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Cognitive and somatic symptoms were worse in women than men up to a year after mild traumatic brain injury (TBI), the prospective TRACK-TBI study showed.

No sex difference in symptom burden was seen in a comparison control group of patients who had orthopedic trauma without head injury. In an exploratory analysis, women 35 to 49 years old had more severe somatic symptoms than women 17 to 34 or those older than 50, reported Harvey Levin, PhD, of Baylor College of Medicine in Houston, and co-authors.

"Our findings suggest that female sex is a risk factor of which clinicians should be aware when triaging patients for follow-up," Levin and colleagues wrote in .

"These age- and sex-specific findings are novel and beg for a better understanding of the role played by female sex hormones in mild TBI pathophysiology," observed Jeffrey Bazarian, MD, MPH, of the University of Rochester in New York, and co-authors in an .

An important innovation of the study was the group of orthopedic trauma patients it used as controls, Bazarian and colleagues noted. This allowed the researchers to demonstrate two key points, they wrote: "First, in contradistinction to the sex differences observed in the mild TBI cohort, there were no sex differences in symptom-based recovery after orthopedic injury."

"Second, the fact that the orthopedic control group reported significantly fewer cognitive and somatic symptoms than the mild TBI cohort suggests that these post-concussive symptoms, traditionally thought to be a nonspecific response to injury, are in fact specific to mild TBI," the editorialists added. "Taken together, these findings support the contention that the observed age-sex interaction in symptom-based recovery is likely rooted in mild TBI pathophysiology."

followed 2,000 patients with mild TBI who were recruited from 18 level I trauma centers in 2014-2018. Most (67%) were men with a mean age of 41; women had an average age of 43. In both groups, about three-quarters of participants were white. A cohort of 299 people with orthopedic trauma from the same sites served as controls.

In the mild TBI group, men had less education, were less likely to be insured, and had higher prevalence of previous TBI than women. They also had more frequent history of drug use and were more likely to have a violent cause of injury and be admitted to the ICU. Women were more likely to live independently, pursue litigation, and have a history of psychiatric diagnoses of anxiety or depression.

The study's primary outcomes were based on the (RPQ), a self-reported measure of post-concussion symptom severity over the past 7 days relative to pre-injury. The RPQ has three domains: somatic (headaches, dizziness, or fatigue), emotional (irritability, depression, or frustration), and cognitive (poor concentration or forgetfulness). Outcome assessments were performed at 2 weeks, 3 months (by telephone), 6 months, and 12 months.

The researchers also evaluated data from the Post-Traumatic Stress Disorder Checklist-5 to gauge severity of post-traumatic stress disorder symptoms, the Patient Health Questionnaire-9 to assess depression based on symptom frequency over the past 2 weeks, and the Brief Symptom Inventory-18 scale of psychological distress.

A TBI × sex interaction was significant for cognitive RPQ symptoms (B=0.76, 5% false discovery rate-corrected P=0.02) and somatic RPQ symptoms (B=0.80, 5% false discovery rate-corrected P=0.02), with worse symptoms in women than men. No significant TBI x sex interaction emerged for other outcomes.

The difference in symptom severity between mild TBI and orthopedic control groups was significantly greater among women 35 to 49 than those 17 to 34 for somatic (B=1.65, 95% CI 0.25-3.06, P=0.02), but not cognitive or emotional symptoms, an exploratory analysis showed. Women 35 to 49 also had more severe somatic symptoms than those older than 50 (B=1.66, 95% CI 0.25-3.07, P=0.02).

"Although this finding is preliminary and should be interpreted accordingly, further investigation measuring psychosocial stress and sex hormone levels could examine the mechanisms underpinning this mild TBI × age interaction," Levin and co-authors wrote.

Greater psychosocial stress in women ages 35 to 49 years than in younger and older women is compatible with multiple roles in life, such as child care, family, and occupation, the researchers noted.

"Although the median age at onset of menopause is 51 years, levels of estrogen and progesterone begin to decline in the premenopausal age range, which begins at 35 to 40 years," they pointed out. "Whether declining levels of these hormones is contributory to the present findings awaits further investigation."

The study had several limitations. Male and female groups were imbalanced and the study was restricted to patients evaluated at level I trauma centers. Estrogen and progesterone levels were not measured and stress in daily life was not assessed.

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