Reproductive Psychopharmacology

Educational Objectives

The goals of this program are to improve diagnosis and management of female patients of reproductive age with mental health disorders. After hearing and assimilating this program, the clinician will be better able to:

1. Advise a patient being treated for depression who is contemplating a pregnancy.

2. Manage depression and psychotic disorders during pregnancy and breastfeeding.

3. Discuss the risks for malformation associated with psychotropic drugs commonly prescribed to women of reproductive age.

Summary

Fear of using medication: providers and patients often hesitant to use drugs during pregnancy; in survey of major residency programs, only 59% provided training on mental health of women and 36% believed that residents competent in that field; patients experience social pressure to have perfect pregnancy; use of medications that help mother but affect fetus raises ethical issues; clinicians may try to avoid bad outcomes by not treating women; instead, should weigh risk from medication against that from untreated illness

Difficulty of clinical research: pregnant women often excluded from clinical trials; most data on safety of drugs during pregnancy come from large registries, not rigorous trials; pharmacokinetics and pharmacodynamics altered in pregnant women, who have increased cardiac output and plasma volume, changes in gastric emptying, and increased renal blood flow; two-thirds of pregnant women take ≥1 prescription drug, and one-third take psychotropic medication; among ≈500 drugs approved by Food and Drug Administration in last 20 yr, only 3 highly teratogenic

Risks from discontinuing medication: risk for relapse of depression 68% if medication discontinued abruptly and 26% if antidepressants continued during pregnancy; for women on mood stabilizers, risk for relapse 85% if medication discontinued abruptly and 37% if drug continued; possible consequences of recurrence include suicide, hospitalization, poor fetal outcomes, and withdrawal after abrupt cessation of medication

Safety of medications: information on malformations and miscarriage easier to collect than data on obstetric and neonatal outcomes and long-term neurodevelopment; studies must account for baseline rate of malformations (2%-4%)

Selective serotonin reuptake inhibitors (SSRIs): most commonly prescribed psychotropic drugs in pregnancy; drugs well tolerated, and experience with safety extensive; SSRIs increase allopregnanolone, which has anxiolytic effect, so may work more quickly during pregnancy; malformations and miscarriage — SSRIs not associated with increased risks; early data on association of paroxetine with cardiac malformations not confirmed in later studies; paroxetine option for patient who does not respond to other therapies; registry of >1 million women found no difference in rate of miscarriage among women exposed during first trimester vs those who took SSRIs 3 to 12 mo before pregnancy; persistent pulmonary hypertension of newborn (PPHN) — initial data linked PPHN with SSRIs during pregnancy, but subsequent studies equivocal; recent study reported lower rates of PPHN than expected (2 to 3 cases/1000, compared with baseline rate of 1 to 2/1000); risk even lower after controlling for maternal depression; autism — study of 16 patients suggested link between SSRIs and autism, but larger studies have found no causal relationship; studies affected by confounders (eg, depression itself may be associated with higher risk for autism); women with more severe depression more likely to be taking medication, so control groups may have less severe depression; many large registry studies do not assess adherence to treatment or account for effect of smoking or autism traits in parent or sibling; for example, in study that examined risk for autism in offspring of patients taking SSRIs in second trimester, diagnosis of autism based only on parental report; when diagnosis of autism made by expert, SSRIs not associated with autism; at present, no causal relationship established between exposure to SSRIs and autism; neonatal adaptation syndrome (NAS) — infants jittery, with respiratory problems, tremor, and difficulty feeding; associated with SSRIs, especially when used near end of pregnancy; NAS present in 20% to 30% of exposed infants but usually resolves in first few days or weeks of life; study evaluated effect of tapering medication before delivery; period of exposure associated with neonatal respiratory distress, but association no longer present after controlling for maternal and neonatal confounders (eg, depression); SSRIs should not be tapered to prevent NAS because of risk for postpartum depression; exposure to SSRIs in utero not associated with cognitive changes or clinically significant changes in gross motor development and language; amount in milk varies with drug (from <1% for sertraline to ≈8% for citalopram); blood levels in infants low or undetectable

Serotonin-norepinephrine reuptake inhibitors: include venlafaxine and duloxetine; similar to SSRIs; venlafaxine not associated with malformations, but may slightly increase risk for hypertension during pregnancy

Bupropion: studies mixed on whether exposure during first trimester associated with significant increase in cardiac defects; one study found increase in risk from 0.8/1000 to 2/1000 but did not control for indication for bupropion (depression vs smoking cessation); rate of malformations 2% to 3% in children exposed to bupropion (similar to rate of 2% to 4% in general population); association with attention-deficit/hyperactivity disorder (ADHD) possible but difficult to study because bupropion often prescribed to patients with ADHD

Other antidepressants: trazodone and mirtazapine — not associated with malformations; tricyclics — not associated with malformations; desipramine and nortriptyline preferred because their lower anticholinergic activity may be less likely to exacerbate orthostatic hypotension

Sleep aids: zolpidem — ≥80% of pregnant women have sleep disturbance; zolpidem not associated with birth defects; large study found association with preterm delivery and lower birth weight; however, study did not control for maternal depression, which may be associated with these outcomes; zolpidem metabolized quickly; 0.02% excreted in breast milk; drug could impair ability of mother to care for infant; diphenhydramine — safe during pregnancy but decreases milk production; melatonin — few studies available; benzodiazepines — association with cleft lip and palate equivocal; if real, rate of such malformations ≈0.7%; associated with floppy baby syndrome (decreased muscle tone, breathing problems, and sedation), especially in patients taking high doses regularly

Mood stabilizers: lamotrigine — commonly prescribed during pregnancy; safety data from large registries reassuring; most data on antiepileptics come from patients with epilepsy, and epilepsy itself associated with several malformations and adverse neonatal outcomes; data from North American Antiepileptic Drug Pregnancy Registry show increased risk for malformations of oral cleft (risk 0.9%); however, additional studies (including study of >10 million women) did not confirm; drug well tolerated and weight neutral; drug levels affected by estrogen and should be checked at baseline, in third trimester, postpartum, and in women on oral contraceptives; ≈40% of lamotrigine crosses into breast milk, but exposure not associated with major negative consequences; one apneic episode reported; no Stevens-Johnson syndrome or other adverse outcomes reported; no major neurocognitive differences found at 18 mo of age in infants exposed in utero; lithium — risk for cardiac malformations 0.05% to 0.1% (smaller than previously reported); level II cardiac ultrasonography should be done during second trimester; medication should be taken in divided doses and levels checked, especially at end of pregnancy and postpartum; breastfeeding permitted but thyroid and renal function of child should be monitored every 6 to 8 wk; lithium and other mood stabilizers usually prescribed for significant bipolar illness; such women at high risk for relapse, so maintaining therapy important; discontinuing medication may double or triple risk for relapse; carbamazepine — associated with 1% risk for neural tube defects; fewer data available on oxcarbazepine; valproic acid (Depakene, Depakote, Stavzor) — not recommended during pregnancy because of 6% to 10% risk for neural tube defects and other malformations (craniofacial, cardiovascular, limb, and genital anomalies); valproic acid after first trimester may significantly affect neurocognitive development; clinician should discuss contraception whenever use of valproic acid contemplated in woman of reproductive age; alternative regimen should be established before conception; gabapentin — risk for malformations low; topiramate — effects include oral cleft malformations, restricted growth, microcephaly, and early delivery; drug may reduce efficacy of oral contraceptives

Antipsychotics: typical antipsychotics — no increased risk for malformation with typical antipsychotics such as haloperidol; haloperidol may be used emergently in pregnant women; high-potency antipsychotics recommended over low-potency drugs; atypical antipsychotics — data on older atypicals (risperidone, quetiapine, and olanzapine) suggest no increased risk for malformations; risks for diabetes and other poor obstetric outcomes must be considered; however, recent study compared exposed patients on older atypical antipsychotics to nonexposed patients, and atypicals did not increase risk for gestational diabetes, hypertensive disorders, or venous thromboembolism; meta-analysis reported more malformations, heart defects, and preterm delivery; however, studies in meta-analysis did not control for several confounders, including substance use, obesity, and concomitant medications; no data available for newer atypical agents such as aripiprazole and lurasidone; patients on these drugs should be entered into pregnancy registry databases; older atypicals linked with NAS

Stimulants: available data on prescribed stimulants sparse but reassuring; drugs associated with preterm delivery and lower birth weights but not with malformations

Supplements: folate and fish oils may improve mood symptoms; no science supports placenta encapsulation for postpartum depression

Novel treatment: Sage Therapeutics developing drug for postpartum depression; 7 of 10 treated women (and 1 woman in placebo group) reported remission of symptoms; drug works on γ-aminobutyric acid system; placebo-controlled trials planned

Readings

Andersen JT et al: Exposure to selective serotonin reuptake inhibitors in early pregnancy and the risk of miscarriage. Obstet Gynecol 2014 Oct;124(4):655-61;Chun-Fai-Chan B et al: Pregnancy outcome of women exposed to bupropion during pregnancy: a prospective comparative study. Am J Obstet Gynecol 2005 Mar;192(3):932-6; Coughlin CG et al: Obstetric and neonatal outcomes after antipsychotic medication exposure in pregnancy. Obstet Gynecol 2015 May;125(5):1224-35; Dolk H et al: Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies. Neurology 2016 May 3;86(18):1716-25; Glezer A: Mind Body Pregnancy. Available at: http://mindbodypregnancy.com/. Accessed November 11, 2016; Holmes LB et al: Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology 2008 May 27;70(22 Pt 2):2152-8; Huybrechts KF et al: Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. JAMA 2015 Jun 2;313(21):2142-51; Jimenez-Solem E et al: Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study. BMJ Open 2012 Jun 18;2(3); Massachusetts General Hospital: MGH Center for Women’s Mental Health. Available at: https://womensmentalhealth.org/. Accessed November 11, 2016; Osborne LM et al: Reproductive psychiatry: the gap between clinical need and education. Am J Psychiatry 2015 Oct;172(10):946-8; Vigod SN et al: Antipsychotic drug use in pregnancy: high dimensional, propensity matched, population based cohort study. BMJ 2015 May 13;350:h2298; Wang LH et al: Increased risk of adverse pregnancy outcomes in women receiving zolpidem during pregnancy. Clin Pharmacol Ther 2010 Sep;88(3):369-74; Warburton W et al: A register study of the impact of stopping third trimester selective serotonin reuptake inhibitor exposure on neonatal health. Acta Psychiatr Scand 2010 Jun;121(6):471-9.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Glezer spoke at the 1st Annual Bay Area Maternal Mental Health Conference, sponsored by University of California, San Francisco, School of Medicine and held September 10, 2016, in San Francisco, CA. To learn about the next Bay Area Maternal Mental Health Conference, visit ucsfcme.cm/2017/MMC17011/info.html. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

PS460102

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.