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Is Sex an Indicator of Prognosis After Mild Traumatic Brain Injury: A Systematic Analysis of the Findings of the World Health Organization Collaborating Centre Task Force on Mild Traumatic Brain Injury and the International Collaboration on Mild Traumatic Brain Injury Prognosis

  • Carol Cancelliere
    Affiliations
    Division of Health Care and Outcomes Research, Toronto Western Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada

    Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada
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  • James Donovan
    Correspondence
    Corresponding author James Donovan, DC, University Health Network, Toronto Western Research Institute, University of Toronto, LuCliff Place, 700 Bay St, Suite 602, Toronto, Ontario, Canada M5G 1Z6.
    Affiliations
    Division of Health Care and Outcomes Research, Toronto Western Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada
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  • J. David Cassidy
    Affiliations
    Division of Health Care and Outcomes Research, Toronto Western Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada

    Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada

    Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

    Institute of Sports Science and Clinical Biomechanics, Faculty of Health, University of Southern Denmark, Odense, Denmark
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Published:February 06, 2015DOI:https://doi.org/10.1016/j.apmr.2014.11.028

      Abstract

      Objective

      To determine sex differences in the recovery and prognosis after mild traumatic brain injury (MTBI) in adults and children.

      Data Sources

      We analyzed all scientifically admissible primary studies in the World Health Organization (WHO) (n=120) and International Collaboration on Mild Traumatic Brain Injury Prognosis (ICoMP) (n=101) systematic reviews regarding prognosis of MTBI for sex-stratified findings. They searched MEDLINE and other databases from 1980 through 2000 (WHO) and 2001 through 2012 (ICoMP) for published, peer-reviewed reports in English and other languages.

      Study Selection

      We selected controlled trials and cohort and case-control studies that assessed the effect of sex on outcomes after MTBI.

      Data Extraction

      Data from the eligible studies from both systematic reviews combined (n=14, 7%) were extracted into evidence tables.

      Data Synthesis

      Prognostic information relating to sex was prioritized according to design as exploratory or confirmatory, and a best-evidence synthesis was conducted. After MTBI, females may have a higher risk of epilepsy (children, young adults) and suicide, and use more health care services; males may be at higher risk for schizophrenia. Most studies did not find a sex difference for postconcussion symptoms in children and adults. No sex difference was found for risk of dementia and primary brain tumor, return to work, or posttraumatic stress syndrome.

      Conclusions

      Sex is not a well-studied prognostic indicator for recovery after MTBI, but small sex differences were found for some outcomes. More well-designed studies are needed that report outcomes according to sex and control for potential confounders.

      Keywords

      List of abbreviations:

      CI (confidence interval), ED (emergency department), ICoMP (International Collaboration on Mild Traumatic Brain Injury Prognosis), MTBI (mild traumatic brain injury), OR (odds ratio), PCS (postconcussion symptoms), PTSD (posttraumatic stress disorder), RPQ (Rivermead Postconcussion Symptoms Questionnaire), RR (relative risk), RTW (return to work), TBI (traumatic brain injury), WHO (World Health Organization)
      Traumatic brain injury (TBI) is a major cause of disability worldwide.
      • Hyder A.A.
      • Wunderlich C.A.
      • Puvanachandra P.
      • Gururaj G.
      • Kobusingye O.C.
      The impact of traumatic brain injuries: a global perspective.
      Concussion or mild TBI (MTBI) is the most common form of TBI and has an incidence in excess of 600 cases per 100,000 people per year.
      • Cassidy J.D.
      • Carroll L.J.
      • Peloso P.M.
      • et al.
      Incidence, risk factors and prevention of mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
      The economic effect of MTBI is substantial, accounting for approximately 44% of the $60 billion annual cost of TBI in the United States.
      • Corso P.
      • Finkelstein E.
      • Miller T.
      • Fiebelkom I.
      • Zaloshnja E.
      Incidence and lifetime costs of injuries in the United States.
      As a result, MTBI has become a major public health problem. In order to improve patient management and outcomes, it is important to identify all potential prognostic indicators, such as sex, that may impact recovery after MTBI.
      Sex plays an important role in health because individuals may experience various processes differently based on their biology.
      • Johnson J.L.
      • Greaves L.
      • Repta R.
      Better science with sex and gender: a primer for health research.
      For example, males and females respond differently to drugs and therapeutics because of differences in body composition, metabolism, and hormones.
      • Johnson J.L.
      • Greaves L.
      • Repta R.
      Better science with sex and gender: a primer for health research.
      Sex differences in outcome after MTBI have been addressed in a number of studies, of which some found females to have a poorer outcome than males.
      • Bazarian J.J.
      • Blyth B.
      • Mookerjee S.
      • He H.
      • McDermott M.P.
      Sex differences in outcome after mild traumatic brain injury.
      • Bay E.
      • Sikorskii A.
      • Saint-Arnault D.
      Sex differences in depressive symptoms and their correlates after mild-to-moderate traumatic brain injury.
      • Styrke J.
      • Sojka P.
      • Bjornstig U.
      • Bylund P.O.
      • Stalnacke B.M.
      Sex differences in symptoms, disability and life satisfaction three years after mild traumatic brain injury: a population-based cohort study.
      However, the evidence is limited and conflicting.
      • Covassin T.
      • Bay E.
      Are there gender differences in cognitive function, chronic stress, and neurobehavioral symptoms after mild-to-moderate traumatic brain injury?.
      • Tsushima W.T.
      • Lum M.
      • Geling O.
      Sex differences in the long-term neuropsychological outcome of mild traumatic brain injury.
      Therefore, the objective of this report is to determine the prognostic significance, if any, of sex on recovery after MTBI in adults and children. This has important implications for rehabilitation and prognosis in the field of MTBI.

      Methods

      We analyzed all the scientifically admissible primary studies in 2 systematic reviews
      • Carroll L.J.
      • Cassidy J.D.
      • Peloso P.M.
      • et al.
      Prognosis for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
      • Cancelliere C.
      • Cassidy J.D.
      • Cote P.
      • et al.
      Protocol for a systematic review of prognosis after mild traumatic brain injury: an update of the WHO Collaborating Centre Task Force findings.
      regarding the prognosis of MTBI for sex-stratified findings. One review
      • Carroll L.J.
      • Cassidy J.D.
      • Peloso P.M.
      • et al.
      Prognosis for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
      was conducted by the World Health Organization (WHO) Collaborating Centre for Neurotrauma, Prevention, Management and Rehabilitation Task Force (WHO Task Force, 2004). The second review
      • Cancelliere C.
      • Cassidy J.D.
      • Cote P.
      • et al.
      Protocol for a systematic review of prognosis after mild traumatic brain injury: an update of the WHO Collaborating Centre Task Force findings.
      was conducted by the International Collaboration on Mild Traumatic Brain Injury Prognosis (ICoMP, 2014). The methodologies for these reviews are outlined in detail elsewhere.
      • Carroll L.J.
      • Cassidy J.D.
      • Peloso P.M.
      • Garritty C.
      • Giles-Smith L.
      WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. Systematic search and review procedures: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
      • Cancelliere C.
      • Cassidy J.D.
      • Li A.
      • Donovan J.
      • Cote P.
      • Hincapie C.A.
      Systematic search and review procedures: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis.

      WHO Task Force review

      Briefly, the WHO Task Force systematically searched the published English literature using MEDLINE and PsycINFO (1980–2000), CINAHL (1982–2000), and Embase (1988–2000). Study types included controlled trials; and cohort, case-control, cross-sectional, and case-series designs. Cohort studies identifying prognostic factors were classified as phase I, II, or III studies.
      • Cote P.
      • Cassidy J.D.
      • Carroll L.
      • Frank J.W.
      • Bombardier C.
      A systematic review of the prognosis of acute whiplash and a new conceptual framework to synthesize the literature.
      Phase I studies are hypothesis-generating investigations that explore the associations between potential prognostic factors and disease outcomes in a descriptive or univariate way. Phase II studies are extensive exploratory analyses that focus on particular sets of prognostic factors or attempt to discover which factors have the highest prognostic value. Phase III studies are large confirmatory studies of explicit prestated hypotheses that allow for a focused examination of the strength, direction, and independence of the proposed relationship between a prognostic factor and the outcome of interest. Accepted studies (ie, those with a low risk of bias) were summarized in evidence tables and included in the best-evidence synthesis. The best-evidence synthesis links summary statements and conclusions to the evidence tables so that the strength of the evidence on which these statements are based is obvious. Strength of the evidence considers both the design of the study and methodological quality. Information from high-quality phase III studies is confirmatory and considered the strongest evidence, followed by evidence from methodologically sound phase II studies. Phase I studies do not consider confounding and are considered more limited evidence, but still potentially more informative about prognosis than cross-sectional and case-series designs.

      ICoMP review

      The main objective of the ICoMP review was to update the WHO Task Force findings.
      • Cancelliere C.
      • Cassidy J.D.
      • Cote P.
      • et al.
      Protocol for a systematic review of prognosis after mild traumatic brain injury: an update of the WHO Collaborating Centre Task Force findings.
      Briefly, MEDLINE, PsycINFO, Embase, CINAHL, and SPORTDiscus were systematically searched from 2001 to 2012 for published literature in English, French, Swedish, Norwegian, Danish, and Spanish. MTBI was defined as an acute brain injury resulting from mechanical energy to the head from external physical forces and (1) 1 or more of the following: confusion or disorientation, loss of consciousness for ≤30 minutes, posttraumatic amnesia for <24 hours, and/or other transient neurologic abnormalities such as focal signs, seizures, and intracranial lesions not requiring surgery; and (2) Glasgow Coma Scale score of 13 to 15 after 30 minutes postinjury or later on presentation for health care.
      • Carroll L.J.
      • Cassidy J.D.
      • Peloso P.M.
      • et al.
      Prognosis for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
      The ICoMP also categorized the evidence on prognostic factors as exploratory or confirmatory using the phases of study framework described above, and performed a best-evidence synthesis.

      Study selection

      Studies had to assess the effect of sex on outcomes after MTBI. For this report, we only analyzed scientifically admissible controlled trials and cohort and case-control studies from both systematic reviews because these designs can infer causality. We excluded admissible primary studies that had cross-sectional and case-series designs (n=1), and studies that included assault cases (n=3). The rationale for this is that recovery from assault may be complicated by feelings of victimization, and to understand their prognosis would require stratifying results by injury intent.

      Data extraction

      Data from 14 eligible studies (16 articles; 4 phase III, 11 phase II, 1 phase I) were extracted into an evidence table.

      Results

      The WHO Task Force critically reviewed 427 articles and accepted 120 (28%) as scientifically admissible. Of these, 3 studies (5 articles) are relevant to our report. The ICoMP critically reviewed 299 articles and accepted 101 (34%) as scientifically admissible. Of these, 11 are relevant for our report. Thus, 14 studies (16 articles) spanning from 1980 through 2012 form the basis of our synthesis regarding sex as a prognostic indicator after MTBI (table 1).
      Table 1Studies (n=14) examining sex differences in the recovery and prognosis after MTBI
      Author, Year,

      Country, Study Phase
      Source Population, Study Size, Participation, Follow-UpInclusion/Exclusion CriteriaMTBI Case DefinitionPrognostic Factors/Self-Reported OutcomesFindings
      Outcomes in children after MTBI
       Christensen et al,
      • Christensen J.
      • Pedersen M.G.
      • Pedersen C.B.
      • Sidenius P.
      • Olsen J.
      • Vestergaard M.
      Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study.
      2009; Denmark

      Phase III cohort
      Danish population born in Denmark between Jan 1, 1977, and Dec 31, 2002

      Population-based cohort: n=1,605,216
      Danish children born in Denmark between Jan 1, 1977, and Dec 31, 2002ICD-8 850.99; ICD-10 S06.0. Diagnosis based on ACRM definition: Direct head trauma that results in LOC, amnesia, confusion, disorientation, or focal temporary neurologic deficit. LOC no longer than 30min, GCS 14 or 15 after 30min, PTA ≤24hPrognostic factors: TBI severity; age at injury; sex; length of hospital stay; family history of epilepsy

      Outcome: Time to diagnosis of epilepsy (ICD-8 345 from 1977–1993 and ICD-10 G40, G41 from 1994–2002)
      RR of epilepsy after MTBI was higher among females (2.49; 95% CI, 2.25–2.76, P=.003) than among males (2.01; 95% CI, 1.83–2.22). RR of epilepsy after MTBI (compared with no TBI) was 2.22 (95% CI, 2.07–2.38). Risk was highest during the 1st year after injury (RR for first 6mo, 5.46; 95% CI, 4.67–6.37) and decreased over time.
      Outcomes in adults after MTBI
       Mehta et al,
      • Mehta K.M.
      • Ott A.
      • Kalmijn S.
      • et al.
      Head trauma and risk of dementia and Alzheimer's disease: the Rotterdam Study.
      1999; The Netherlands

      Phase III cohort
      Community-based: Rotterdam, The Netherlands

      Total cohort: N=6645 59.1% women

      Average F/U: 2y
      Inclusion: Dementia-free status at baselinePatient interview: Head trauma, duration of LOC, and PTA.Prognostic factors: MTBI with LOC <15min, adjusting for sex, number of TBIs, and time since trauma

      Outcome: Dementia
      No increased dementia (RR=1.0; 95% CI, 0.5–2.0) or AD (RR=0.8; 95% CI, 0.4–1.9) risk with MTBI

      There were no major differences in the RRs of AD and dementia between men and women.

      Patients who developed incident dementia or AD were older, more often women, and were less educated.
       Nygren et al,
      • Nygren C.
      • Adami J.
      • Ye W.
      • et al.
      Primary brain tumors following traumatic brain injury—a population-based cohort study in Sweden.
      2001; Sweden

      Phase III cohort
      All patients from the Swedish Inpatient Register from the period 1965–1994 discharged from hospital with a diagnosis of skull trauma

      Total cohort: N=311,006 patients contributing 3,222,317 person-years

      Male: 192,090

      Female: 118,916

      Mean F/U: 10.4y
      Inclusion: Discharge diagnosis of skull trauma

      Exclusion: Death during first hospitalization, prevalent cancer at the time of entry to cohort, inconsistencies during record linkage
      ICD-7, 8, and 9 injury codesPrognostic factors: TBI adjusted for sex and TBI severity

      Outcome: Primary brain tumor
      No increased risk of brain tumor after a head injury of any severity. The overall SIR was 1.0 (0.9–1.2) with little variation by sex.
       Nielsen et al,
      • Nielsen A.S.
      • Mortensen P.B.
      • O'Callaghan E.
      • Mors O.
      • Ewald H.
      Is head injury a risk factor for schizophrenia?.
      2002; Denmark

      Phase III case control
      Danish population. 8288 cases and 82,880 controls. Database study so complete participation and F/U. Time between MTBI and schizophrenia was split into <1y, 1–5y, and >5yInclusion criteria: Cases were all admissions to Danish psychiatric hospitals or psychiatric wards with diagnosis of schizophrenia (ICD-8 295) from Jan 1, 1978, to Dec 31, 1993. Excluded cases were those ever diagnosed with bipolar affective disorder. Controls were randomly selected from the Central Person Register (total Danish population), matched to sex, year of birth, and being alive on Jan 1, 1978. Excluded controls were those who had ever been admitted to a psychiatric hospital on or before the date of the case's first psychiatric admission.Any admission to hospital with MTBI (ICD-8 code 850)Prognostic factors: MTBI or severe head injury vs no TBI, adjusted for “accident proneness” (non–skull fractures, leading to hospitalization).

      Outcome: First psychiatric hospitalization of an individual who was then or subsequently diagnosed with schizophrenia. Time lag from MTBI to psychiatric hospitalization was <1y, 1–5y, and >5y.
      MTBI may increase the risk of schizophrenia in males. Where they exist, effect sizes are modest. In unadjusted analyses, overall OR of association between MTBI and schizophrenia was .936 (NS). Association between MTBI and schizophrenia was affected by both sex and time lag. In adjusted analyses, males with schizophrenia were more exposed to MTBI (OR=1.501, P<.001). Effect was seen at <1y (OR=2.034, P=.004) and >5y (OR=1.499, P=.012). No effect in adjusted analyses for sex for any time frame.
       Dischinger et al,
      • Dischinger P.C.
      • Ryb G.E.
      • Kufera J.A.
      • Auman K.M.
      Early predictors of postconcussive syndrome in a population of trauma patients with mild traumatic brain injury.
      2009; United States

      Phase II cohort
      180 MTBI patients admitted to a level I trauma center

      64% male

      Baseline measures were made within 3–10d postinjury and F/U at 3mo postinjury
      Inclusion: 18–64y of age, acceptable score on Mini-Mental State Examination, and English speaking

      Exclusion: Brain lesion requiring intervention, moderate/severe multiple injuries, focal neurologic findings, skull fracture requiring clinical intervention, cerebrospinal fluid leak requiring clinical intervention, prior moderate or severe brain injury, new or prior seizures, history of psychiatric disorder requiring hospitalization or hallucinations, recent history of substance abuse, current probation/parole, and active duty in military
      ACRM: admission GCS, 13–15; presence of ≥1 of the following: LOC <30min, loss of memory of events immediately before or after injury, or alteration of mental state after injury (eg, confusion, disorientation, feeling dazed). PTA >24h.Prognostic factors: PCS: 6 physical (headache, dizziness, blurry/double vision, fatigue, sensitivity to light, sensitivity to noise), 3 cognitive (difficulty concentrating, memory problems, trouble thinking), and 3 emotional (anxiety, depression, irritability).

      Also sociodemographic factors: Age, sex, education, history of substance abuse and depression

      Outcomes: Postconcussion syndrome defined by ≥4 PCS
      At baseline, 84.2% had ≥4 PCS, and 41.4% reported postconcussion syndrome at 3mo.

      Postconcussion syndrome was associated with female sex (OR=2.4; 95% CI, 1.10–5.32). Anxiety was associated with postconcussion syndrome in women only (OR=48.66; 95% CI, 7.50–315.8).
       Gil et al,
      • Gil S.
      • Caspi Y.
      • Ben-Ari I.Z.
      • Koren D.
      • Klein E.
      Does memory of a traumatic event increase the risk for posttraumatic stress disorder in patients with traumatic brain injury? A prospective study.
      2005; Israel

      Phase II cohort
      120 MTBI patients recruited from 2 surgical wards of a hospital

      58% male

      F/U: 1wk, 1mo, and 6mo
      Inclusion criteria: Age 18–50y and fluent in Hebrew

      Exclusion criteria: Actively receiving psychiatric care, prior history of head trauma, cognitive deficit, substance abuse, and major untreated medical condition
      GCS 13–15 at the time of admission. None had LOC at the time of admission.Prognostic factors: Memory of the injury event within the first 24h of injury. Also measures of depression and anxiety at 1wk using the Beck Depression and Anxiety Inventories, acute posttraumatic symptoms using PTSS and CA-PTSDS, history of psychiatric disorder, age, sex, education, ISS, marital status, country of origin, history of physical illness.

      Outcome: PTSD diagnosis based on CA-PTSDS and PTSS
      By 6mo, 14% had developed PTSD. PTSD was more prevalent in those with a memory of the injury event (23%) than those without memory (6%). PTSD was associated with memory of event (OR= 2.2; 95% CI, 1.0–10.1), acute posttraumatic symptoms (OR=5.3; 95% CI, 1.1–9.3 for CA-PTSDS; and OR=5.2; 95% CI, 1.0–9.4 for PTSS), anxiety (OR=4.9; 95% CI, 1.0–9.1), depression (OR=5.1; 95% CI, 1.0–9.2), and history of psychiatric disorder (OR=3.7; 95% CI, 1.1–8.9). Sex was not associated with PTSD at 6mo.
       Hou et al,
      • Hou R.
      • Moss-Morris R.
      • Peveler R.
      • Mogg K.
      • Bradley B.P.
      • Belli A.
      When a minor head injury results in enduring symptoms: a prospective investigation of risk factors for postconcussional syndrome after mild traumatic brain injury.
      2012; United Kingdom

      Phase II cohort
      126 MTBI patients seen at an ED of a general hospital

      63% male

      F/U: 3 and 6mo
      Inclusion: 18–60y of age

      Exclusion: Those with multitrauma requiring hospitalization and those with major neurologic or psychiatric disorders
      Traumatically induced physiological disruption of brain function with at least one of the following: LOC ≤15min, PTA ≤60min, any alteration in mental state at the time of the injury, lack of focal neurologic deficit, and GCS 13–15Prognostic factors: BIPQ measures patients' perceptions of their injury, BRIQ measures behavior after onset of illness/injury and the “all or nothing” subscale measures patterns of activity and rest, HADS, IES measures distress after the injury, SSQ measures perceived social support including availability and satisfaction, sex, age, GCS 14 or 15, LOC, PTA, education, marital status, occupation, and litigation status

      Outcome: PCS defined by ICD-10 criteria of ≥3 of headache; dizziness; fatigue; irritability; insomnia; concentration problems; memory difficulty; or intolerance of stress, emotion or alcohol measured using RPQ
      Postconcussion syndrome was present in 22% at 3mo and 21% at 6mo. Fatigue, forgetfulness and sleep disturbance were most commonly reported at 3mo. Headache, fatigue and sleep disturbance were most commonly reported at 6mo.

      No significant differences between postconcussion syndrome cases and noncases with respect to sex at 3 and 6mo postinjury
       Stulemeijer et al,
      • Stulemeijer M.
      • Van Der Werf S.
      • Borm G.F.
      • Vos P.E.
      Early prediction of favourable recovery 6 months after mild traumatic brain injury.
      2008; The Netherlands

      Phase II cohort
      201 MTBI patients admitted to a level I trauma center

      62% male

      F/U: 6mo postinjury
      Inclusion: 18–60y of age, able to speak and write in Dutch, no premorbid mental retardation or dementia

      Exclusion: Questionnaires that were completed >6wk postinjury
      European Federation of Neurological Societies' definition of MTBI: History of impact to head with or without LOC ≤30min, with or without PTA, and admission GCS of 13–15Prognostic factors:

      1. Preinjury: Age, sex, education, emotional problems, physical comorbidities, or prior head injury

      2. Peri-injury: GCS, LOC, PTA duration, brain CT abnormality, early symptoms (ie, dizziness, nausea/vomiting, headache), additional extracranial injuries (ie, score ≥2 on AISS)

      3. Early postinjury: PCS (RPQ), posttraumatic stress (IES with scores >26 classified as severe), severe fatigue (AFQ with a cutoff value of 20), pain severity score in 5 body regions, self-efficacy (ie, GSES median split)

      Outcome: RPQ—recovered defined as a score <3 on at least 13 of 16 PCS and RTW at 6mo
      Sex did not predict low PCS or full RTW.

      Absence of comorbid physical problems (OR=3.5; 95% CI, 1.6–7.8), low levels of early PCS (OR=5.5; 95% CI, 2.3–13.2), and low levels of early posttraumatic stress (OR=10.0; 95% CI, 2.3–42.9) predicted low PCS (ie, 90% chance of remaining free of PCS). Discriminative ability was good with AUC=.73.

      Prediction of full RTW: High level of education (≥11y): OR=6.4 (95% CI, 2.3–18.3); middle level of education (11–14y): OR=4.6 (95% CI, 1.7–12.6); absence of nausea/vomiting on admission: OR=5.1 (95% CI, 1.8–14.3); absence of additional extracranial injuries: OR=3.4 (95% CI, 1.6–7.3); no severe pain early after injury: OR=2.3 (95% CI, 0.9–5.9).
       Cassidy et al,
      • Cassidy J.D.
      • Boyle E.
      • Carroll L.J.
      Population-based, inception cohort study of the incidence, course, and prognosis of mild traumatic brain injury after motor vehicle collisions.
      2014; Canada

      Phase II cohort
      1716 MTBI patients treated after a traffic injury

      53% female

      F/U: 6wk, 3, 6, 9, and 12mo
      Inclusion: All Saskatchewan residents aged ≥18y who were treated for, or made an insurance claim for, a traffic injury over a 2-year period

      Exclusion: Those who made a claim, or were treated for a traffic injury more than 42d after the collision, or sustained a serious injury (ie, died, could not answer questionnaire because of injury), or could not understand English. Also excluded were workers' compensation claims and those with LOC >30min.
      Answered yes to “Did you hit your head in the collision” and answered “yes” or “don't know” to 1 of the following: LOC, PTA, disorientation or confusion. Also had to answer “yes” to having at least 1 of the following symptoms: dizziness or unsteadiness, memory problems or forgetfulness, and concentration or attention problems.Prognostic factors: Demographics (age, sex, income, marital status, education), position in vehicle, days in hospital, symptoms (checklist of PCS), fractured bones, LOC, PTA, pain intensity (NRS-11: neck, headache, face, low back, midback, arms, hands, leg, foot, abdomen, chest or groin), prior health, current health, expectations for recovery, depression (CES-D cut point, 16), and number of comorbid health conditions

      Outcome: Self-reported recovery (ie, “all better or cured” or “very much improved”)
      Median time to recovery was 99d (95% CI, 97–102).

      Sex was not associated with time to recovery of PCS.

      Factors associated with prolonged recovery were age >50y vs 18–23y (HRR=.76; 95% CI, .63–.91); > high school education vs some high school (HRR=1.24; 95% CI, 1.07–1.44); expectations for recovery—never get better (HRR=.26; 95% CI, .14–.50), —don't know when will get better (HRR=.52; 95% CI, .43–.63), and —will get better slowly (HRR=.79; 95% CI, .67–.94) compared with —get better soon; depression (HRR=.99; 95% CI, .99–1); arm numbness (HRR=.83; 95% CI, .73–.94); hearing problems (HRR=.75; 95% CI, .59–.96); confusion after collision—don't know (HRR=.78; 95% CI, .62–.96) vs none; low back pain intensity (HRR=.97; 95% CI, .95 .98); headache intensity (HRR=.98; 95% CI, .96–1); and midback pain intensity (HRR=.97; 95% CI, .95–.99).
       Kristman et al,
      • Kristman V.L.
      • Cote P.
      • Xiaoqing Y.
      • Hogg-Johnson S.
      • Marjan V.
      • Rezai M.
      Health care utilization of Workers' Compensation claimants associated with mild traumatic brain injury: a historical population-based cohort study of workers injured in 1997-1998.
      2014; Canada

      Phase II cohort
      728 injured workers with MTBI who made a workers' compensation claim

      65.8% males

      F/U: up to 2y
      Inclusion: Lost-time workers' compensation claim made over 1-y period in Ontario. Age ≥18y.

      Exclusion: Skull fracture and more severe brain injuries
      Workers' compensation claim codes for part of body injured (brain–1100) and nature of injury (concussion–6200). Positive predictive value for MTBI is 92%.Prognostic factors: Age, sex, preclaim health utilization, claim duration, specialty of clinician, and diagnostic treatment codes

      Outcome: Weekly moving averages of health care services per 1000 claimants per day before and after the injury
      Health care utilization was constant before the injury at 67.6 services per 1000 claimants per day. During the first 4wk postinjury, it peaked at 319/1000. From month 2 to 1y, it averaged 99.2/1000.

      Women had higher rates of health care utilization except for the 1-mo postclaim.
       Covassin et al,
      • Covassin T.
      • Schatz P.
      • Swanik C.B.
      Sex differences in neuropsychological function and post-concussion symptoms of concussed collegiate athletes.
      2007; United States Phase II cohort
      79 concussed varsity athletes from 5 northeastern universities (full range of varsity sports)

      AAN concussion grading:

      Grade 1 (62%): 24 men, 25 women

      Grade 2 (34%): 14 men, 13 women

      Grade 3 (4%): 3 men

      F/U: Preseason (baseline), up to 3d (time 2), 7–10d postconcussion (time 3)
      Inclusion: Voluntary participation; varsity athletes who sustained concussions that required serial testing across all 3 periods (baseline/preseason, up to 3d, 7–10d)AAN criteriaPrognostic factors: Sex, time

      Outcomes: PCS (Postconcussion Symptom Checklist), neurocognitive testing (ImPACT version 2.0)
      No greater likelihood of sustaining a grade 2 or 3 concussion as a function of sex (P=.50)

      No between-subject multivariate effect of sex (P=.69) and no significant sex-by-time interaction (P=.59) were identified.
       Preiss-Farzanegan et al,
      • Preiss-Farzanegan S.J.
      • Chapman B.
      • Wong T.M.
      • Wu J.
      • Bazarian J.J.
      The relationship between gender and postconcussion symptoms after sport-related mild traumatic brain injury.
      2009; United States

      Phase II cohort
      Nested cohort from NIH-funded TBI registry designed to evaluate epidemiology and 3-mo outcomes of concussion. Individuals who presented to a regional trauma center ED with concussion Feb 3, 2003, to Sept 20, 2003, were recruited (n=1438).

      260 were admitted with a primary sports-related concussion; 215 eligible for analysis.

      Adult (>17y): n=78

      47 male

      31 female

      Minor (≤17y): n=137

      97 male

      40 female

      F/U: 3mo after initial assessment
      Inclusion: Subset of NIH registry patients who reported their mechanism of injury involved a sport; did not report intentions to file a lawsuit as a result of their injuryACRM: A blow to head or acceleration/deceleration movement of head resulting in ≥1 of the following: LOC <30min or PTA <24h or altered mental status at the time of injury; GCS ≥13 measured ≥30min after injuryPrognostic factors: Sex

      Adjustment factors: Age, source of postconcussion symptom reporting (self, proxy, or interviewer), previous head injury or LOC, sport

      Outcome: PCS (RPQ)
      Compared with males, adult females (≥18y) are at greater risk for elevated RPQ scores (OR=2.57; 95% CI, 1.09–6.08; P=.013) but not female minors (≤17y) (OR=1.07; 95% CI, .52–2.19). Adult females, compared with males, appear to have elevated risk for specific symptoms of headache (OR=4.5; 95% CI, 1.6–12.4), dizziness (OR=2.8; 95% CI, 1.0–7.9), fatigue (OR=2.8; 95% CI, 1.0–7.4), irritability (OR=2.8; 95% CI, 1.0–7.7), and concentration problems (OR=3.0; 95% CI, 1.1–8.4) at 3mo after sports-related concussion.
       Paniak et al,
      • Paniak C.
      • Reynolds S.
      • Phillips K.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Patient complaints within 1 month of mild traumatic brain injury: a controlled study.
      2002; Canada

      Phase II cohort
      Presentations to ED.

      MTBI: n=118

      52% female

      Controls: n=118

      Age-, sex-, and education-matched controls (staff and students)

      60% female

      F/U: Within 1mo
      Inclusion: See MTBI definition.

      Exclusion: A history of inpatient treatment for any psychiatric disorder; diagnosis of mental retardation; inability to read fluently in English; history of TBI more severe than MTBI at any time in their life; an MTBI within 1y before involvement in this study; any ongoing central nervous system disorder or concurrent pregnancy
      ACRM: GCS 13–15, LOC <30min, PTA <24h.Prognostic factors: MTBI, sex, age, education, and SES

      Outcome: Symptom presence and severity (Problem Checklist)
      MTBI averaged 18.7 symptoms (severity, 1.7) vs controls (12.6 symptoms; severity, 0.8).

      No relationship between symptoms and sex, age, or education
       Paniak et al,
      • Paniak C.
      • Reynolds S.
      • Phillips K.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Patient complaints within 1 month of mild traumatic brain injury: a controlled study.
      2002; Canada

      Phase II cohort
      Consecutive admissions to 2 EDs

      MTBI: n=68

      Controls: n=118

      Age-, sex-, and education-matched controls (staff and students).

      F/U: 3 and 12mo
      Inclusion: See MTBI definition.

      Exclusion: A history of inpatient treatment for any psychiatric disorder; diagnosis of mental retardation; inability to read fluently in English; history of TBI more severe than MTBI at any time in their life; a second MTBI within 1y before involvement in this study; any ongoing central nervous system disorder or concurrent pregnancy
      ACRM: GCS 13–15, LOC <30min, PTA <24hPrognostic factors:

      Compensation seeking, SES, ISS (non–brain injuries), treatment satisfaction, age, sex, ethnicity, head injury severity, medication use, and prior psychological treatment

      Outcomes: Symptom presence and severity (Problem Checklist)
      Demographic and injury-related variables did not predict compensation seeking.

      Compensation seeking/receiving associated with higher symptom report.

      None of age, years of education, premorbid SES, sex, or ethnic affiliation significantly affected the decision to seek compensation.
       Paniak et al,
      • Paniak C.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Prediction of vocational status three to four months after treated mild traumatic brain injury.
      2000; Canada

      Phase II cohort
      Consecutive admissions to 2 ERs. Participants part of randomized controlled trial.

      MTBI: n=118

      62 women

      56 men

      F/U: 3mo
      Inclusion: See MTBI definition.ACRM: GCS 13–15, LOC <30min, PTA <24hPrognostic factors: Age, sex, injury severity, alcohol use, prior health and life events, medication use, SES, and financial compensation

      Outcome: Preinjury vocational status
      Overall, 74% had returned to full-time preinjury employment by 3mo.

      Best predictor of RTW was seeking or receiving financial compensation at F/U.

      No effect of sex as predictor of RTW 3–4mo postinjury
       Teasdale and Engberg,
      • Teasdale T.W.
      • Engberg A.W.
      Suicide after traumatic brain injury: a population study.
      2001; Denmark

      Phase I cohort
      Population of Denmark. Data sources were National Bureau of Health registry of all hospitalization discharges in Denmark from 1979 to 1993, and national register of deaths.

      Total: n=145,440

      MTBI: n=126,114

      60.2% men
      Inclusion: Hospital discharge between 1979 and 1993 with a main or secondary diagnosis of TBI: ICD-8 850 (MTBI), 800, 801, 803 (cranial fracture); 851–854 (cerebral lesion)

      Exclusion: Children aged <15y by end of study, died in hospital or did not survive at least 1mo past discharge
      ICD-8 code 850Prognostic factors: Type of TBI, age at injury, sex, days in hospital, codiagnosis of substance misuse

      Outcome: Death by suicide, as recorded in a national register of deaths up to and including 1993
      .59% of those with MTBI committed suicide. SMRs stratified by age and sex showed that the incidence of suicide in MTBI was 3.02 (95% CI, 2.82–3.25) compared with the general population. Suicide rates were higher for females (SMR=3.89; 95% CI, 3.43–4.42) than males (SMR=2.74; 95% CI, 2.51–2.99).
      Abbreviations: AAN, American Academy of Neurology; ACRM, American Congress of Rehabilitation Medicine; AD, Alzheimer disease; AFQ, Abbreviated Fatigue Questionnaire; AISS, Abbreviated Injury Severity Score; AUC, area under the curve; BIPQ, Brief Illness Perception Questionnaire; BRIQ, Behavioral Responses to Illness Questionnaire; CA-PTSDS, Clinician-Administered Posttraumatic Stress Disorder Scale; CES-D, Center for Epidemiological Studies Depression Scale; CT, computed tomography; F/U, follow-up; GCS, Glasgow Coma Scale; GSES, General Self-Efficacy Scale; HADS, Hospital Anxiety and Depression Scale; HRR, hazard rate ratio; ICD, International Classification of Diseases; IES, Impact of Event Scale; ImPACT, Immediate Postconcussion Assessment and Cognitive Testing; ISS, Injury Severity Score; LOC, loss of consciousness; NIH, National Institutes of Health; NS, not significant; NRS, numeric rating scale; PCS, postconcussion symptoms; PTA, posttraumatic amnesia; PTSS, Posttraumatic Stress Scale; SES, socioeconomic status; SIR, standardized incidence ratio; SMR, standardized mortality ratio; SSQ, Social Support Questionnaire.
      Overall, most of the evidence suggests that sex is not a strong prognostic indicator for recovery after MTBI. However, small sex differences were found for some outcomes. After MTBI, females may have a higher risk of epilepsy (children, young adults) and suicide, and use more health care services during the 2 years postinjury, and males may be at increased risk of schizophrenia. After MTBI, sex did not predict recovery from postconcussion symptoms (PCS) (children, adults), risk of dementia, primary brain tumor development, return to work (RTW), or posttraumatic stress disorder (PTSD).

      Children

      We accepted 2 studies: 1 phase III study from Denmark assessing the risk of epilepsy after MTBI, and 1 phase II study from the United States assessing PCS after MTBI.

      Risk of epilepsy after MTBI

      In a large phase III Danish population-based cohort study, Christensen et al
      • Christensen J.
      • Pedersen M.G.
      • Pedersen C.B.
      • Sidenius P.
      • Olsen J.
      • Vestergaard M.
      Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study.
      followed up 1,605,216 people born in Denmark ≥10 years after TBI for a total of 19,527,337 person-years. Compared with no brain injury, the risk of epilepsy was 2 times higher after MTBI (RR=2.22; 95% confidence interval [CI], 2.07–2.38), and remained high ≥10 years postinjury (RR=1.51; 95% CI, 1.24–1.85). The risk was higher among females (RR=2.49; 95% CI, 2.25–2.76; small-medium effect size) than among males (RR=2.01; 95% CI, 1.83–2.22). Interestingly, there was no interaction with sex for patients with skull fractures or severe brain injury.

      Risk of self-reported PCS after MTBI

      Preiss-Farzanegan et al
      • Preiss-Farzanegan S.J.
      • Chapman B.
      • Wong T.M.
      • Wu J.
      • Bazarian J.J.
      The relationship between gender and postconcussion symptoms after sport-related mild traumatic brain injury.
      (phase II, United States) assessed 137 minors (aged ≤17y) who presented to a regional trauma center emergency department (ED) and who were not involved in litigation. Three months after a sports-related MTBI, females were not at greater risk for elevated scores on the Rivermead Postconcussion Symptoms Questionnaire (RPQ).

      Adults

      Of the 13 studies, 3 are phase III (The Netherlands,
      • Mehta K.M.
      • Ott A.
      • Kalmijn S.
      • et al.
      Head trauma and risk of dementia and Alzheimer's disease: the Rotterdam Study.
      Sweden,
      • Nygren C.
      • Adami J.
      • Ye W.
      • et al.
      Primary brain tumors following traumatic brain injury—a population-based cohort study in Sweden.
      Denmark
      • Nielsen A.S.
      • Mortensen P.B.
      • O'Callaghan E.
      • Mors O.
      • Ewald H.
      Is head injury a risk factor for schizophrenia?.
      ), 9 are phase II (Canada, 3
      • Kristman V.L.
      • Cote P.
      • Xiaoqing Y.
      • Hogg-Johnson S.
      • Marjan V.
      • Rezai M.
      Health care utilization of Workers' Compensation claimants associated with mild traumatic brain injury: a historical population-based cohort study of workers injured in 1997-1998.
      • Paniak C.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Prediction of vocational status three to four months after treated mild traumatic brain injury.
      • Paniak C.
      • Reynolds S.
      • Phillips K.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Patient complaints within 1 month of mild traumatic brain injury: a controlled study.
      • Paniak C.
      • Reynolds S.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      • Schmidt D.
      A longitudinal study of the relationship between financial compensation and symptoms after treated mild traumatic brain injury.
      • Cassidy J.D.
      • Boyle E.
      • Carroll L.J.
      Population-based, inception cohort study of the incidence, course, and prognosis of mild traumatic brain injury after motor vehicle collisions.
      ; United States, 3
      • Preiss-Farzanegan S.J.
      • Chapman B.
      • Wong T.M.
      • Wu J.
      • Bazarian J.J.
      The relationship between gender and postconcussion symptoms after sport-related mild traumatic brain injury.
      • Covassin T.
      • Schatz P.
      • Swanik C.B.
      Sex differences in neuropsychological function and post-concussion symptoms of concussed collegiate athletes.
      • Dischinger P.C.
      • Ryb G.E.
      • Kufera J.A.
      • Auman K.M.
      Early predictors of postconcussive syndrome in a population of trauma patients with mild traumatic brain injury.
      ; Israel, 1
      • Gil S.
      • Caspi Y.
      • Ben-Ari I.Z.
      • Koren D.
      • Klein E.
      Does memory of a traumatic event increase the risk for posttraumatic stress disorder in patients with traumatic brain injury? A prospective study.
      ; United Kingdom, 1
      • Hou R.
      • Moss-Morris R.
      • Peveler R.
      • Mogg K.
      • Bradley B.P.
      • Belli A.
      When a minor head injury results in enduring symptoms: a prospective investigation of risk factors for postconcussional syndrome after mild traumatic brain injury.
      ; The Netherlands, 1
      • Stulemeijer M.
      • Van Der Werf S.
      • Borm G.F.
      • Vos P.E.
      Early prediction of favourable recovery 6 months after mild traumatic brain injury.
      ), and 1 is phase I (Denmark
      • Teasdale T.W.
      • Engberg A.W.
      Suicide after traumatic brain injury: a population study.
      ). The findings are presented according to outcome: (1) PCS,
      • Preiss-Farzanegan S.J.
      • Chapman B.
      • Wong T.M.
      • Wu J.
      • Bazarian J.J.
      The relationship between gender and postconcussion symptoms after sport-related mild traumatic brain injury.
      • Paniak C.
      • Reynolds S.
      • Phillips K.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Patient complaints within 1 month of mild traumatic brain injury: a controlled study.
      • Paniak C.
      • Reynolds S.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      • Schmidt D.
      A longitudinal study of the relationship between financial compensation and symptoms after treated mild traumatic brain injury.
      • Cassidy J.D.
      • Boyle E.
      • Carroll L.J.
      Population-based, inception cohort study of the incidence, course, and prognosis of mild traumatic brain injury after motor vehicle collisions.
      • Covassin T.
      • Schatz P.
      • Swanik C.B.
      Sex differences in neuropsychological function and post-concussion symptoms of concussed collegiate athletes.
      • Dischinger P.C.
      • Ryb G.E.
      • Kufera J.A.
      • Auman K.M.
      Early predictors of postconcussive syndrome in a population of trauma patients with mild traumatic brain injury.
      • Hou R.
      • Moss-Morris R.
      • Peveler R.
      • Mogg K.
      • Bradley B.P.
      • Belli A.
      When a minor head injury results in enduring symptoms: a prospective investigation of risk factors for postconcussional syndrome after mild traumatic brain injury.
      • Stulemeijer M.
      • Van Der Werf S.
      • Borm G.F.
      • Vos P.E.
      Early prediction of favourable recovery 6 months after mild traumatic brain injury.
      (2) RTW,
      • Paniak C.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Prediction of vocational status three to four months after treated mild traumatic brain injury.
      • Stulemeijer M.
      • Van Der Werf S.
      • Borm G.F.
      • Vos P.E.
      Early prediction of favourable recovery 6 months after mild traumatic brain injury.
      (3) risk of dementia,
      • Mehta K.M.
      • Ott A.
      • Kalmijn S.
      • et al.
      Head trauma and risk of dementia and Alzheimer's disease: the Rotterdam Study.
      (4) risk of primary brain tumor development,
      • Nygren C.
      • Adami J.
      • Ye W.
      • et al.
      Primary brain tumors following traumatic brain injury—a population-based cohort study in Sweden.
      (5) risk of schizophrenia,
      • Nielsen A.S.
      • Mortensen P.B.
      • O'Callaghan E.
      • Mors O.
      • Ewald H.
      Is head injury a risk factor for schizophrenia?.
      (6) PTSD,
      • Gil S.
      • Caspi Y.
      • Ben-Ari I.Z.
      • Koren D.
      • Klein E.
      Does memory of a traumatic event increase the risk for posttraumatic stress disorder in patients with traumatic brain injury? A prospective study.
      (7) health care utilization,
      • Kristman V.L.
      • Cote P.
      • Xiaoqing Y.
      • Hogg-Johnson S.
      • Marjan V.
      • Rezai M.
      Health care utilization of Workers' Compensation claimants associated with mild traumatic brain injury: a historical population-based cohort study of workers injured in 1997-1998.
      and (8) suicide.
      • Teasdale T.W.
      • Engberg A.W.
      Suicide after traumatic brain injury: a population study.

      Self-reported PCS after MTBI

      We accepted 7 phase II studies.
      • Preiss-Farzanegan S.J.
      • Chapman B.
      • Wong T.M.
      • Wu J.
      • Bazarian J.J.
      The relationship between gender and postconcussion symptoms after sport-related mild traumatic brain injury.
      • Paniak C.
      • Reynolds S.
      • Phillips K.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Patient complaints within 1 month of mild traumatic brain injury: a controlled study.
      • Paniak C.
      • Reynolds S.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      • Schmidt D.
      A longitudinal study of the relationship between financial compensation and symptoms after treated mild traumatic brain injury.
      • Cassidy J.D.
      • Boyle E.
      • Carroll L.J.
      Population-based, inception cohort study of the incidence, course, and prognosis of mild traumatic brain injury after motor vehicle collisions.
      • Covassin T.
      • Schatz P.
      • Swanik C.B.
      Sex differences in neuropsychological function and post-concussion symptoms of concussed collegiate athletes.
      • Dischinger P.C.
      • Ryb G.E.
      • Kufera J.A.
      • Auman K.M.
      Early predictors of postconcussive syndrome in a population of trauma patients with mild traumatic brain injury.
      • Hou R.
      • Moss-Morris R.
      • Peveler R.
      • Mogg K.
      • Bradley B.P.
      • Belli A.
      When a minor head injury results in enduring symptoms: a prospective investigation of risk factors for postconcussional syndrome after mild traumatic brain injury.
      • Stulemeijer M.
      • Van Der Werf S.
      • Borm G.F.
      • Vos P.E.
      Early prediction of favourable recovery 6 months after mild traumatic brain injury.
      Most of the participants were ED admissions; 1 study comprised American collegiate athletes,
      • Covassin T.
      • Schatz P.
      • Swanik C.B.
      Sex differences in neuropsychological function and post-concussion symptoms of concussed collegiate athletes.
      and another was a Canadian population-based study.
      • Cassidy J.D.
      • Boyle E.
      • Carroll L.J.
      Population-based, inception cohort study of the incidence, course, and prognosis of mild traumatic brain injury after motor vehicle collisions.
      Mean ages ranged from 30 to 38 years. Follow-up periods ranged from 1 week to 12 months, the most common being 3 months. PCS were predominantly assessed with standard instruments: the RPQ,
      • Preiss-Farzanegan S.J.
      • Chapman B.
      • Wong T.M.
      • Wu J.
      • Bazarian J.J.
      The relationship between gender and postconcussion symptoms after sport-related mild traumatic brain injury.
      • Hou R.
      • Moss-Morris R.
      • Peveler R.
      • Mogg K.
      • Bradley B.P.
      • Belli A.
      When a minor head injury results in enduring symptoms: a prospective investigation of risk factors for postconcussional syndrome after mild traumatic brain injury.
      • Stulemeijer M.
      • Van Der Werf S.
      • Borm G.F.
      • Vos P.E.
      Early prediction of favourable recovery 6 months after mild traumatic brain injury.
      Problem Checklist,
      • Paniak C.
      • Reynolds S.
      • Phillips K.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Patient complaints within 1 month of mild traumatic brain injury: a controlled study.
      • Paniak C.
      • Reynolds S.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      • Schmidt D.
      A longitudinal study of the relationship between financial compensation and symptoms after treated mild traumatic brain injury.
      Immediate Postconcussion Assessment and Cognitive Testing,
      • Covassin T.
      • Schatz P.
      • Swanik C.B.
      Sex differences in neuropsychological function and post-concussion symptoms of concussed collegiate athletes.
      and Concussion Symptom Checklist.
      • Dischinger P.C.
      • Ryb G.E.
      • Kufera J.A.
      • Auman K.M.
      Early predictors of postconcussive syndrome in a population of trauma patients with mild traumatic brain injury.
      The findings were mixed, but most studies (n=5)
      • Paniak C.
      • Reynolds S.
      • Phillips K.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Patient complaints within 1 month of mild traumatic brain injury: a controlled study.
      • Paniak C.
      • Reynolds S.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      • Schmidt D.
      A longitudinal study of the relationship between financial compensation and symptoms after treated mild traumatic brain injury.
      • Cassidy J.D.
      • Boyle E.
      • Carroll L.J.
      Population-based, inception cohort study of the incidence, course, and prognosis of mild traumatic brain injury after motor vehicle collisions.
      • Covassin T.
      • Schatz P.
      • Swanik C.B.
      Sex differences in neuropsychological function and post-concussion symptoms of concussed collegiate athletes.
      • Hou R.
      • Moss-Morris R.
      • Peveler R.
      • Mogg K.
      • Bradley B.P.
      • Belli A.
      When a minor head injury results in enduring symptoms: a prospective investigation of risk factors for postconcussional syndrome after mild traumatic brain injury.
      • Stulemeijer M.
      • Van Der Werf S.
      • Borm G.F.
      • Vos P.E.
      Early prediction of favourable recovery 6 months after mild traumatic brain injury.
      found that sex did not predict PCS after MTBI. Paniak et al
      • Paniak C.
      • Reynolds S.
      • Phillips K.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Patient complaints within 1 month of mild traumatic brain injury: a controlled study.
      • Paniak C.
      • Reynolds S.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      • Schmidt D.
      A longitudinal study of the relationship between financial compensation and symptoms after treated mild traumatic brain injury.
      studied 118 consecutive admissions to 2 Canadian EDs. Symptom complaints, assessed with the Problem Checklist at 1 month postinjury, were compared with those of 118 matched control participants without MTBI.
      • Paniak C.
      • Reynolds S.
      • Phillips K.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Patient complaints within 1 month of mild traumatic brain injury: a controlled study.
      The authors did not find a relationship between symptoms and sex, age, or education. A subset analysis (n=68) revealed that sex was also not associated with the decision to seek compensation at 3 and 12 months postinjury. In the study by Hou et al,
      • Hou R.
      • Moss-Morris R.
      • Peveler R.
      • Mogg K.
      • Bradley B.P.
      • Belli A.
      When a minor head injury results in enduring symptoms: a prospective investigation of risk factors for postconcussional syndrome after mild traumatic brain injury.
      107 ED patients with MTBI in the United Kingdom completed the RPQ at 3 and 6 months postinjury. No significant differences were found between postconcussion syndrome cases and noncases with respect to sex at both periods. Stulemeijer et al
      • Stulemeijer M.
      • Van Der Werf S.
      • Borm G.F.
      • Vos P.E.
      Early prediction of favourable recovery 6 months after mild traumatic brain injury.
      developed a prediction rule for recovery at 6 months postinjury. They assessed 201 MTBI patients admitted to a level 1 trauma center in The Netherlands, and also found that sex did not predict low PCS as assessed by the RPQ. Covassin et al
      • Covassin T.
      • Schatz P.
      • Swanik C.B.
      Sex differences in neuropsychological function and post-concussion symptoms of concussed collegiate athletes.
      similarly concluded that sex does not predict PCS in collegiate athletes, as assessed by the Immediate Postconcussion Assessment and Cognitive Testing within 1 week postinjury. Lastly, in a large Canadian population-based study,
      • Cassidy J.D.
      • Boyle E.
      • Carroll L.J.
      Population-based, inception cohort study of the incidence, course, and prognosis of mild traumatic brain injury after motor vehicle collisions.
      a final model based on 1476 participants found that sex, along with loss of consciousness, posttraumatic amnesia, and comorbid health conditions, was not associated with time to recovery of PCS after traffic collisions.
      Two U.S. studies
      • Preiss-Farzanegan S.J.
      • Chapman B.
      • Wong T.M.
      • Wu J.
      • Bazarian J.J.
      The relationship between gender and postconcussion symptoms after sport-related mild traumatic brain injury.
      • Dischinger P.C.
      • Ryb G.E.
      • Kufera J.A.
      • Auman K.M.
      Early predictors of postconcussive syndrome in a population of trauma patients with mild traumatic brain injury.
      found that female sex predicted PCS 3 months after MTBI. Dischinger et al
      • Dischinger P.C.
      • Ryb G.E.
      • Kufera J.A.
      • Auman K.M.
      Early predictors of postconcussive syndrome in a population of trauma patients with mild traumatic brain injury.
      assessed 180 level I trauma center patients with MTBI and found that females had approximately 2.5 times the risk of postconcussion syndrome than males (odds ratio [OR]=2.40; 95% CI, 1.10–5.32) using the Concussion Symptom Checklist. Further, anxiety was associated with postconcussion syndrome in females only (OR=48.66; 95% CI, 7.50–315.8). Preiss-Farzanegan
      • Preiss-Farzanegan S.J.
      • Chapman B.
      • Wong T.M.
      • Wu J.
      • Bazarian J.J.
      The relationship between gender and postconcussion symptoms after sport-related mild traumatic brain injury.
      assessed 78 adults who presented to a regional trauma center ED with a sports-related concussion and who were not involved in litigation. Compared with males, adult females (≥18y) were at greater risk of PCS as assessed with the RPQ (OR=2.57; 95% CI, 1.09–6.08; large effect size), but not female minors (≤17y). Additionally, adult females appeared to have an elevated risk for headache (OR=4.5; 95% CI, 1.6–12.4), dizziness (OR=2.8; 95% CI, 1.0–7.9), fatigue (OR=2.8; 95% CI, 1.0–7.4), irritability (OR=2.8; 95% CI, 1.0–7.7), and concentration problems (OR=3.0; 95% CI, 1.1–8.4).
      • Preiss-Farzanegan S.J.
      • Chapman B.
      • Wong T.M.
      • Wu J.
      • Bazarian J.J.
      The relationship between gender and postconcussion symptoms after sport-related mild traumatic brain injury.

      Return to work after MTBI

      Two phase II studies from Canada
      • Paniak C.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Prediction of vocational status three to four months after treated mild traumatic brain injury.
      and The Netherlands
      • Stulemeijer M.
      • Van Der Werf S.
      • Borm G.F.
      • Vos P.E.
      Early prediction of favourable recovery 6 months after mild traumatic brain injury.
      found that sex did not predict RTW. Paniak et al
      • Paniak C.
      • Toller-Lobe G.
      • Melnyk A.
      • Nagy J.
      Prediction of vocational status three to four months after treated mild traumatic brain injury.
      studied 118 adults who had received specialized treatment soon after MTBI and were interviewed 3 to 4 months later to evaluate whether they had returned to full-time preinjury vocational activity. Stulemeijer et al
      • Stulemeijer M.
      • Van Der Werf S.
      • Borm G.F.
      • Vos P.E.
      Early prediction of favourable recovery 6 months after mild traumatic brain injury.
      did not find sex to predict RTW at 6 months after MTBI among 201 ED patients. Patients were classified as having full RTW when they were not on sick leave at the time of follow-up, or reported no change in working status to partial or lower-level employment because of the MTBI.

      Risk of dementia after MTBI

      One phase III study
      • Mehta K.M.
      • Ott A.
      • Kalmijn S.
      • et al.
      Head trauma and risk of dementia and Alzheimer's disease: the Rotterdam Study.
      from The Netherlands investigated the relation between head trauma and the incidence of dementia in 6645 participants of the prospective, population-based Rotterdam Study, aged ≥55 years, who were free of dementia at baseline. Follow-up assessments occurred after an average ± SD of 2.1±0.8 years. The results suggested that MTBI is not a major risk factor for incident dementia, and there were no major differences in the relative risks between men and women.

      Risk of primary brain tumor development after MTBI

      One phase III cohort study
      • Nygren C.
      • Adami J.
      • Ye W.
      • et al.
      Primary brain tumors following traumatic brain injury—a population-based cohort study in Sweden.
      investigated patients hospitalized for TBI from 1965 to 1994 by using the Swedish Inpatient Register (n=311,006; 3,225,317 person-years). A total of 281 cases of brain tumors were diagnosed during follow-up at approximately 10.5 years. The results indicated no excess risk of any kind of brain tumor after a head trauma of any severity, and no variation by sex; however, the follow-up period may have been relatively short for this outcome.

      Risk of schizophrenia after MTBI

      A large Danish population-based study
      • Nielsen A.S.
      • Mortensen P.B.
      • O'Callaghan E.
      • Mors O.
      • Ewald H.
      Is head injury a risk factor for schizophrenia?.
      of residents without a history of psychiatric illness (phase III case-control) found a modest association between concussion and onset of schizophrenia for males only. After adjusting for premorbid “accident proneness” (defined as history of non–skull fractures), there was an MTBI-related increased risk of schizophrenia for 5 years subsequent to the injury, although the risk was greatest during the first year postinjury (males, OR=2.034; females, OR=1.663; small-medium effect size). Nielsen et al
      • Nielsen A.S.
      • Mortensen P.B.
      • O'Callaghan E.
      • Mors O.
      • Ewald H.
      Is head injury a risk factor for schizophrenia?.
      concluded that MTBI may contribute to the risk for schizophrenia in males, and while this relation may also exist in females, it is paralleled by an increased liability to traumas in general.

      Risk of PTSD after MTBI

      One phase II study (Israel)
      • Gil S.
      • Caspi Y.
      • Ben-Ari I.Z.
      • Koren D.
      • Klein E.
      Does memory of a traumatic event increase the risk for posttraumatic stress disorder in patients with traumatic brain injury? A prospective study.
      investigated 120 patients with MTBI recruited from 2 surgical wards. All participants underwent psychiatric evaluation and self-assessment of their memory of the traumatic event. Symptoms of PTSD were assessed with the Clinician-Administered PTSD Scale and the Posttraumatic Stress Scale. The results indicated that sex was not associated with an increased risk of PTSD at 6 months.

      Health care utilization after MTBI

      One phase II study (Canada)
      • Kristman V.L.
      • Cote P.
      • Xiaoqing Y.
      • Hogg-Johnson S.
      • Marjan V.
      • Rezai M.
      Health care utilization of Workers' Compensation claimants associated with mild traumatic brain injury: a historical population-based cohort study of workers injured in 1997-1998.
      compared the health care use of injured workers during the year before and 2 years after making a workers' compensation claim for MTBI. Kristman et al
      • Kristman V.L.
      • Cote P.
      • Xiaoqing Y.
      • Hogg-Johnson S.
      • Marjan V.
      • Rezai M.
      Health care utilization of Workers' Compensation claimants associated with mild traumatic brain injury: a historical population-based cohort study of workers injured in 1997-1998.
      found that filing a claim for MTBI is associated with a long-term increase in the utilization of health care services, especially for females. For example, during the 13- to 24-week period after MTBI, the cumulative rate of health care utilization per 1000 workers per day was 133.7 (95% CI, 120.5–146.8) for females but only 102.4 (95% CI, 95.4–109.3) for males.

      Risk of suicide after MTBI

      One phase I Danish population-based study
      • Teasdale T.W.
      • Engberg A.W.
      Suicide after traumatic brain injury: a population study.
      reported that .59% of those with a documented history of concussion committed suicide. The follow-up periods varied from 1 month to 14 years. The incidence of suicide after concussion was 3 times that of the general population (3.02; 95% CI, 2.82–3.25), with a higher risk for females (3.89; 95% CI, 3.43–4.42) than for males (2.74; 95% CI, 2.51–2.99).

      Discussion

      Only 14 (7%) of 221 accepted primary studies of the WHO and ICoMP systematic reviews were eligible for our analysis. Overall, sex is not a well-studied prognostic indicator for recovery after MTBI, and only small sex differences were found for some outcomes.
      For most serious disease-related outcomes, including brain tumor development and dementia, MTBI did not increase the risk for disease, and as a result, sex cannot be prognostic for the outcome. Regarding the objective outcomes where sex may be a prognostic factor (ie, schizophrenia, health care usage, epilepsy, suicide), these must be understood in the context of possible reverse causality, known population trends, absolute risk of disease, and premorbid health status. For example, Neilsen
      • Nielsen A.S.
      • Mortensen P.B.
      • O'Callaghan E.
      • Mors O.
      • Ewald H.
      Is head injury a risk factor for schizophrenia?.
      found that males appear to be at an increased risk for schizophrenia after MTBI. However, the highest odds of receiving a schizophrenia diagnosis occurred less than 1 year after MTBI, suggesting an alternative explanation including possible reverse causality or protopathic bias, whereby schizophrenia precedes the MTBI. This same trend of increased odds with diminished time lag occurred for sustaining a fracture and having a subsequent schizophrenia diagnosis. A more recent population-based Danish study
      • Orlovska S.
      • Pedersen M.S.
      • Benros M.E.
      • Mortensen P.B.
      • Agerbo E.
      • Nordentoft M.
      Head injury as risk factor for psychiatric disorders: a nationwide register-based follow-up study of 113,906 persons with head injury.
      found no sex interaction between schizophrenia and head injury, irrespective of injury severity.
      Compared with males, females were at increased risk for epilepsy and suicide after MTBI, and used more health care services after MTBI. However, it is well known that men generally use fewer medical services than women.
      • Pinkhasov R.M.
      • Wong J.
      • Kashanian J.
      • et al.
      Are men shortchanged on health? Perspective on health care utilization and health risk behavior in men and women in the United States.
      With respect to an increased risk of epilepsy in female children and young adults, the absolute risk for any increase in epilepsy from MTBI, regardless of sex, remains very low at approximately 1 case per 1000 person-years.
      • Christensen J.
      • Pedersen M.G.
      • Pedersen C.B.
      • Sidenius P.
      • Olsen J.
      • Vestergaard M.
      Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study.
      Furthermore, the higher detection in females may be because they are more likely to be registered in the National Hospital Register because of sex-specific factors such as pregnancy. Finally, the association between MTBI and suicide risk in females may have resulted from concomitant and premorbid characteristics, such as psychosocial disadvantage, rather than the MTBI itself.
      • Teasdale T.W.
      • Engberg A.W.
      Suicide after traumatic brain injury: a population study.
      Sex was not shown to be a strong prognostic indicator for self-reported PCS after MTBI in our study; however, a recent Swedish population-based cohort study
      • Styrke J.
      • Sojka P.
      • Bjornstig U.
      • Bylund P.O.
      • Stalnacke B.M.
      Sex differences in symptoms, disability and life satisfaction three years after mild traumatic brain injury: a population-based cohort study.
      found sex differences in PCS. Three years after MTBI, postconcussion syndrome was found in 50% of the women and 30% of the men. Moreover, women with MTBI more frequently reported back pain than men. Interestingly, pain (eg, headache, neck and back pain) is the most common PCS and is associated with overall recovery after MTBI.
      • Styrke J.
      • Sojka P.
      • Bjornstig U.
      • Bylund P.O.
      • Stalnacke B.M.
      Sex differences in symptoms, disability and life satisfaction three years after mild traumatic brain injury: a population-based cohort study.
      • Cassidy J.D.
      • Boyle E.
      • Carroll L.J.
      Population-based, inception cohort study of the incidence, course, and prognosis of mild traumatic brain injury after motor vehicle collisions.
      • Hartvigsen J.
      • Boyle E.
      • Cassidy J.D.
      • Carroll L.J.
      Mild traumatic brain injury after motor vehicle collisions: what are the symptoms and who treats them? A population-based 1-year inception cohort study.
      A wide body of literature suggests that compared with men, women have increased pain sensitivity and an increased risk for clinical pain, and are more likely to report pain.
      • Bartley E.J.
      • Fillingim R.B.
      Sex differences in pain: a brief review of clinical and experimental findings.
      Thus, sex differences in PCS might be partially explained by pain. Of note, with the exception of 1 study,
      • Cassidy J.D.
      • Boyle E.
      • Carroll L.J.
      Population-based, inception cohort study of the incidence, course, and prognosis of mild traumatic brain injury after motor vehicle collisions.
      all studies we reviewed on self-reported outcomes after MTBI did not account for pain as a potential factor affecting prognosis; however, Cassidy et al
      • Cassidy J.D.
      • Boyle E.
      • Carroll L.J.
      Population-based, inception cohort study of the incidence, course, and prognosis of mild traumatic brain injury after motor vehicle collisions.
      found that having back pain or headache was associated with delayed recovery in those with MTBI, while sex was not. Women may experience pain more than men because of multiple biological (eg, sex hormones) and psychosocial factors (eg, coping).
      • Bartley E.J.
      • Fillingim R.B.
      Sex differences in pain: a brief review of clinical and experimental findings.

      Study strengths

      This report is based on the best-evidence syntheses conducted by 2 international groups of MTBI experts and methodologists. Both systematic reviews included comprehensive search strategies and in-depth methodological quality assessment of individual studies.

      Study limitations

      Our report also has limitations. We were only able to analyze a small number of studies (n=14, 7%) because outcome data were rarely classified by sex. Other limitations include those inherent to most systematic reviews such as publication bias and the potential for missing relevant studies. However, given the rigorous methodology used in both the WHO Task Force and ICoMP reviews, we feel that their potential for missing relevant studies was low.

      Conclusions

      We analyzed the best available evidence of the WHO Task Force and ICoMP systematic reviews, and based our results on 14 studies (7%) that reported sex-stratified outcomes after MTBI. We found that sex is not a consistent or strong prognostic indicator for recovery after MTBI, irrespective of outcome or patient population. However, this should be interpreted with caution given that so few studies reported sex differences.

      Implications for future research

      Future research should explore possible sex differences in self-reported PCS, especially pain, as this is an area where controversy may still remain. Studies should incorporate more pain-related questions when assessing PCS and include sufficient follow-up (ie, >3mo) to better determine the effect of pain on possible sex-related differences in MTBI recovery. Outcomes for males and females should be analyzed separately given increasing evidence for a sex-specific approach to care.
      • Doyal L.
      Sex, gender, and health: the need for a new approach.
      Studies should control for other potential confounders such as premorbid and concomitant conditions, coping mechanisms, external causes of injury, treatment variables, and differences in reporting and health care use between males and females. Finally, replicating initial findings is necessary to demonstrate consistency in other patient populations. A better understanding of any sex-related differences regarding MTBI prognosis has implications for treatment and rehabilitation. Males and females might need to be managed differently given the differences in biological and psychosocial factors.

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