serotonergic as well, they are also associated with this syndrome. Treatment is supportive and may include a day or two in the NICU for monitoring. There have been no long term adverse effects associated with this syndrome, which is believed to represent a withdrawal phenomenon from the antidepressant, similar to that seen in adults
Structural malformations: SSRIs
Meta-analysis of SSRIs in first trimester: no increased risk of congenital birth defects (Einarson 2005)
Slone Epidemiology Center Birth Defects Study: No increase in birth defects with SSRIs in pregnancy (Louik NEJM 2007)
National Birth Defect Prevention Study: No increase in OR for sertraline, citalopram, escitalopram exposure in utero (Reefhuis BMJ 2015) Increased OR for birth defects with paroxetine (N=214) Increased OR for craniosynostosis and right ventricular
outflow tract obstruction with fluoxetine (N=331)
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Structural malformations are perhaps the most feared and controversial of all potential complications of antidepressant treatment in pregnancy. In response to increasing public concern regarding the risks of treating depression in pregnancy with medication, the American College of Obstetritians and Gynecologists teamed up with the American Psychiatric Association in 2009 to review the literature and draft guidelines for the treatment of prenatal depression. These guidelines were published in both General Hospital Psychiatry and Obstetrics and Gynecology in September of that year. In carefully reviewing the extant literature on the risks of structural malformations following in utero exposure to antidepressants, the authors said this:
Structural malformations: other antidepressants
SNRIs (Lassen 2015) – no increased risk found Venlafaxine (N=3186) Duloxetine (N= 668)
Bupropion OR =1.6 for VSD (Louik 2014)
TCAs – no increased risk found Mirtazapine (N= 300s) -no birth defects reported
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In contrast to the controversy surrounding SSRIs in pregnancy with respect to structural malformations, there is little evidence to suggest that TCAs are teratogenic – the majority of studies show no increased risk of structural malformaitons. The data for newer antidepressants is more sparse, but there is no evidence yet of increased rate of congenital anomalies with these medications
Persistent pulmonary hypertension Increased endothelin-1 and decreased NO lead to
increased pressure in the pulmonary vasculature, R to L shunting of blood, and neonatal hypoxia
Up to 10% mortality rate, depending on cause (6% with meconium aspiration)
Maternal risk factors: C-section, DM, NSAIDs, and tobacco OR = 6.1with SSRIs in the second half of pregnancy
(Chambers et al., NEJM 2006) Rate increases from 0.5-2 per 1000 to 3-6 per1000 FDA black box warning for PPHN was retracted in 2011
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Another area of concern with in utero SSRI exposure is an increased risk of persistent pulmonary hypertension. Chambers and colleagues reported in the NEJM in 2006 a 6 fold increase in this phenomenon after exposure to SSRIs in the second half of pregnancy. This study led to a black box warning on PPHN on all SSRIs. No elevated risk was associated with exposure in the first half of pregnancy. This is a rare complication: the absolute risk even with SSRI exposure is only 3-6 per 1000 births. Neonates born with persistent pulmonary hypertension exhibit hypoxia due to R to L shunting of blood, which can lead to right heart failure and death in up 10 % of infants. Maternal risk factors for PPH include DM, use of NSAIDs or tobacco, and having a C-section. Due to subsequent conflicting data regarding the risk of PPHN with in utero SSRI exposure, the FDA black box warning was retracted in 2011.
Neurodevelopmental outcomes1
Cognition: no adverse outcomes (Nulman) Behavioral: no adverse outcomes (Oberlander; Caspi)
Education IQ Temperament Internalizing and externalizing symptoms
1Gentile S and Galbally M (2010) J Affect Disord,
doi:10.1016/j.jad.2010.02.125
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In a review of the literature published in 2010, Gentile and Galbally report that there are no adverse cognitive or behavioral outcomes following in utero exposure to antidepressants, including educational attainment, IQ, temperament, or mental health symptoms
SSRIs and SNRIs: Summary
Small effects on pregnancy health and fetal growth 15-30% risk of transient “poor neonatal adaptation” 6 fold increase in persistent pulmonary hypertension but a low
absolute risk of 3-6 per 1000
No documented risk of structural malformations with sertraline, citalopram, escitalopram (large N)
Most studies show no risk with fluoxetine Avoid paroxetine unless it is only effective agent
No documented risk of structural malformations with venlafaxine or duloxetine (smaller N)
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In summary, the existing data regarding SSRIs in pregnancy points to…
Other antidepressants: Summary
Tricyclic antidepressants: Useful for agitated depression or severe insomnia Not associated with structural malformations or PPH
Atypical antidepressants: Bupropion
may be useful if patient also wants to quit smoking Reduces nicotine exposure but does not increase rate of cessation (Nanovskaya 2016)
Also may be useful for comorbid ADHD ? Risk of VSD (OR=1.6)
Mirtazapine: useful with comorbid hyperemesis gravidarum
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TCA are associated with neonatal syndrome but not structural malformations or PPH. They can be a useful treatment for agitated depression or depression with severe insomnia. Atypical antidepressants are not well studied in pregnancy but could be used if previously helpful in a patient or if treating comorbid nicotine dependence in the case of bupropion or comborbid hyperemesis gravidarum in the case of mirtazepine, since this antidepressant is very kind to the stomach, often increasing appetite instead of causing nausea. SNRIs such as venlafaxine or duloxetine are not well studied in pregnancy and decisions regarding use of these medications are made on a case by case basis
Preconceptual treatment planning Approach to depression in an unmedicated pregnant patient Approach to depression in a medicated pregnant patient
Treatment Guidelines for Prepartum Depression 26
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Next I’ll discuss some treatment guidelines for depression in pregnancy, beginning with preconceptual treatment planning, then the approach to the depressed unmedicated patient, and finally the approach to a patient who finds herself pregnant while taking antidepressant medication
Family planning
50% of pregnancies are unplanned. Women of childbearing age should be approached as if they were pregnant
CDC and ACOG recommend that every woman of reproductive age take 400 mcg of folic acid daily Reduces neural tube defects by 50-70% Reduces rate of autism spectrum disorders
Divalproex and carbamazepine should be avoided in women who might get pregnant
Reliable birth control should be encouraged in women suffering from severe depression, mania, or psychosis
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Keeping in mind that 50% of all pregnancies are unplanned, all women…
1. Assess severity
2. Length of treatment
3. Chronicity
4. Response to therapy
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This is an algorithm presented in the joint report from ACOG and the APA. I was not able to distribute copies of this article due to copyright laws, but I do recommend that you obtain this article and keep it handy for future reference. In this scenario of pre-conceptual planning, the severity and chornicity of illness is assessed as well as the length of treatment. A stable period of at least 6 months is recommended before conception. In a patient with nonsevere depression it is reasonable to taper the antidepressant and commence individual psychotherapy as a means of treatment and relapse prevention. However, patient preferences play a large role in the decision making process and if she wants to remain on medication, this is also reasonable and she should be given information about potential risks.
General Principles
Discuss the risks of exposing the fetus to the mother’s mental illness vs the risks of exposure to medication
Decision is driven by illness chronicity and severity as well as patient’s comfort level
The more severe and chronic the illness, the more likely pharmacologic management will need to be continued in pregnancy and postpartum
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In this risk benefit discussion, both the risks of prenatal depression and antidepressant treatment should be discussed with the patient. If her depression has been severe and/or chronic, then medication may be neccesary to optimize her mood throughout the pregnancy and postpartum peroid
Approach to a patient with MDD who is pregnant & unmedicated:
1. Assess severity
2. Willingness to take medication
3. Response to psychotherapy
4. R/o bipolar disorder
5. Comorbid conditions?
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The next scenario involves an unmedicated pregnant patient who becomes depressed. Again the first step is to assess severity and the patient’s preferences regarding medication. Her response to therapy in the past can also guide treatment
Treating Depression in Pregnancy
In a patient who is unmedicated: A trial of psychotherapy alone is warranted unless the
depression is severe or patient prefers medication SSRIs (except paroxetine) or TCAs are first line Use information on previous successful trials to guide
drug choice – this is no time to experiment! If there is no medication history, sertraline, fluoxetine,
or citalopram are reasonable choices TCAs may be helpful for agitated depression,
especially with insomnia
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Thus, in a depressed pregnant patient who is unmedicated… For more severe depression, medication is often indicated, with
Approach to a patient with MDD who is pregnant and currently taking antidepressants
1. Assess severity
2. Willingness to continue medication
3. Response to therapy
4. Chronicity and recurrence
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Finally, if a patient who is taking antidepressants finds herself pregnant, what should you do? Again, assess severity, patient preference re: medication, response to therapy in the past, and chronicity of illness. If a patient has recurrent depression that has relapsed without medication, it is advisable for her to continue medication if that is acceptable to her. If she wishes to discontinue medication, this should be done gradually, by no more than 25% every 1-2 weeks, while monitoring her mood closely.
Treating Depression in Pregnancy
In a patient who is taking an antidepressant: If the patient chooses to continue medication,
consider if the medication is working: Yes: continue medication – switching can induce relapse No: increase the dose if not maximized OR switch to a
previously helpful medication or one with extensive safety data (fluoxetine, sertraline, citalopram)
If the patient chooses to taper medication, do so slowly, reducing by 25% every 1-2 weeks and monitoring closely for worsening depression
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If a woman decides to continue antidepressant medication and her current medication is working, then doing nothing is often the best choice. If it is not working…
Ways to Improve Maternal Mental Health
Psychotherapy Exercise Increase light exposure Increase social supports Optimize nutrition, including prenatal vitamins
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Remember that there are nonpharmacologic ways that women can improve their mental health, such as … However, these are not a substitute for medication for treating severe depression
Ways to Optimize Fetal Health
Prenatal care Prenatal vitamins Adequate hydration (64 oz recommended) Reduce stress Avoid substances
Tobacco Alcohol Marijuana Other illicit drugs Unneccesary OTC or prescription medication
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There are also ways to optimize fetal health and thereby reduce the likelihood of obstetric and neonatal complications. These include regular prenatal care, daily prenatal vitamins, adequate hydration, stress reduction, and abstinence from substances, including tobacco, alcohol, and marijuana. Additionally, if there are any OTC or prescription drugs that the patient can do without, it is prudent to discuss this with her or her other physicians to try to streamline her medication exposure.
Lithium Lamotrigine Haldol Atypical antipsychotics
Treating Bipolar Disorder in Pregnancy 36
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Now I’ll briefly touch on the approach to bipolar disorder in pregnancy, which, like epilepsy, nearly always requires pharmacologic prophylaxis.
Date of download: 5/2/2012
Copyright © American Psychiatric Association. All rights reserved.
Risk of Recurrence in Women With Bipolar Disorder During Pregnancy: Prospective Study of Mood Stabilizer Discontinuation
Am J Psychiatry. 2007;164(12):1817-1824 doi:10.1176/appi.ajp.2007.06101639
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There is an enormous risk of relapse to either depression or mania when a mood stabilizer is discontinued in pregnancy. Once a mood episode sets in, it can be very difficult to resolve, especially within the context of hormonal fluctutations and additional psychosocial stress. Therefore, mood stabilizer treatment is usually recommended in pregnancy, particularly with more severe forms of bipolar disorder
Lithium: complete placental passage 38
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Lithium remains the gold standard in treating bipolar disorder in pregnancy. As a salt it has demonstrates complete placental passage in utero
Lithium: potential complications
Cardiac malformations: RR=1.11 dose of 600 mg or less RR=1.6 for 601-900 mg RR=3.22 for > 900 mg
Absolute risk of Ebstein’s anomaly < 0.1% (Cohen 1994)
Fetus: neonatal goiter, fetal diabetes insipidus, neonatal hypoglycemia, hydronephrosis, hypotonia, atrial flutter
Pregnancy: gestational diabetes, preeclampsia, preterm delivery, LBW, cyanosis, polyhydramnios
No evidence of adverse long term neurobehavioral outcomes in school age kids (Shou, 1976)
Greatest risk is in the first month of pregnancy with variable risk in the remainder of the first trimester
Lithium registry (Healthcare Technology Systems, Inc., Madison, WI 53717)
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Thus, the fetus is exposed to as much lithium as the mother and can experience changes in thyroid production, kidney function, and cardiac conduction. For mom, lithium can increase the risk of …. The most notorious risk with lithium in pregnancy is that of Ebstein’s anomaly, a right sided cardiac defect that affects less than 0.1% of exposed infants. Thus, the absolute risk for this malformation is quite small. However, the fear of this defect led to a class D pregnancy class rating which remains today. It is important to remember that the fetal heart is formed in the first 6 weeks of life and thus resuming lithium after this period may reduce risk
Guidelines for Li in late pregnancy
Use minimum effective dose Monitor plasma [Li] closely throughout pregnancy as GFR
changes (1.2 mEq/L is upper limit) Adjust Li dose as needed when used concomitantly with
antihypertensives or in the presence of polyhydramnios Suspend Li administration 24-48 hours before scheduled
delivery or at onset of parturition Check Li level on admission to L&D Administer IVF throughout labor and delivery Resume Li when medically stable after delivery
Newport DJ et al., Am J Psychiatry 2005
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To reduce complications with lithium in late pregnancy as the mother’s fluid status changes dramatically, use the least effective dose, monitor blood levels frequently, reduce the dose if antihypertensives are added, and suspend lithium adminsitration at least 24 hours before delivery if possible, administering IVF throughout parturition. Fortunately, the obstetricians at Meriter in the Perinatal Clinic are familiar with lithium and can perform pre-pregnancy consultation if desired – I have those referral forms if anyone is interested.
Lamotrigine
Initial concern about increased incidence of cleft lip/palate the North American Antiepileptic Drug (NAAED) Pregnancy Registry has not been substantiated
OR =1.31 (1/550) all oral clefts (Dolk 2016) Meta-analysis of 21 studies: no increased risk of
major malformations (Pariente 2017) International lamotrigine pregnancy registry:
http://www.inversk.com/activereg/activereg.asp
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Lamotrigine is a lot less complicated to use in pregnancy and postpartum. The overall rate of major congenital malformations in the lamotrigine registries is 2.7-2.9%, or less than the average rate of malformations in the general population, which is 3%. However, the rate of orofacial cleft malformations is 8.9 per 1000, or just under 1%, with a RR of 24. This risk may be greatest for exposures in the first trimester.
Valproate and Carbemazepine
4 fold increase in major congenital malformations as well as increased cognitive deficits later in life
Do not prescribe to women of childbearing age unless a reliable form of birth control is used
If either are necessary, then prescribe 4 mg folic acid daily to reduce the risk of neural tube defects
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Valproate and carbemazepine carry a 4 fold risk of major congenital malformations as well as incresaed cognitive deficits later in life. Therefore, they should not be prescribed to women of childbearing age unless a reliable form of birth control is used….
Antipsychotic use in pregnancy
FGAs 2011: FDA warning about EPS and withdrawal Lower BW, increased risk of preterm birth (Habermann 2013) No increased risk of congenital malformations Haloperidone is generally preferred among perinatal specialists
Atypical antipsychotics: 2011: FDA warning about EPS and withdrawal Increased risk of gestational diabetes (Boden 2012) Associated with developmental delay until age 1 (Peng 2013; Johnson
2012) Quetiapine has least placental passage =0.44 (Paulzen 2018)
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There is no increased risk of congenital malformations with haldol, making it a drug of choice in pregnant women with bipolar disorder or psychosis. There is less data on the atypical antipsychotics, but these can be used if clinically indicated in pregnancy
Choosing an atypical antipsychotic
Seroquel: No increase in congenital malformations (Cohen 2018,
Damkir 2018) Low penetration into fetal circulation =0.18 (Paulzen 2018)
Olanzapine: No increase in congential malformations (Damkir 2018)
Aripiprazole: No increase in congential malformations (Damkir 2018)
Risperidone: Hyperprolactinemia ?associated with small increase in congenital malformations
(Damkir 2018) Ziprasidone: limited data
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The amount of …
Benzodiazepines
Treat acute agitation, insomnia, or mood instability Safety data are controversial Initial reports of cleft lip and cleft palate with
diazepam (OR = 4) Early reports suggested an overall risk of cleft
lip/palate = 0.7% when fetus is exposed to benzodiazepines in the first trimester.
Meta-analysis found an increased rate of cleft lip (OR = 1.76) with benzodiazepines in case control studies but not cohort studies. (Dolovich et al., 1998)
Addition of 4 mg folate can potentially reduce risk
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Benzodiazepines may be used cautiously and temporarily in pregnancy to acutely target severe agitation, insomnia, or mood instability. Their safety data is controversial because of initial reports of cleft lip/palate associated with diazepam. Recent meta-analyses found that the OR of cleft lip is 1.76 with benzodiazepines in case control but not cohort studies. The greatest risk for this appears to be in the first trimester
Benzodiazepines (cont)
When used in 2nd and 3rd trimesters, main concerns are fetal side effects and dependence
Use minimum effective dose and monitor newborn closely for: toxicity (sedation, decreased muscle tone, and breathing
problems) withdrawal (irritability, sleep disruption, and, less
commonly, seizure) Lorazepam (0.5-1mg) is used most commonly in
clinical and emergency settings
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In the 2nd and 3rd trimesters, the main concerns with benzodiazepine use are fetal side effects and dependence. Therefore, one should always prescribe the minimum effective dose and monitor the infant closely for ..
Treating Insomnia
Sleep is essential to good health! Review Sleep Hygiene first Tricyclic antidepressants
Amitriptyline (25-50mg) Imipramine (25-50 mg)
Benzodiazepines (lorazepam 0.5-1 mg) Diphenhydramine (25-50 mg)
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Insomnia is a common problem in pregnancy and postpartum. Proper sleep hygiene should be encouraged before the use of hypnotics. This includes… Because of their extensive safety data, tricyclic antidepressants are often recommended for insomnia, especially in the context of an anxiety or depressive disorder. Short term benzodiazepines or antiistamines may also be used for severe insomnia.
Nonpharmacologic treatment options
Psychotherapy Interpersonal therapy Cognitive behavior therapy
Light therapy ECT (severe mood disorders)
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For mild to moderate depression, psychotherapy with or without light box therapy may be sufficient. For severe depression with SI or psychosis, ECT is also an option.
Optimizing outcomes
Encourage adequate fluid intake Daily PNV with at least 4 mg of folate Good nutrition; Sleep hygiene Exercise (preferably outdoors 20 min 3-5 times per
week) Close follow up with psychiatrist or therapist Minimize other exposures: caffeine, alcohol,
tobacco, OTC medications, and unneccessary prescription medications
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To optimize outcomes, expectant mothers are encouraged to consume adequate fluids, take a daily PNV with at least 4 mg of folate, practice good sleep hygiene, exercise regularly, preferably oudoors, abstain from substances, and follow up closely with their providers.
Risk Diagnosis Treatment
Long term consequences
Postpartum depression, anxiety & psychosis 50
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Finally, I’ll discuss the assessment and management of postpartum depression, anxiety, and psychosis
Postpartum depression
10-15% women Distinct from baby blues: later, more persistent,
anhedonia, interferes with sleep and appetite Begin in the first 3-6 months postpartum Screen with EPDS = Edinburgh Postnatal Depression
Scale* Emphasizes mood and cognitive features of depression
rather than neurovegetative symptoms Score >13 is suggestive of clinically significant depression
warranting further assessment
*Cox, J.L., Holden, J.M., and Sagovsky, R. 1987
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PPD affects 10-15% of women in the first three months after delivery. It is distinct from the baby blues in that it occurs later and is more persistent, interferring with sleep and appetite as well as causing daily sad mood and anhedonia. All postpartum women should be screened for depression with the EPDS. Those scoring greater than 13 should be assessed clinically for severity of illness and level of treatment needed
Postpartum depression
Postpartum depression may be the first “early adverse life event” for the infant, contributing to psychiatric vulnerability later in life (Stowe Z)
Single best predictor of mental health problems in early and middle childhood (Essex MJ)
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Remember that maternal depression may be a child’s first early adverse life event and increase his or her vulnerability to mental health problems in middle childhood and adulthood.
Transmission of Risk
Depressed mothers have been found to be intrusive or withdrawn in interactions with their infants (Cohen 1986)
In preclinical studies, changes in maternal nurturing permanently alter the offspring’s HPA axis in such a way as to make the individual more vulnerable to stress
Infants of depressed mothers display (Abrams, 1995): increased gaze aversion poorer orienting skills depressed motor tone lower activity levels
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Like low licking and grooming mother rats, depressed moms tend to ignore their infants. They are often withdrawn, fail to make eye contact, and turn their infant outward when holding him. Infants in turn, learn to avert their own gaze from others, become more psychomotorically slowed, and explore their environment less. Thus, intervening in maternal depression is very important.
Postpartum risk assessment
Postpartum depression often presents with intrusive thoughts of harming the newborn
Screen for homicidal thoughts Normalize them Ask: “Do you ever have intrusive thoughts of harming
your baby?” Obtain details on thoughts, intent, distress with thoughts
and whether partner is aware of these thoughts Ask if she feels comfortable caring for her child
Screen for suicidal thoughts
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All women endorsing postpartum depression should be carefully screened for the presence of suicidal and homocidal thoughts, which are not uncommon in this population. Homicidal thoughts are best characterized as intrusive thoughts of harm coming to the baby, often at the hands of the mother. These thoughts are akin to obsessions seen in OCD, and they are usually viewed as egodystonic. Most women are horrified at these thoughts and afraid and ashamed to mention them to anyone. It is important to educate women with PPD that these thoughts are common and a symptom of the illness, not a reflection on them as a mother. By normalizing as part of the illness, you are more likely to get an honest answer to the following question:…Follow up by asking if she feels safe around her child and if she has any thoughts of wishing she were dead or of harming herself. Inquire about her ability to bond with her baby. Women who are severely depressed will often not want to interact with their child – this is an indication for aggressive treatment and involvement of the father or other family member in the discussion of treatment and safety. If a women endorses homicidal thoughts, you must assess how she responds to them. If they are ego dystonic and she understands that they are a part of her illness AND she is emphatic that she would not act on them, then there is no need to separate mom from child, instead you may want to encourage a family member to help out for a few weeks until she begins to feel better. If she is extremely agitated with the thoughts, is uncomfortable caring for her child or is in any way psychotic, she will need to be supervised by another family member at all times or hospitalized.
Postpartum anxiety
GAD: mom fears often infant dying, unable to sleep Challenge catastrophic thinking, encourage return to exercise ASAP
Engage partner or extended family in helping to care for the child. Complete FMLA paperwork if needed for caregivers
Initiate psychotherapy – psychoeducation, CBT, IPT
May use low doses of diphenhydramine or lorazepam at bedtime to facilitate sleep
Consider use of sertraline 25 mg QHS or other SSRI
OCD: spike in incidence postpartum
Contamination fears > forbidden thoughts > symmetry
Intrusive thoughts of harming the infant are egodystonic
Normalize intrusive thoughts as part of illness
Good prognosis, responds to SSRI + CBT
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A related problem is postpartum anxiety, most often in the form of an exacerbation of GAD or OCD.
Antidepressants and lactation
Remember exposure via breast milk is “a drop in the bucket” compared with in utero exposure
No need to “pump and dump” Can continue whatever drug was used in pregnancy
with exception of lithium (requires high motivation and compliance)
May return to paroxetine if much more effective If selecting initial agent, best data for sertraline,
paroxetine. Venlafaxine passes more freely into breast milk than others but can use if helpful
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Remember that with antidepressants, exposure…
Postpartum psychosis
Psychiatric hospital admission is 7 fold more likely in the first month postpartum than in the pregancy
Incidence 0.1% in the general population 10% in women with bipolar disorder 50% in women with previous postpartum psychosis
Usually reflects bipolar disorder diathesis Delusions of guilt or hyperreligiosity, perplexed
affect, irritability, racing thoughts, inability to sleep Refusal/inability to be with the newborn
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The most serious psychiatric condition in the postpartum period is postpartum psychosis. Women are more likely to become psychotic in the first two weeks after delivery than any other time in their life. PPP is characterised by … This is a psychiatric emergency that requires hospitalization or separation of the mother from her newborn while she receives intensive outpatient treatment. It is important to understand that PPP usually reflects a bipolar diathesis
Postpartum Psychosis
Often misdiagnosed as postpartum depression More rapid onset: First two weeks postpartum Family history of bipolar disorder or postpartum psychosis
4% rate of infanticide, making it a psychiatric emergency that requires hospitalization or separation from the newborn and intensive outpatient treatment
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Postpartum Psychosis
Pure mania much more common than pure depression in women admitted for postpartum psychosis; mixed symptoms are rare
Mood incongruent delusions are common Women with depressive symptoms exhibit later median onset
than women with manic symptoms: 18 vs. 7 days postpartum
Psychotic depression also takes longer to remit: 115 days vs 34 days for pure psychotic mania
Most women require both an antipsychotic and lithium + benzodiazepine (66%) to achieve remission
Bergink, J Clin Psychiatry 72, 2011
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Postpartum psychosis
Mood stabilizers Antipsychotics are first line: haldol, risperidone, olanzapine,
quetiapine. If not better in 1-2 weeks, add either Lithium – use if nursing is ceased. Check Anti-TPO Ab –
predict low T4 w/ Li Antiepileptics: Divalproex and Carbemazepine Check infant drug levels and liver enzymes q1-3 months Mom must use birth control
Risk of recurrence is up to 50%: Treat prophylactically beginning 1 mo before birth OR Monitor closely (twice a week postpartum) with the help of husband
or other family member
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Usually antipsychotics are the treatment of choice, including… Divalproex can be used if needed… Lithium is only recommended if the infant has been weaned The risk of recurrence is up to 50%, therefore in subsequent pregnancies it is recommended to treat prophylactically beginning in the third trimester approximately 1 month before delivery OR monitor closely..
Postpartum Psychosis: Etiology
Most common in first pregnancy 19% of women with postpartum psychosis exhibit elevated
thyroid peroxidase (TPO) antibodies; half of these also exhibit thyroid dysfunction.
At 9 months postpartum, the rate of autoimmune thyroid dysfunction (AITD) in postpartum psychosis remained elevated (29% vs 13%) with thyroid dysfunction in 19% of woman with postpartum psychosis and only 3% in the control group.
Significance on mood or vulnerability to postpartum psychosis is unclear
Bergink, Br J Psychiatry, Feb 2011
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Psychotropics in Lactation
Typical Antipsychotics:
Haldol is preferred, avoid chlorpromazine and other low potency antipsychotics if possible
Atypical Antipsychotics: Infant dose ~ 0.1-1% of maternal dose for risperidone, olanzapine, &
quetiapine
Benzodiazepines: Undetectable in infant serum in 9 out of 10 infants (Birnbaum, Pediatrics 1999)
Usually no subjective sedation after nursing with lorazepam or clonazepam alone (Kelly, J Pediatrics 2012)
Avoid in premature infants or infants with hyperbilirubinemia
Lamotrigine: monitor infant for Stevens Johnson Syndrome (never reported but infant’s blood level = 20-50% of moms)
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Case 1: prenatal depression
32 yo woman with h/o recurrent MDD well treated with 200 mg sertraline plans for first pregnancy. She feels strongly that she does not want to take medication in pregnancy and tapers off sertraline before conception. By the end of the first trimester she is severely depressed. Sertraline is reintroduced and titrated. She does not feel comfortable taking a “full” dose of sertraline until after delivery; her depression does not remit until after she returns to 200 mg postpartum.
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Case 1: Errors
Assuming sertraline is worse than prenatal depression
Expecting that she can remain euthymic without sertraline
Using a non therapeutic dose of sertraline In this case, her fetus was exposed not only to
sertraline but also to severe prenatal depression Had she remained on 200 mg sertraline in
pregnancy her fetus would most likely only have been exposed to sertraline
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Case 2: panic disorder
26 yo with h/o panic disorder well controlled with 100 mg sertraline plans a pregnancy
She strongly desires to taper off medication In the second trimester she develops severe panic
and is unable to sleep Resuming sertraline is insufficient. Clonazepam,
quetiapine, and diphenhydramine are also prescribed with limited benefit. Still cannot sleep
Child has to go to the NICU because of dependence on clonazepam at birth
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Case 2: Errors
Going off sertraline: if she had stayed on sertraline it is much less likely that her panic would have returned
Fetus was exposed to 4 medications instead of 1 Fetus was dependent on clonazepam at birth Counsel patients that panic disorder will recur in
50% of patients who stop their antidepressant and in the case of recurrence, may require more medication to get it under control
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Case 3: postpartum psychosis
30 yo woman is hospitalized 1 week after delivery for what is initially diagnosed as postpartum depression
At the initial post-discharge outpatient visit she describes out of body experiences related to childbirth and is hyperreligious and perplexed on interview
Olanzapine is initiated and titrated to 10 mg QHS, resolving her hyperreligiousity.
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Case 3: continued
Olanzapine alone did not fully abate hyperreligiosity. Lithium was added and her MSE returned to normal.
Olanzapine was eventually cross tapered to aripiprazole for SE management
In the years after her child was born, she demonstrated intermittent manic symptoms and was eventually diagnosed with bipolar disorder I
In preparation for a second pregnancy her medication was changed to quetiapine + lithium
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Resources
www.womensmentalhealth.org Yonkers et al: The management of depression during pregnancy:
a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. General Hospital Psychiatry 31 (2009): 403-413.
Bridget M Kuchn: No Easy Answers for Physiciand Caring for Pregnant Women with Depression. JAMA, Dec 2010; Vol 302: 2413-2420.
Don’t rely exclusively on the FDA pregnancy categories. The ratings for many psychiatric drugs are often based on limited or unpublished data
Julianne Zweifel 824-6160
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Presentation Notes
I recommend keeping the following resources for future reference: the most valuable I’ve found is the website … updated frequently by Lee Cohen’s group at Mass General. It is comprehensive, up to date, and user friendly for both practitioners and patients, and I frequently give this website to patients so that they can review the current data themselves. I would also recommend printing a copy of the ACOG and APA report on managing depression in pregnancy by Yonkers and colleagues. Don’t simply rely on FDA pregnancy categories as these are often based on old or limited data. Finally, when in doubt, consult with a psychiatrist.
