Abstract
Meador KJ, Stowe ZN, Brown CA, Robalino CP, Matthews AG, Kalayjian LA, Voinescu PE, Gerard EE, Penovich P, Gedzelman E, Cavitt J, Pennell PB. MONEAD Investigator Group. Neurology. 2022;99(15): e1573-e1583. doi:10.1212/WNL.0000000000200958
Assess the incidence and factors associated with major depressive episodes (MDE) and symptoms of depression and anxiety during pregnancy and postpartum periods in pregnant women with epilepsy (PWWE) compared to healthy pregnant women (HPW) and to non-pregnant women with epilepsy (NPWWE) in comparable timeframes. Previous studies have reported higher rates of postpartum depression in women with epilepsy compared to women without epilepsy. However, the incidence of MDE using a structured interview during pregnancy and postpartum has not been directly compared to control groups, and the comparison of depression and anxiety symptoms and the role of associated factors remain ambiguous. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a multicenter NIH-funded prospective observational parallel-group cohort study of PWWE and their children. This report examines mood disorders. Unlike prior epilepsy pregnancy studies, the Structured Clinical Interview for DSM-IV (SCID) provided lifetime diagnoses, and repeated SCID mood modules assessed for MDE, the a priori primary outcome. Symptoms of depression (Beck Depression Inventory [BDI], Edinburg Postnatal Depression Scale [EPDS]) and anxiety (Beck Anxiety Inventory [BAI]) were also assessed along with multiple clinical factors. The study included PWWE (n = 331) and HPW (n = 102) during pregnancy and postpartum, and NPWWE (n = 102) at comparable times. No difference in SCID-diagnosed MDE incidence was found across groups, but BDI depressive symptoms were worse during pregnancy in PWWE vs NPWWE, and during postpartum vs HPW and NPWWE. BAI anxiety symptoms were worse during pregnancy in PWWE vs HPW and NPWWE, and during postpartum vs HPW. Factors associated with MDE during pregnancy/postpartum for PWWE included >1 seizure/90 days, anticonvulsant polytherapy, unplanned pregnancy, and lifetime history of mood disorder. Suicidal ideation from BDI or EPDS was related to BAI anxiety symptoms. Although SCID-based MDE did not differ across groups, this prospective study confirms higher rates of psychiatric symptoms in patients with epilepsy during pregnancy and postpartum, provides new data on associated factors, and underscores the importance of anxiety in risk for depression and thoughts of death/dying or suicide. Given the risks, PWWE should be routinely assessed, and symptomatic patients should be offered treatment. The study is registered at ClinicalTrials.gov as NCT01730170.Background and Objective:
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Commentary
Women in the general population are at increased risk for depression in pregnancy and postpartum. 1 Among people with epilepsy overall, numerous studies indicate anxiety and depression are more prevalent compared to controls. 2 Further, studies have demonstrated increased postpartum depression among women with epilepsy compared to controls, and a population-based study demonstrated increased depression and anxiety symptoms in epilepsy during pregnancy and postpartum, relative to a comparator group. 3,4 This prior research was limited by use of self-report symptom scales to evaluate for depression and anxiety, and prior studies included limited assessment of potential risk factors for anxiety and/or depression in pregnancy and postpartum. No studies examined gold-standard, structured interview-based evaluation of depression in pregnant and postpartum women with epilepsy, nor compared this type of assessment to both nonpregnant epilepsy controls and pregnant/postpartum healthy controls.
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study expanded significantly on prior literature through rigorous, baseline structured diagnostic interview assessment for lifetime psychiatric diagnoses followed by repeated evaluation for incident major depressive episodes at each study visit (among those who indicated some depression symptoms on a self-report scale). 5 Diagnoses were ascertained using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-IV (SCID). Incident major depressive episodes arising during pregnancy and the postpartum period were compared among pregnant women with epilepsy, nonpregnant women with epilepsy (during a parallel follow-up time frame), and healthy pregnant women. The results demonstrated no statistically significant increase in incident major depressive episodes among pregnant women with epilepsy compared to either control group. However, the pregnant women with epilepsy group differed from the nonpregnant epilepsy control group in ways that may have biased findings toward lower risk of major depressive episodes: the pregnant woman had higher income, lower lifetime history of anxiety disorder, and fewer antidepressants. Indeed, the rate of new major depressive episodes among the pregnant women with epilepsy and both control groups was lower than expected (less than 8% for the entire pregnancy + postpartum follow-up among all groups). The observed low incidence may also be due in part to characteristics of the highly motivated individuals willing to participate in a long-term study with multiple follow-up visits over years, and future research should attempt to examine more generalizable samples.
Nevertheless, important, clinically relevant findings emerged from analysis of secondary outcomes in this study. Factors associated with incident major depressive episodes among pregnant women with epilepsy included markers of more severe epilepsy (higher seizure frequency and anti-seizure medication polytherapy), history of mood disorder, and unplanned pregnancy. 5 These findings underscore the importance of counseling on contraception for all women with epilepsy, identification and management of mood disorders during epilepsy care prior to pregnancy, and close monitoring especially of individuals with more severe epilepsy.
Perhaps even more important were the results of self-report symptom scales for depression, postpartum depression, and anxiety. During pregnancy and postpartum, the pregnant women with epilepsy had significantly higher depression and anxiety symptom scores than one or both of the control groups, and scores were significantly higher during pregnancy than the postpartum period. Also, higher anxiety symptom scores were associated with higher rates of suicidal thoughts. 5 These findings are clinically important because they indicate the postpartum period, and especially pregnancy, are timeframes when women with epilepsy are at particularly high risk for anxiety and depression symptoms, and potentially suicide. Given the already well-established baseline increased risk of anxiety, depression, and suicide among people with epilepsy overall, and recommendations for routine screening and management of these comorbidities in epilepsy, the MONEAD results suggest a potential need for further enhanced screening and management during pregnancy and postpartum, as a part of comprehensive epilepsy care. The results also reinforce the importance of screening for anxiety in addition to depression, rather than depression alone.
Current practice habits among epileptologists surrounding screening and management of anxiety and depression during pregnancy care are unclear, but it would not be surprising if this is a time when psychiatric symptom screening and comorbidity management is less robust than outside of pregnancy. In pregnancy, there is already increased care intensity for epilepsy given the focus on monitoring medication levels and counseling about medication changes, breastfeeding, delivery considerations, and other pregnancy-specific factors. Further, pregnancy and the postpartum period may be a time when epileptologists and other physicians are reluctant to actively manage depression or anxiety symptoms, due to concern about potential risks of antidepressant medications in pregnancy or during breastfeeding. However, proactively identifying and managing these symptoms in pregnancy may be particularly important, not only to prevent symptoms detected on self-report scales from progressing to full major depressive episodes, but to potentially improve outcomes among children born to women with epilepsy. Data in the general population indicate various adverse child outcomes are associated with psychiatric conditions in pregnancy and postpartum, 6 and the MONEAD cognitive results demonstrated an association of maternal anxiety with lower IQ in children at 2 years of age. 7
Overall, these results bring attention to the potential need for enhancements in clinical practice, namely increased attention to screening and management of anxiety and depression in pregnant women with epilepsy, and the findings also highlight a significant need for future research to address multiple remaining unknowns. These include whether use of briefer, freely available anxiety and depression screening instruments suitable for clinical practice would detect the subsyndromic symptoms of relevance detected by the longer, proprietary research instruments administered in MONEAD. These validated brief screening instruments include the Neurological Disorders Depression Inventory-Epilepsy (NDDI-E) and Patient Health Questionnaire-9 (PHQ-9) 8 for depression and the Generalized Anxiety Disorder-7 (GAD-7) and brief Epilepsy Anxiety Survey Instrument (brEASI) 9 for anxiety. Other key areas for future research include interventions for anxiety and depression among pregnant women with epilepsy, to evaluate efficacy and safety, as there is a paucity of literature on this topic in epilepsy, though numerous interventions have been evaluated in the general population. 10 Finally, research is needed on interventions to mitigate the potential impact of psychiatric comorbidity in pregnant and postpartum women with epilepsy on their children.
Footnotes
Authors’ Note
The author has received funding from the NIH, DOD, and Duke Endowment for research on anxiety and depression in adults with epilepsy, distinct from the study discussed in the commentary.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.