Adverse Childhood Experiences and Primary Headache Disorders: A Systematic Review, Meta-analysis, and Application of a Biological Theory.

BACKGROUND AND OBJECTIVES: Headache disorders are among the leading causes of disability worldwide. While an association between adverse childhood experiences and primary headaches has been reported, the pooled magnitude across studies and pathways of the association are unknown. Our objectives were (1) to estimate the pooled effect of ≥1 adverse childhood experience (ACE) on primary headache disorders in adulthood and (2) to test the hypothesis that ACEs categorized as "threat" traumas or "deprivation" traumas have distinct effects on primary headaches based on a selected theory from our narrative review of how ACEs affect human development along the life course. METHODS: PubMed, EMBASE, MEDLINE, Web of Science, Google Scholar, Biological Psychiatry, and gray literature were searched up to March 16, 2023 (PROSPERO, CRD42020223403). Selected articles included (1) observational studies with a comparator group, (2) ACEs that occurred before 18 years of age, and (3) primary headaches occurring at or after 21 years of age. Pooled odds ratios (ORs) were calculated using multilevel linear random-effects modeling. The narrative review included theories that describe how ACEs affect human development and disease across the life course. We selected a theory from our narrative review and tested ACEs categorized according to this theory for any modification of point estimates. RESULTS: Our search identified 32 studies, of which 28 were eligible for meta-analysis (n = 154,739 participants, 19 countries). The occurrence of ≥1 adverse childhood experience(s) was associated with primary headaches (pooled OR = 1.48 [95% CI 1.36-1.61]; high-quality evidence, 134,696 participants). As the number of ACEs increased, the odds of primary headaches increased (range: 1 ACE OR = 1.24 [95% CI 1.14-1.35] to ≥4 ACEs OR = 2.09 [95% CI 1.83-2.38], p for trend <0.0001). From the narrative review, a neurodevelopmental theory that categorizes ACEs into threat or deprivation was tested, and both were independently associated with primary headaches (threat OR = 1.46 [95% CI 1.32-1.60] and deprivation OR = 1.35 [95% CI 1.23-1.49], respectively), accounting for heterogeneity (p = 0.021). DISCUSSION: This systematic review and meta-analysis confirm that ACEs are important risk factors of primary headache disorders in adulthood. Our findings provide epidemiologic support that ACEs categorized as threat and deprivation may manifest as distinct pathways of early adversity.