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. Author manuscript; available in PMC: 2016 Mar 29.
Published in final edited form as: J Affect Disord. 2014 Oct 22;172:390–396. doi: 10.1016/j.jad.2014.10.032

Depression, Anxiety and Stress among Pregnant Migraineurs in a Pacific-Northwest Cohort

Olivia R Orta a,*, Bizu Gelaye a, Chungfang Qiu b, Lee Stoner c, Michelle A Williams a
PMCID: PMC4406774  NIHMSID: NIHMS641203  PMID: 25451442

Abstract

Background

The co-occurrence of migraine and unipolar psychiatric disorders has been well documented in non-pregnant populations, however little is known in pregnant populations.

Methods

A cohort of 1,321 women was interviewed during the first trimester of pregnancy. At the time of interview lifetime migraine status was ascertained using International Classification of Headache Disorders diagnostic criteria (ICHD-II). Information regarding unipolar depression, anxiety and stress during pregnancy was collected using the Patient Health Questionnaire Depression Module-9 (PHQ-9), and the Depression Anxiety Stress Scales 21-item Short Form (DASS-21). Multivariable logistic regression procedures were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of migraine and mood disorders during pregnancy.

Results

Approximately 28.2% (N=372) were classified as having a lifetime history of migraine; among migraineurs 122 were classified as migraineurs with aura and 250 as migraineurs without aura. Compared with non-migraineurs, migraineurs were associated with 1.60-fold increased odds of depression as measured by a PHQ-9 score ≥10 (AOR=1.60; 95% CI: 1.12–2.31). Overall, migraine with aura was more strongly associated with depression than was migraine without aura. Migraineurs, as compared with non-migraineurs, also had higher odds of mood disorders as measured by the DASS-21.

Conclusions

The comorbidity of mood and migraine disorders in pregnant populations supports the need for integrated mental and physical clinical evaluation, increased vigilance, and treatment of patients with such disorders.

Keywords: Migraine, Pregnancy, Depression, Stress, Anxiety

Introduction

Headache disorders, the most prevalent disorders of the neurological system, disproportionately affect women of reproductive age (Buse et al., 2013; Smitherman et al., 2013; WHO, 2011). Despite their non-lethality, migraines are a personal and societal burden, ubiquitous, and disabling (WHO, 2011). Estimates of lifetime prevalence of migraine among pregnant women range from 9–20% (Adeney et al., 2006; Frederick et al., 2014). Several studies have reported higher frequencies of preterm delivery, low birth weight, placental abruption, preeclampsia, and other hypertensive disorders among pregnant migraineurs when compared to pregnant non-migraineurs (Adeney and Williams, 2006; Chen et al., 2010; Marozio et al., 2012; Sanchez et al., 2010; Williams et al., 2011).

Mood and anxiety disorders are complications during pregnancy and the postpartum period (O'Hara and Wisner, 2014). Meta-analyses of perinatal depression report point prevalence estimates between 6–13% (Gavin et al., 2005) and studies have shown that 16% present with clinically anxious symptoms during the first trimester (Rubertsson et al., 2014); in addition, 84% of women report some form of psychosocial stress during pregnancy (Woods et al., 2010). Depression, anxiety, and stress during pregnancy have been associated with inadequate antenatal care, low birth weight, preterm delivery, small gestational age, placental abruption, self-harm, suicidal-ideation, postpartum depression, and maladaptive emotional and behavioral development of offspring (de Paz et al., 2011; Farias et al., 2013; Graignic-Philippe et al., 2014; Lee et al., 2007; Sanchez et al., 2013; Satyanarayana et al., 2011; Szegda et al., 2014; Wisner et al., 2013).

The World Health Organization (WHO) estimates that depression is three times more common in people with migraine or severe headaches compared to healthy individuals (WHO, 2012). The co-occurrence of migraine and mood disorders has been well documented in non-pregnant populations (Breslau et al., 1994; Breslau et al., 2003; Fuller-Thomson et al., 2013; Gelaye et al., 2013; Jette et al., 2008; Kalaydjian and Merikangas, 2008; McWilliams et al., 2004; Merikangas et al., 1990; Nguyen and Low, 2013; Patel et al., 2004; Saunders et al., 2014; Swartz et al., 2000; Zwart et al., 2003). Recent evidence suggests that migraine and mood disorders may be common among pregnant women (Cripe et al., 2010; Williams et al., 2010). In a study of 2,293 pregnant women, 55.1% of migraineurs reported moderate to severe depressive symptoms during pregnancy compared to 36.7% of pregnant non-migraineurs (Cripe et al., 2010). Furthermore, migraineurs score higher on the Perceived Stress Scale (PSS) than non-migraineurs during the first trimester of pregnancy (mean ± SD: 4.2 ± 2.4 vs. 3.7 ± 2.3; p-value: 0.008) (Williams et al., 2010). To our knowledge very few studies have reported on the co-occurrence of migraine and mood disorders during the antepartum period (Cripe et al., 2011; Cripe et al., 2010; Williams et al., 2010). Therefore, we sought to examine the extent to which migraine is associated with depression, anxiety, and stress during pregnancy from a large prospective cohort study of pregnant women.

METHODS

2.1 Study population and Data Collection Procedures

This study was conducted among 1,321 pregnant women enrolled in the ongoing Migraine and Pregnancy Study, a prospective cohort study designed to investigate the relationship between migraine and headache symptoms prior to and during pregnancy, and the risk of adverse perinatal outcomes including preeclampsia. Pregnant women attending prenatal care at clinics affiliated with the Swedish Medical Center in Seattle Washington from November 2009 to March 2013 were recruited. Women were eligible if they initiated prenatal care at or prior to 20 weeks gestation, were 18 years of age or older, spoke and read English, planned to carry the pregnancy to term, and planned to deliver at the Swedish Medical Center. At enrollment participants completed an interviewer-administered survey where information regarding sociodemographics, pre-pregnancy general health, reproductive and medical history, and migraineur status were collected. Participants were then asked to complete two brief self-administered survey instruments to screen for symptoms of depression, anxiety, and stress using the Patient Health Questionnaire Depression Module-9 (PHQ-9), and the Depression Anxiety Stress Scales 21-item Short Form (DASS-21), both of which have been validated for use in perinatal populations (Kroenke et al., 2001; Meades and Ayers, 2011; Spitzer et al., 2000; Zhong et al., 2014). Multiple psychiatric instruments were used to improve our ability to assess maternal antepartum mood disorders as they relate to migraine status. The procedures used in the study were in agreement with the protocol approved by the Institutional Review Board of Swedish Medical Center, Seattle, WA. All participants provided written informed consent.

2.2 Survey Instruments

Migraine

Migraine was assessed using a structured questionnaire adapted from the deCode Genetics migraine questionnaire (DMQ3). The DMQ3 was recently validated to diagnose migraine with a sensitivity of 99%, specificity of 86%, and kappa statistic of 0.89 (Kirchmann et al., 2006). During the migraine assessment participants were asked if they had ever experienced headache episodes. Headache classification was determined using the International Classification of Headache Disorders diagnostic criteria (ICHD-II), established by the International Headache Society (ICHD, 2004). Women with “any migraine” refer to women with definitive migraine. Definitive migraine was defined by at least 5 lifetime headache attacks lasting 4–72 hours with: (1) at least two of the qualifying pain characteristics (unilateral location, pulsating quality, moderate or severe pain intensity, or aggravation by routine physical exertion); and (2) at least one of the associated symptoms (nausea and/or vomiting, photo/phonophobia); and (3) not readily attributed to another central nervous system disorder or head trauma (according to subject self-report). Women who met these criteria are referred to as migraineurs throughout our study. Migraineurs with aura fulfilled all of the aforementioned criteria for definitive migraine in addition to at least two aura attacks consisting of: (1) at least one of the following (fully reversible visual symptoms, fully reversible sensory symptoms, or fully reversible dysphasic speech disturbance) but no motor weakness; and (2) at least two of the following (homonymous visual symptoms and/or unilateral sensory symptoms, the development of at least one aura symptom that develops gradually over ≥5 minutes, and/or each symptom lasts ≥5 and ≤ 60 minutes). (ICHD, 2004) Using these criteria we categorized migraineurs to either migraineur with aura, or migraineur without aura.

PHQ-9

The PHQ-9 is a self-administered module that ascertains unipolar depression by asking: “Over the last two weeks, how often have you been bothered by any of the following problems”. The problems assessed feelings of feigned interest, hopelessness, trouble sleeping, lack of energy, changes in appetite, self-deprecation, trouble concentrating, changes in physical behavior, and thoughts of self-harm. The 9-item instrument asks respondents to rate the relevancy of each statement over the past two weeks on a four-point scale ranging from: (0) not at all, (1) several days, (2) more than half the days, and (3) nearly every day. Scores range from 0 to 27. Validated cutoffs were used to categorize PHQ-9 scores (Kroenke et al., 2001). Briefly, a score of ≥10 on the PHQ-9 is associated with 88% sensitivity and 88% specificity in diagnosing unipolar major depressive disorder (MDD) using the Diagnostic Statistical Manual Fourth Edition criteria (Kroenke et al., 2001). Additionally, we categorized participants as exhibiting minimal (score 0–4), mild (score 5–9), moderate (score 10–14), and severe (score ≥15) depressive symptoms on the PHQ-9 scale.

DASS-21

The DASS-21 is a set of three self-report scales designed to measure the negative emotional states of depression, anxiety, and stress (Depression Anxiety Stress Scales 2013) (Depression Anxiety Stress Scales 2013) (Depression Anxiety Stress Scales 2013). The depression scale assessed dysphoria, hopelessness, devaluation of life, self-deprecation, lack of interest or involvement, anhedonia, and inertia; the anxiety scale assessed autonomic arousal, situational anxiety, and subjective experience of anxious affect; and the stress scale assessed difficulty relaxing, nervous arousal, easy agitation, irritability, and impatience (Lovibond, 1998; Lovibond and Lovibond, 1995). The 21-item instrument asks respondents to rate the relevancy of each of the three negative affective states over the past week on a four-point scale ranging from: (0) not at all, (1) some of the time, (2) a good part of the time, and (3) most of the time. Scores range from 0 to 21 in each of the three domains, and are then multiplied by two to produce a possible score of 0 to 42 in each of the three domains. Validated cutoffs were used to categorize DASS scores (Lovibond and Lovibond, 1995). Briefly, we categorized participants as exhibiting minimal (score 0–9), mild (score 10–13), moderate (score 14–20), and severe (score ≥21) depressive symptoms on the DASS Depression subscale. The corresponding cutoffs for the DASS Anxiety subscale were minimal (score 0–7), mild (score 8–9), moderate (score 10–14), and severe (score ≥15). The corresponding cutoffs for the DASS Stress subscale were minimal (score 0–14), mild (score 15–18), moderate (score 19–25), and severe (score ≥26). In addition to the established DASS subscale cutoffs, we further analyzed DASS global quartile scores. Internal consistencies for each scale for the DASS normative sample are: depression 0.91; anxiety 0.84; and stress 0.90 (Lovibond and Lovibond, 1995).

2.3 Other Covariates

Age at last menstrual period was categorized as: <25, 25–34, and ≥35 years. Other variables included: maternal race/ethnicity (non-Hispanic white, African-American, Asian, other), annual household income in U.S. thousands (<50, 50–69, ≥70), single marital status (yes, no), nulliparous (yes, no), unplanned pregnancy (yes, no), cigarette smoker (never, prior, current), family history of headache or migraine (yes, no), and self-reported history of chronic hypertension (yes/no). Pre-pregnancy body mass index (BMI) was calculated from pre-pregnancy height and weight (kg/m2) and categorized as: <18.5, 18.5–24.9, 25.0–29.9, and ≥30 kg/m2 based on cutoffs from the WHO Global Database on BMI (WHO, 2006).

2.4 Statistical Analysis

Frequency distributions of maternal sociodemographic, reproductive, medical and behavioral histories were compared by migraine status defined by ICHD-II (no migraine, any migraine), and migraine subtype (no migraine, migraine with aura, migraine without aura). We examined whether mean and inter-quartile scores differed by migraine status and subtype using Student’s t-test and the Kruskal-Wallis test respectively. Logistic regression procedures were used to calculate maximum likelihood estimates of odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for potential confounders. Confounding was assessed by entering covariates (Table 1 variables) into the logistic regression model one at a time, and by comparing adjusted ORs (AORs) to unadjusted ORs. Final multivariate logistic regression models included those covariates that altered unadjusted ORs by at least 10%. Covariates in the final model included maternal age, unplanned pregnancy, and maternal pre-pregnancy BMI. In multivariate logistic analysis to test for a linear trend of increasing psychiatric severity we modeled the mood severity variables as continuous. All analyses were performed using Stata 13.1 (Stata College Station, TX) statistical analysis software, and all reported p-values are two-sided and deemed statistically significant at α=0.05.

Table 1.

Characteristics of the Study Population According to Migraine Status

Characteristics No
Migraine
(N=949)		 Any
Migraine
(N=372)		 Migraine
with Aura
(N=122) 		Migraine
without Aura
(N=250)
Maternal Age (years) 33.4 ± 4.1 33.1 ± 4.3 33.0 ± 4.8 33.2 ± 4.0
    <25 5 (0.5) 7 (1.9) 5 (4.1) 2 (0.8)
    25 – 34 595 (62.7) 235 (63.2) 73 (59.8) 162 (64.8)
    ≥ 35 349 (36.8) 130 (34.9) 44 (36.1) 86 (34.4)
Maternal Race/Ethnicity
    Non-Hispanic White 770 (81.1) 310 (83.3) 104 (85.3) 206 (82.4)
    African American 14 (1.5) 6 (1.6) 3 (2.5) 3 (1.2)
    Asian 110 (11.6) 33 (8.9) 8 (6.6) 25 (10.0)
    Other 55 (5.8) 23 (6.2) 7 (5.7) 16 (6.4)
Annual Household Income ($)
    <50,000 24 (2.5) 12 (3.2) 8 (6.6) 4 (1.6)
    50,000–69,000 48(5.1) 22 (5.9) 6 (4.9) 16 (6.4)
    ≥ 70,000 845 (89.0) 329 (88.4) 105 (86.1) 224 (89.6)
    Not Reported 32 (3.4) 9 (2.4) 3 (2.5) 6 (2.4)
Single Marital Status 75 (7.9) 29 (7.8) 11 (9.0) 18 (7.2)
Nulliparous 507 (53.4) 190(51.1) 59 (48.4) 131 (52.4)
Unplanned Pregnancy 114 (12.0) 50 (13.4) 24 (19.7) 26 (10.4)
Cigarette Smoker
    Never 711 (74.9) 274 (73.7) 92 (75.4) 182 (72.8)
    Prior 201 (21.2) 83 (22.3) 24 (19.7) 59 (23.6)
    Current 37 (3.9) 15 (4.0) 6 (4.9) 9 (3.6)
Family History of Headache/Migraine* 311 (32.8) 232 (62.4) 82 (67.2) 150 (60.0)
History of Chronic Hypertension 14 (1.5) 11 (3.0) 3 (2.5) 8 (3.2)
Pre-Pregnancy Body Mass Index (kg/m2)* 23.3 ± 4.0 24.0 ± 4.9 24.0 ± 4.8 23.3 ± 4.0
    <18.5 29 (3.1) 12 (3.2) 2 (1.6) 10 (4.0)
    18.5–24.9 694 (73.1) 245 (65.9) 83 (68.0) 162 (64.8)
    25.0–29.9 170 (17.9) 79 (21.2) 26 (21.3) 53 (21.2)
    ≥ 30.0 56 (5.9) 36 (9.7) 11 (9.0) 25 (10.0)
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Data in mean ± SD or number (%)

*

P-value from ANOVA <0.05 for no migraine vs. migraine with aura, migraine without aura

RESULTS

Based on ICHD-II criteria approximately 28.2% (N=372) of the cohort were classified as having a lifetime history of any migraine. Migraineurs were further categorized as 122 migraineurs with aura and 250 migraineurs without aura. Maternal characteristics according to migraine status are summarized in Table 1. When compared with non-migraineurs, migraineurs were more likely to report a family history of migraine/headache and to have a pre-pregnancy BMI ≥25.0 kg/m2. Other characteristics including age, race/ethnicity, annual household income, marital status, parity, unplanned pregnancy, smoking status, and history of chronic hypertension were similar for the two study groups.

Table 2 shows mean and median PHQ-9 and DASS-21 summary scores by migraineur status. Compared with non-migraineurs, migraineurs had statistically higher mean PHQ-9 scores (6.2 ± 3.6 vs. 5.3 ± 3.5; p-value <0.001) and mean DASS-21 total scores (19.5 ± 13.9 vs. 15.9 ± 13.1; p-value <0.001). Mean DASS-21 subscale scores were also statistically higher for migraineurs compared to non-migraineurs in all three domains: depression (5.0 ± 5.3 vs. 4.1 ± 4.8; p-value <0.001), anxiety (4.3 ± 4.2 vs. 3.4 ± 4.1; p-value <0.001), and stress (10.3 ± 6.9 vs. 8.5 ± 6.6; p-value <0.001). The highest mean PHQ-9 and DASS-21 total and sub-scale scores were observed among migraineurs with aura, and were significantly higher to the mean scores of non-migraineurs.

Table 2.

Summary of Patient Health Questionnaire-9 (PHQ-9) Score and Depression Anxiety Stress Scale (DASS) Scores According to Migraine Status

Index No
Migraine
(N=949)		 Any
Migraine
(N=372)		 Migraine
with Aura
(N=122) 		Migraine
without Aura
(N=250) 		P-value**
Depression PHQ-9 Total Score
    Mean ± SD 5.3 ± 3.5 6.2 ± 3.6* 6.6 ± 3.8 6.0 ± 3.5 <0.001
    Median (IQR) 5 (3–7) 6 (3–9)* 6 (3–9) 5 (3–8) <0.001
DASS Total Score
    Mean ± SD 15.9 ± 13.1 19.5 ± 13.9* 22.7 ± 16.3 18.0 ± 12.4 <0.001
    Median (IQR) 14 (8–22) 16 (10–26)* 20 (12–30) 16 (10–24) <0.001
DASS Depression Sub-scale Score
    Mean ± SD 4.1 ± 4.8 5.0 ± 5.3* 6.0 ± 5.9 4.5 ± 4.9 <0.001
    Median (IQR) 2 (0–6) 4 (2–8)* 4 (2–8) 4 (2–6) <0.001
DASS Anxiety Sub-scale Score
    Mean ± SD 3.4 ± 4.1 4.3 ± 4.2* 5.2 ± 5.2 3.8 ± 3.6 <0.001
    Median (IQR) 2 (0–4) 4 (2–6)* 4 (2–8) 4 (0–6) <0.001
DASS Stress Sub-scale Score
    Mean ± SD 8.5 ± 6.6 10.3 ± 6.9* 11.5 ± 7.9 9.7 ± 6.4 <0.001
    Median (IQR) 8 (4–12) 10 (6–14)* 10 (6–16) 10 (4–14) <0.001
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*

P-value <0.05 in 2-sample student t test comparing any migraine versus no migraine

**

P-value from ANOVA or Kruskal-Wallis non-parametric ANOVA

Compared with non-migraineurs, migraineurs were more likely to exhibit mild (AOR= 1.42; 95% CI: 1.09–1.85), moderate (AOR=1.56; 95% CI: 1.06–2.29), and severe depression (AOR=1.95; 95% CI: 0.84–4.57), although the association for severe depression did not reach statistical significance (Table 3). When we combined moderate and severe depression, defined as major depressive disorder (MDD), migraineurs had 1.60-fold higher odds of experiencing depression (AOR=1.60; 95% CI: 1.12–2.31), as measured by a PHQ-9 score ≥10 (Table 3). Migraineurs with aura, as compared with non-migraineurs, were more likely to have moderate depression (AOR=1.76; 95% CI: 0.99–3.11) and severe depression (AOR=3.28; 95% CI: 1.13–9.50). The corresponding AORs for migraineurs without aura were lower and statistically nonsignificant (Table 3).

Table 3.

Adjusted Odds Ratio (AOR) and 95% Confidence Interval (CI) for Depression Symptom Severity According to Migraine Status

No Migraine
(N=949)		 Any Migraine
(N=372)		 Migraine with Aura
(N=122) 		Migraine without Aura
(N=250)
Depressive Symptoms n (%) n (%) AOR (95% CI) n (%) AOR (95% CI) n (%) AOR (95% CI)
PHQ-9 Total Score
    Minimal (0–4) 454 (47.8) 141 (37.9) 1.00 (referent) 46 (37.7) 1.00 (referent) 95 (38.0) 1.00 (referent)
    Mild (5–9) 375 (39.5) 170 (45.7) 1.42 (1.09–1.85) 51 (41.8) 1.32 (0.86–2.02) 119 (47.6) 1.47 (1.09–2.00)
    Moderate (10–14) 105 (11.1) 52 (14.0) 1.56 (1.06–2.29) 20 (16.4) 1.76 (0.99–3.11) 32 (12.8) 1.45 (0.92–2.29)
    Severe (≥15) 15 (1.6) 9 (2.4) 1.95 (0.84–4.57) 5 (4.1) 3.28 (1.13–9.50) 4 (1.6) 1.30 (0.42–4.01)
        p-value for trend 0.002 0.008 0.032
PHQ-9 Total Score
    Minimal (0–4) 454 (47.8) 141 (37.9) 1.00 (referent) 46 (37.7) 1.00 (referent) 95 (38.0) 1.00 (referent)
    Mild (5–9) 375 (39.5) 170 (45.7) 1.42 (1.09–1.85) 51 (41.8) 1.32 (0.86–2.02) 119 (47.6) 1.47 (1.09–2.00)
    MDD (≥10) 120 (12.7) 61 (16.4) 1.60 (1.12–2.31) 25 (20.5) 1.94 (1.14–3.30) 36 (14.4) 1.43 (0.93–2.21)
        p-value for trend 0.003 0.014 0.024
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Adjusted for maternal age, unplanned pregnancy and maternal pre-pregnancy body mass index (BMI)

Migraineurs, as compared with non-migraineurs had higher odds of depressive, anxiety and stress symptoms as measured using the DASS-21 questionnaire (Table 4). The adjusted odds and 95% CI for successive quartiles of the global DASS-21 score associated with history of migraine were: Q2: 1.32 (0.89–1.95), Q3: 1.82 (1.25–2.64), and Q4: 2.30 (1.60–3.30) with the lowest quartile as the referent group (p-value for trend < 0.001). Associations were notably stronger for migraineurs with aura as compared with non-migraineurs. Similar patterns of associations were observed when we repeated analyses for each of the DASS-21 subscales for anxiety and stress symptoms.

Table 4.

Adjusted Odds Ratios (AOR) and 95% Confidence Intervals (CM for Psvchiatric Characteristics According to Migraine Status

No migraine Any Migraine Migraine with Aura Migraine without Aura
DASS Items (N=949) (N=372) (N=122) (N=250)
n (%) n (%) AOR (95% CI) n (%) AOR (95% CI) n (%) AOR (95% CI)
DASS Global Quartile
    Q1 (<8) 234 (24.6) 56 (15.1) 1.00 (referent) 15 (12.3) 1.00 (referent) 41 (16.4) 1.00 (referent)
    Q2 (8–12) 235 (24.8) 75 (20.2) 1.32 (0.89–1.95) 20 (16.4) 1.33 (0.66–2.66) 55 (22.0) 1.31 (0.84–2.04)
    Q3 (13–20) 237 (25.0) 103 (27.7) 1.82 (1.25–2.64) 31 (25.4) 2.04 (1.07–3.88) 72 (28.8) 1.74 (1.14–2.66)
    Q4 (≥21) 243 (25.6) 138 (37.1) 2.30 (1.60–3.30) 56 (45.9) 3.38 (1.85–6.16) 82 (32.8) 1.90 (1.25–2.89)
        p-value for trend <0.001 <0.001 0.001
DASS Depression Sub-Scale
    Minimal (0–9) 825 (86.9) 309 (83.1) 1.00 (referent) 96 (78.7) 1.00 (referent) 213 (85.2) 1.00 (referent)
    Mild (10–13) 72 (7.6) 37 (9.9) 1.33 (0.88–2.03) 11 (9.0) 1.25 (0.64–2.44) 26 (10.4) 1.37 (0.85–2.21)
    Moderate (14–20) 43 (4.5) 18 (4.8) 1.14 (0.65–2.02) 13 (10.7) 2.57 (1.33–4.99) 5 (2.0) 0.47 (0.18–1.20)
    Severe (≥21) 9 (1.0) 8 (2.2) 2.18 (0.83–5.73) 2 (1.6) 1.69 (0.36–7.99) 6 (2.4) 2.43 (0.85–6.92)
        p-value for trend 0.082 0.011 0.601
DASS Anxiety Sub-Scale
    Minimal (0–7) 816 (86.0) 291 (78.2) 1.00 (referent) 88 (72.1) 1.00 (referent) 203 (81.2) 1.00 (referent)
    Mild (8–9) 52 (5.5) 39 (10.5) 2.05 (1.32–3.17) 12 (9.8) 2.06 (1.05–4.01) 27 (10.8) 2.05 (1.25–3.34)
    Moderate (10–14) 59 (6.2) 31 (8.3) 1.42 (0.90–2.25) 13 (10.7) 1.95 (1.02–3.74) 18 (7.2) 1.19 (0.69–2.07)
    Severe (≥15) 22 (2.3) 11 (3.0) 1.38 (0.66–2.90) 9 (7.4) 3.47 (1.53–7.88) 2 (0.8) 0.38 (0.09–1.62)
        p-value for trend 0.015 <0.001 0.599
DASS Stress Sub-Scale
    Minimal (0–14) 803 (84.6) 292 (78.5) 1.00 (referent) 87 (71.3) 1.00 (referent) 205 (82.0) 1.00 (referent)
    Mild (15–18) 85 (9.0) 040 (10.7) 1.25 (0.84–1.87) 15 (12.3) 1.51 (0.83–2.75) 25 (10.0) 1.14 (0.71–1.83)
    Moderate (19–25) 43 (4.5) 26 (7.0) 1.61 (0.97–2.68) 11 (9.0) 2.22 (1.10–4.48) 15 (6.0) 1.35 (0.73–2.48)
    Severe (≥26) 18 (1.9) 14 (3.8) 2.01 (0.98–4.12) 9 (7.4) 4.19 (1.81–9.71) 5 (2.0) 1.05 (0.38–2.86)
        p-value for trend 0.007 <0.001 0.396
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Adjusted for maternal age, unplanned pregnancy and maternal pre-pregnancy body mass index (BMI)

DISCUSSION

Overall we found that compared with non-migraineurs, migraineurs were more likely to have unipolar depression, anxiety, and stress as measured by the PHQ-9 and DASS-21. The odds of MDD, severe anxiety, and severe stress symptoms were particularly elevated among migraineurs with aura. Our results are in accordance with previous reports indicating an increased prevalence of affective disorders among individuals with headache or migraine, albeit generally in non-pregnant adult populations and adolescents (Breslau et al., 1994; Breslau et al., 2003; Fuller-Thomson et al., 2013; Gelaye et al., 2013; Jette et al., 2008; Kalaydjian and Merikangas, 2008; McWilliams et al., 2004; Merikangas et al., 1990; Patel et al., 2004; Saunders et al., 2014; Swartz et al., 2000; Zwart et al., 2003). Furthermore, our results are also in accordance with the two other studies that have reported on observations of such associations in pregnant women (Cripe et al., 2010; Williams et al., 2010), and thus extends this literature.

Our observation of nearly two-fold increased odds of unipolar depression (PHQ-9 ≥10) (AOR=1.60; 95% CI: 1.12–2.31) and severe stress (AOR=2.01; 95% CI: 0.98–4.12) among migraineurs compared to non-migraineurs are consistent with the limited number of studies that have reported on the association between migraine and depression, and migraine and perceived stress in pregnant populations (Cripe et al., 2010; Williams et al., 2010). In a study of 2,293 pregnant women in Peru, the odds of moderate to severe depressive symptoms (PHQ-9 score 10–27) among women with strict migraine was 2.06 times that of women without a history of migraine (AOR=2.06; 95% CI: 1.54–2.76) adjusted for maternal age and race (Cripe et al., 2010). The odds of moderate (PHQ-9 score 10–14), moderately severe (PHQ-9 score 15–19), and severe depression (PHQ-9 score 20–27) during pregnancy were also significantly higher and nearly twofold among women with strict migraine when compared to women without a history of migraine; AOR=2.12; 95% CI: 1.54–2.93, AOR=1.85; 95% CI: 1.16–2.96, and AOR=2.23; 95% CI: 1.08–4.62, respectively. In another study of women delivering in Seattle, Washington, we (2010) noted that migraine (based on self-reports of a clinical diagnosis) was associated with 1.57-increased odds of perceived stress in the past 3-months (based on a Perceived Stress Scale score ≥7) compared to non-migraineurs, (AOR=1.57; 95% CI 1.06–2.31), adjusted for parity, history of pre-gestational hypertension and pre-pregnancy body mass index (Williams et al., 2010). Taken together, these increased odds provide evidence of a mood-migraine association among pregnant women.

Our prevalence estimates of lifetime history of migraine (28.2%) are somewhat higher than previous estimates from other pregnancy cohorts (9–20%), (Adeney et al., 2006; Frederick et al., 2014) yet comparable to the 2011 National Health Interview Survey’s three-month prevalence of migraine or other severe headache among women of reproductive age (26.1%) (Smitherman et al., 2013). Although slightly attenuated, our observations are also concordant with other cross-sectional population-level studies across North America reporting on associations between migraine and mood disorders in non-pregnant populations. In a recent Canadian study, women migraineurs (based on self-report of a clinical diagnosis) had 1.89-increased odds of depression over a period of at least two-weeks in the previous year (based on the Composite International Diagnostic Interview-Short Form, CIDI-SF) compared to women without migraine, adjusting for sociodemographic and disability covariates (OR=1.89; 95% CI: 1.71–2.10) (Fuller-Thomson et al., 2013). In a nationally representative sample of the U.S. from 1999–2004 adults who self-reported severe headache or migraine had nearly three-fold increased odds of depression and generalized anxiety disorder (GAD) (as measured by the WHO CIDI) compared to individuals who did not self-report severe headache or migraine, (depression AOR=2.84; 95% CI: 1.71–4.73 and GAD AOR=3.03; 95% CI: 1.43–6.38) adjusting for age, race, sex, and education status (Kalaydjian and Merikangas, 2008). In another U.S. study in Baltimore, Swartz et.al (2000) reported that the odds of lifetime history of major depression (as measured by the National Institute of Mental Health Diagnostic Interview Schedule) was 2.25 times higher among migraineurs (as measured using an interviewer-administered survey based on ICHD-II criteria) compared to self-reported non-migraineurs (95% CI: 1.43–3.54), adjusting for age and sex (Swartz et al., 2000). Although our current study inquired about unipolar depression, bipolar depression is a well-recognized co-morbid condition with migraine in studies mostly conducted among men and non-pregnant women (Dilsaver et al., 2009a; Dilsaver et al., 2009b, c; Peterlin and Ward, 2005). For instance Dilsaver et al in their study among Latino adolescents of Mexican American origin found that those with bipolar depression were 6.15-times as likely (OR=6.15, 95% CI = 1.25–30.4) to have migraine headache than those in the control group (Dilsaver et al., 2009c). Future research evaluating the neurobiology of bipolar depression in pregnancy is warranted.

The pathogenesis for comorbid migraine-mood disorders remains unclear. Common neuropathology of the serotoninergic and dopaminergic systems has been proposed, (D'Andrea et al., 1989; Frediani and Villani, 2007) as well as dysregulation of the hypothalamic-pituitary adrenalin (HPA) axis (McWilliams et al., 2004; Overeem et al., 2002). Increased secretion of corticotrophin-releasing factor and changes in cortisol secretion may additionally play a role in the pathophysiology of migraine and mood disorders (Overeem et al., 2002). It has also been proposed that stress and depression affect inflammatory immune parameters and endothelial functioning during pregnancy, (Christian, 2014; Christian et al., 2009) and that neurogenic inflammation plays a role in migraine pathogenesis (Brietzke et al., 2012; Geppetti et al., 2005). Other plausible mechanisms include shared genetics and environmental trigger factors, or that a causal relationship between migraine and mood disorders exists (Ligthart et al., 2014; Martin et al., 2005). However the directionality of a causal relationship also remains unclear. Studies that favor the shared pathophysiological mechanism explanation suggest that each disorder increases the risk for the first onset of the other (Breslau et al., 1994). Until a general consensus is reached regarding the biological mechanisms of migraine-mood disorders their comorbidity continues to affect the quality of life, total disability, and therapeutic drug strategies for such patients (Finocchi et al., 2010). Additionally, this comorbidity may adversely affect birthing outcomes and childrearing if left untreated among pregnant women.

Several important limitations should be considered when interpreting our results. First, our cross-sectional study design prohibits clarification of temporality of the association between migraine and symptoms of mood disorders, as well as our ability to make statements regarding the role of pregnancy. Longitudinal studies with prospective clinical assessments of mood-migraine symptoms during the pre-conception, antepartum and early postpartum periods are needed to understand the underlying mechanisms of this association and to pinpoint optimal screening windows. Second, despite our use of validated instruments and trained interviewers, participants did not receive formal clinical evaluation and diagnoses for migraine and mood disorders, thus we cannot rule out some misclassification errors. However, such errors are likely to have resulted in an attenuation of estimated associations. Third, our sample was comprised of few women who endorsed severe psychiatric symptomology, likely resulting in a reduction of the precision of our estimates, as reflected by the 95% confidence intervals reported in some instances. Lastly, in our study we adjusted for putative confounders. However, as with all observational studies, we cannot rule out the possibility of residual confounding by unmeasured covariates such as maternal medication use.

In summary, we found increased odds of unipolar mood disorders among pregnant migraineurs compared with pregnant non-migraineurs. The odds of mood disorders were particularly elevated among migraineurs with aura. Our findings supports the need for prospective studies designed to (1) enhance the understanding of the biological mechanisms underlying these observed associations; and (2) develop and evaluate the clinical effectiveness of integrated somatic and mental antepartum screening and treatment strategies that mitigate the burden of these highly comorbid conditions in pregnant women.

ACKNOWLEDMENTS

This research was supported by grants from the National Institutes of Health (NIH), the Eunice Kennedy Shriver Institute of Child Health and Human Development (NICHD): R01-HD-059835; the National Institute for Minority Health and Health Disparities, National Institutes of Health (T37-MD001449); and Olivia R. Orta was supported by the National Institute of Child Health and Human Development, National Institutes of Health Training Grant in Reproductive, Perinatal and Pediatric Epidemiology (T32-HD060454). The NIH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Contributors: MAW had full access to all the data in the study and takes responsibility for the integrity of the data, the accuracy of the data analysis, and the decision to submit for publication. MAW conceived, designed, and obtained funding for the study. CQ analyzed the data. ORO, BG, and MAW drafted the manuscript. ORO, BG, MAW, and LS aided in the interpretation of the data, and all authors critically revised the draft for important intellectual content, and gave final approval of the manuscript to be published.

Conflict of Interest: The authors declare that they have no competing interests

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