Objective:
Migraine affects 28% of women in their pregnancy-capable years,1 and is associated with systemic inflammation, endothelial dysfunction, and increased risk of pregnancy-associated thromboembolic events.2, 3 Migraine history has been associated with adverse pregnancy outcomes (APO) of placental origin, including hypertensive disorders of pregnancy (HDP) and preterm birth (PTB).4 We tested the hypothesis that self-reported migraine in nulliparous individuals is associated with higher odds of APO.
Study Design:
The multi-center Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b) study enrolled 10,038 nulliparous US participants with singleton gestation in early pregnancy, following them prospectively through delivery.5 Medical histories were collected from study participants by standardized interview: participants were asked “Have you ever had any of the following medical conditions or diagnoses?” followed by a list of diagnoses, which included “migraine headaches.” We considered participants who responded “yes” to this question at the first-trimester study visit to have a migraine history. We defined “APO” as ≥1 of the following outcomes, defined according to standardized definitions and adjudicated by maternal-fetal medicine specialists after delivery: gestational hypertension, preeclampsia/eclampsia, PTB (medically indicated or spontaneous), small-for-gestational-age at birth, or stillbirth. We compared characteristics between participants who did and did not report migraine, including demographics, family history of preeclampsia, and comorbidities such as obesity, recent smoking, chronic hypertension, chronic kidney disease, pre-gestational diabetes and autoimmune disorders. We created logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association of migraine with APO, adjusting for characteristics that showed between-group differences (p<0.1) in univariable analysis. In secondary analyses, we estimated associations between migraine and individual APOs, and tested for interactions between migraine and chronic hypertension, obesity, and diabetes. We performed sensitivity analyses restricting the exposed group to 1) those who reported using migraine medications within the last two months, and 2) those who reported migraine headaches at all four study visits during the pregnancy.
Results:
Of 9,450 participants with complete data included in the analysis, 1,752 (19.1%) reported a diagnosis of migraine at visit 1. Cohort characteristics are presented in the Supplement. Age, income level and body mass index did not differ between exposure groups. Participants with migraine had higher proportions of self-identified white race, recent smoking history, autoimmune disorders, and chronic kidney disease. Adjusting for all factors which differed to p<0.1 in univariable analysis, participants with migraine had increased odds of any APO (adjusted OR 1.26, 95% CI 1.12, 1.41). For individual APO, participants with migraine had higher odds of any HDP, and both medically indicated and spontaneous PTB, but not small-for-gestational age or stillbirth (Table). There were no significant interactions between migraine and obesity, chronic hypertension or diabetes. Sensitivity analyses showed a larger effect in participants who reported recent medication use (adjusted OR 1.49, 95% CI 1.18, 1.88).
Table.
Adverse pregnancy outcomes in nuMoM2b participants, with and without migraine
| Migraine (N=1752) | No Migraine (N=7698) | Unadjusted OR* (95% CI) | Adjusted OR* (95% CI) | |
|---|---|---|---|---|
| N (%) | N (%) | |||
| Any APO | 700 (40.0) | 2658 (34.5) | 1.26 (1.13–1.40) | 1.26 (1.12–1.41) |
| Any hypertensive disorder of pregnancy | 451 (25.7) | 1738 (22.6) | 1.19 (1.06–1.34) | 1.18 (1.04–1.33) |
| - Gestational Hypertension | 273 (15.6) | 1082 (14.1) | 1.13 (0.98–1.30) | 1.12 (0.96–1.30)1 |
| - Preeclampsia or eclampsia (including superimposed preeclampsia) | 178 (10.2) | 656 (8.5) | 1.22 (1.02–1.44) | 1.18 (0.97–1.41) |
| Stillbirth | 12 (0.7) | 45 (0.6) | 1.17 (0.59–2.15) | 0.97 (0.42–1.99) |
| Preterm Birth | 186 (10.6) | 599 (7.8) | 1.41 (1.18–1.67) | 1.44 (1.19–1.73) |
| - Medically indicated | 77 (4.4) | 232 (3.0) | 1.48 (1.13–1.92) | 1.44 (1.08–1.89) |
| - Spontaneous | 109 (6.2) | 367 (4.8) | 1.33 (1.06–1.65) | 1.40 (1.11–1.77) |
| Small for Gestational Age | 206 (11.8) | 811 (10.5) | 1.13 (0.96–1.33) | 1.16 (0.97–1.38) |
| Sensitivity Analysis 1 | Migraine with medication use, visit 1 (N=332) | No Migraine (N=7698) | Unadjusted OR* (95% CI) | Adjusted OR* (95% CI) |
| N (%) | N (%) | |||
| Any APO | 146 (44.0) | 2658 (34.5) | 1.49 (1.19–1.86) | 1.49 (1.18–1.88) |
| Sensitivity Analysis 2 | Reported migraine all 4 visits (N=1011) | No Migraine (N=7698) | Unadjusted OR* (95% CI) | Adjusted OR* (95% CI) |
| N (%) | N (%) | |||
| Any APO | 413 (40.9) | 2658 (34.5) | 1.31 (1.14–1.50) | 1.32 (1.15–1.52) |
OR: odds ratio. CI: confidence interval. APO: adverse pregnancy outcome. Models were adjusted for the following covariates which differed significantly between exposure groups (p<0.1) in univariable analysis: race/ethnicity, chronic hypertension, renal disease, autoimmune disorders (systemic lupus erythematosus or antiphospholipid syndrome), smoking in the 3 months prior to pregnancy, and family history of preeclampsia in mother or sister.
Bolded ORs indicate p<0.05.
Chronic hypertension not included in adjusted model for outcome of gestational hypertension.
Sensitivity Analysis 1: Exposure group defined as those who reported migraine headaches with medication use within the last two months at visit 1
Sensitivity Analysis 2: Exposure group defined as those who reported migraine headaches at all four study visits
Conclusion:
In a diverse, prospective cohort of 9,450 nulliparous US participants, self-reported migraine headaches were associated with 26% higher odds of APO, an effect driven by HDP and both medically-indicated and spontaneous PTB. Migraine may be an underrecognized risk factor for APO.
Supplementary Material
FUNDING:
Dr. Miller is supported by the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (K23NS107645, R01NS122815) and the Gerstner Family Foundation (Gerstner Scholars Program). Dr. Bello is supported by the NIH National Heart, Lung and Blood Institute (K23-HL136853, R01-HL153382) and the NIH Loan Repayment Program (1L30HL129418–03). The nuMoM2b study was supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): U10 HD063036, RTI International; U10 HD063072, Case Western Reserve University; U10 HD063047, Columbia University; U10 HD063037, Indiana University; U10 HD063041, University of Pittsburgh; U10 HD063020, Northwestern University; U10 HD063046, University of California Irvine; U10 HD063048, University of Pennsylvania; and U10 HD063053, University of Utah.
Footnotes
CONFLICTS OF INTEREST: Dr. Miller reports no conflicts of interest. Ms. Chau reports no conflicts of interest. Dr. Mammadli reports no conflicts of interest. Dr. Levine reports no conflicts of interest. Dr. Grobman reports no conflicts of interest. Dr. Wapner reports no conflicts of interest. Dr. Bello reports no conflicts of interest.
Preliminary findings of this study were presented at the 68th Annual Meeting of the Society for Reproductive Investigation, July 6–9, 2021, Boston, Massachusetts, and the American Academy of Neurology 2022 Annual Meeting, April 2–7, 2022, Seattle, Washington.
REFERENCES:
- 1.Buse DC , Loder EW , Gorman JA, et al. Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache 2013;53:1278–99. [DOI] [PubMed] [Google Scholar]
- 2.Levy D , Labastida-Ramirez A , MaassenVanDenBrink A. Current understanding of meningeal and cerebral vascular function underlying migraine headache. Cephalalgia 2019;39:1606–22. [DOI] [PubMed] [Google Scholar]
- 3.Wabnitz A , Bushnell C. Migraine, cardiovascular disease, and stroke during pregnancy: systematic review of the literature. Cephalalgia 2015;35:132–9. [DOI] [PubMed] [Google Scholar]
- 4.Aukes AM , Yurtsever FN , Boutin A , Visser MC , de Groot CJM. Associations Between Migraine and Adverse Pregnancy Outcomes: Systematic Review and Meta-analysis. Obstet Gynecol Surv 2019;74:738–48. [DOI] [PubMed] [Google Scholar]
- 5.Haas DM , Parker CB , Wing DA, et al. A description of the methods of the Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be (nuMoM2b). Am J Obstet Gynecol 2015;212:539 e1–39 e24. [DOI] [PMC free article] [PubMed] [Google Scholar]
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