Jyoti Sachdeva, MD

[Acknowledgment-the authors acknowledge Christina Wichman, DO, FAPM and Catherine C. Crone, MD, of the 

 (APM), for helping to bring this article to fruition. The APM is the professional home for psychiatrists providing collaborative care bridging physical and mental health. Over 1200 members offer psychiatric treatment in general medical hospitals, primary care, and outpatient medical settings for patients with comorbid medical conditions.]



Psychiatric symptoms are among the most prevalent perinatal complications. During pregnancy, discontinuing or under-dosing psychotropic medication often results in symptom recurrence. The postpartum period confers heightened risk for expression of depressive disorders, bipolar disorder, generalized anxiety disorder, and obsessive-compulsive disorder.

Recent research has identified interactive influences on vulnerability to perinatal psychiatric symptoms, including genotypes, hormonal fluctuations, neurosteroids, neurotransmitters, inflammatory cytokines, hypothalamic-pituitary-adrenal axis reactivity, stressors, and social role transitions. Studies of epigenetic influences on fetal development have begun to elucidate why maternal antenatal stress and depression increase the risk of preterm birth and heightened stress sensitivity in offspring. The availability of large databases and improvements in study methodology has greatly expanded knowledge of the risks of psychotropic medications during pregnancy. Moreover, new models of integrating mental health care into perinatal care settings have begun to tackle the dilemma of widespread under-detection and under-treatment of perinatal psychiatric problems. 

 highlights some of the challenges surrounding the treatment of women of reproductive age.

Despite considerable expansion of available data, physicians may be reluctant to prescribe psychotropic medication to pregnant patients.

 This may be due, in part, to confusing information regarding the risks of psychotropic medication during pregnancy.

[[{"type":"media","view_mode":"media_crop","fid":"44337","attributes":{"alt":"Â© WAVEBREAKMEDIA/SHUTTERSTOCK.COM","class":"media-image media-image-right","id":"media_crop_2406770500329","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4939","media_crop_rotate":"0","media_crop_scale_h":"183","media_crop_scale_w":"150","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"Â© WAVEBREAKMEDIA/SHUTTERSTOCK.COM","typeof":"foaf:Image"}}]]This article summarizes clinically relevant advances in the psychiatric care of women during pregnancy and postpartum, including recent changes in how the FDA classifies pregnancy risk for medications, best practices in perinatal psychopharmacology, and innovative models of integrating mental health care delivery with perinatal care to improve access to evidence-based treatments.

FDA final rule on pregnancy/breastfeeding safety labeling

In 1979, the FDA introduced pregnancy risk categories A, B, C, D, and X in response to the thalidomide disaster in the 1960s. Drugs were assigned to a particular category based on the risk of harm to the fetus and newborn (per available animal and human studies) and the potential benefit in pregnancy and breastfeeding. The categories implied increasing risk with each letter. This system was overly simplistic, misleading, and incomplete.

In December 2014, the FDA published the Pregnancy and Lactation Labeling Rule (PLLR), or Final Rule, which will be implemented over the next 3 years.

 The PLLR includes new content and formatting in the form of explanations, based on available and relevant data, across 3 subsections. Each section includes a risk summary and clinical considerations as well as animal and human data:

 Pregnancy: dosing, impact on fetus, and registry information

 Lactation: amount of drug in breast milk and potential effects, if any

 Females and males of reproductive potential: pregnancy testing, contraception, and fertility related to the drug

This has several implications for the clinician. The risk category by letter is being phased out; new safety information will be provided with a focus on risk, individualized consideration of illness, history and circumstances, access to registry information, and data. Conversations with patients will be more informed by evidence. The new format, available at 

, will help orient clinicians and prepare them for the transition.

Best practices in perinatal psychopharmacology

Discussions regarding medication use during pregnancy must take into account the risks of 

 psychiatric disorders in pregnancy. Women with active psychiatric symptoms during pregnancy are at risk for inadequate prenatal care, substance abuse, preterm delivery, low birth weight of the newborn, and other obstetric/ neonatal complications. Domains of reproductive safety include risk of congenital malformation, effect on duration of pregnancy, neonatal toxicity and withdrawal, and long-term neurobehavioral sequelae.

High-quality studies have concluded that, as a group, antidepressants do not increase the risk of congenital malformations above the baseline risk of 2% to 4% in the general population. There are conflicting studies regarding a possible increased risk of cardiovascular malformations with exposure to paroxetine. Serotonergic antidepressants increase the risk of persistent pulmonary hypertension, but the absolute risk remains low. Both antidepressants and untreated depressive symptoms increase the risk of premature labor; gestational age is reduced by about 4 days from exposure to either, and birth weight is lower. These are statistically but not clinically significant. Antidepressant exposure is not associated with an increased risk of autism or other neurodevelopmental problems, although women who take antidepressants may have other risk factors for these problems in their offspring.

 In most cases of moderate to severe psychiatric illness, the benefits of medication used to remit symptoms outweigh putative risks of exposure.

The high recurrence rate of bipolar illness during and after pregnancy complicates an already challenging risk-to-benefit analysis, given that many mood-stabilizing medications are known teratogens. The risk of untreated symptoms may exceed medication-linked risks in individual cases. Valproic acid is strongly contraindicated in pregnancy because it increases the risk of multiple teratogenic effects: for example, a 1% to 6% rate of neural tube defects and high rates of impaired neurocognitive development. Carbamazepine also has multiple teratogenic effects including a 1% risk of neural tube defects. Lithium has a 0.05% to 0.1% increased risk of Ebstein’s anomaly with exposure during the first trimester. However, the risk is much lower than that with valproate or carbamazepine, and much lower than previously thought. Lamotrigine has no increased risk of congenital anomalies after antenatal exposure. Reports of an association with oral cleft defects are conflicting. There are limited data on gabapentin, oxcarbazepine, tiagabine, and topiramate. Atypical antipsychotics may be considered as an alternative for acute mania or maintenance treatment (see below).

 high risk for complications during the perinatal period-nearly double that in the general population. They include higher rates of operative deliveries, neonatal intensive care unit admissions, and neonatal morbidity.

While first-generation antipsychotics have a fairly well described history in pregnancy, with high- potency agents being preferred to low potency, less has been published about second-generation antipsychotics. Overall, no increased risk of congenital anomalies has emerged to date, including recent studies by Habermann and colleagues

 However, metabolic effects, blood dyscrasias, and movement disorders in the mother, fetus, and newborn must be taken into account with the use of these agents.

In summary, some key points to bear in mind in the pharmacological treatment of perinatal women are

• Consider psychotherapy as an initial treatment approach for patients with mild to moderate depression or anxiety and for augmentation as indicated

• Avoid discontinuing medications that provide psychiatric stability

• Maintain patients on previously effective medications at the minimal effective dose with symptom remission as the goal

• Carefully substitute less teratogenic agents if necessary

• Dose requirements may be higher in the second half of pregnancy and should be adjusted accordingly

Although the vast majority of perinatal women are amenable to being screened for depression, screening alone does not improve treatment rates or patient outcomes. Fewer than 30% of women who screen positive for depression attend an initial or subsequent mental health visit, and fewer than 10% adhere to a full treatment course.

Patient, provider, and systemic barriers prevent perinatal women from receiving the mental health care they need. These include

• Stigma, the fear of losing parental rights, and being judged as an unfit mother

• Lack of obstetric provider training in clinical aspects of depression care and communication skills

• An absence of standardized processes and procedures for depression care

• Lack of mental health providers willing or trained to treat women during pregnancy and postpartum

• Inadequate capacity for follow-up and care coordination

In addition to training women’s health providers to be attuned to mental health issues and to have a level of comfort and confidence in diagnosing and managing psychiatric symptoms and syndromes, obstetric practices need supports in place to adequately address depression in their patients.

Translating integrated care models, such as stepped and collaborative care, into obstetric settings could provide a solution. Collaborative models can improve mental and physical outcomes for individuals with mental illness, and they provide a robust framework for integrating obstetric and depression care. Stepped-care models involve interventions appropriate to illness severity, with intensification of care (such as adding case management or specialist consultation) for those with persistent illness. Such programs include mental health training for perinatal care providers, on-site access to prompt evaluation and treatment initiation, integrated social workers or nurses who provide supportive services and follow-up, and access to perinatal psychiatry consultation for perinatal care providers.

In addition to fee for service, funding for such programs can be obtained through grants from state legislatures, private foundations, or Medicaid. As health care reform evolves, accountable care organizations may see the benefit and cost savings of such integration and over time implement changes that would make this the standard of care. 

 describes integrated care models and what clinicians can do to improve outcomes.

Interpreting the rapidly changing field of perinatal psychiatry may be a daunting task for the general psychiatrist, placing patient and provider between Scylla and Charybdis, or a rock and a hard place. The FDA Final Rule, together with a deeper and broader understanding of the effects of mental illness and the role of psychotropics in perinatal outcomes, has diminished polarization in this field and set the stage for evidence-based decisions. Current efforts in health care reform present unprecedented opportunity for the development and implementation of integrated mental health programs in perinatal clinics, which not only lower overall health care costs but improve the quality and impact of care as well.

the authors acknowledge Christina Wichman, DO, FAPM and Catherine C. Crone, MD, of the Academy of Psychosomatic Medicine (APM), for helping to bring this article to fruition. The APM is the professional home for psychiatrists providing collaborative care bridging physical and mental health. Over 1200 members offer psychiatric treatment in general medical hospitals, primary care, and outpatient medical settings for patients with comorbid medical conditions.

Dr Dresner is Director of Wellsprings Health Associates, and Associate Professor of Clinical Psychiatry and Obstetrics Gynecology at Northwestern University Feinberg School of Medicine in Chicago. Dr Byatt is Medical Director of the Massachusetts Child Psychiatry Access Project for Moms, and Assistant Professor of Psychiatry and Obstetrics Gynecology, UMass Memorial Medical Center/UMass Medical School in Worcester, MA. Dr Gopalan is Assistant Professor of Psychiatry and Medical Director of the Psychiatry Consultation-Liaison Service, and Chief of Psychiatry at the Magee-Women’s Hospital at the University of Pittsburgh Medical Center/Western Psychiatric Institute and Clinic in Pittsburgh, PA. Dr Miller is Medical Director of Women’s Mental Health at the Edward Hines Jr. VA Hospital, and Professor of Psychiatry at the Loyola Stritch School of Medicine in Maywood, IL. Dr Sachdeva is Adjunct Associate Professor of Clinical Psychiatry in the Department of Psychiatry and Behavioral Science at the University of Cincinnati Medical School in Cincinnati, OH. The authors report no conflicts of interest concerning the subject matter of this article.

 Byatt N, Biebel K, Debordes-Jackson G, et al. Community mental health provider reluctance to provide pharmacotherapy may be a barrier to addressing perinatal depression: a preliminary study. 

 US Food and Drug Administration. Pregnancy and Lactation Labeling Final Rule. 

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm

 Grigoriadis S, VonderPorten EH, Mamisashvili L, et al. Antidepressant exposure during pregnancy and congenital malformations: is there an association? A systematic review and meta-analysis of the best evidence. 

 Vigod SN, Kurdyak PA, Dennis CL, et al. Maternal and newborn outcomes among women with schizophrenia: a retrospective population-based newborn study. 

 Habermann F, Fritzsche J, FuhlbrÃ¼ck F, et al. Atypical antipsychotic drugs and pregnancy outcome: a prospective cohort study. 

 Cohen LS, Viguera AC, McInerney KA, et al. Reproductive safety of second-generation antipsychotics: current data from the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics. 

. October 6, 2015; [Epub ahead of print].

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• MGH Center for Womens Mental Health. 

Articles

This article summarizes clinically relevant advances in the psychiatric care of women during and after pregnancy, including recent changes in how the FDA classifies pregnancy risk for medications, and best practices in perinatal psychopharmacology.

Jyoti Sachdeva, MD

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