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Systematic Review and Meta-Analysis: Anxiety and Depressive Disorders in Offspring of Parents With Anxiety Disorders

Open AccessPublished:October 31, 2018DOI:https://doi.org/10.1016/j.jaac.2018.07.898

      Objective

      We conducted meta-analyses to assess risk for anxiety disorders among offspring of parents with anxiety disorders, and to establish whether there is evidence of specificity of risk for anxiety disorders as opposed to depression in offspring, and whether particular parent anxiety disorders confer risks for particular child anxiety disorders. We also examined whether risk was moderated by offspring age, gender, temperament, and the presence of depressive disorders in parents.

      Method

      We searched PsycINFO, PubMed, and Web of Science in June, 2016, and July, 2017 (PROSPERO CRD42016048814). Study inclusion criteria were as follows: published in peer-reviewed journals; contained at least one group of parents with anxiety disorders and at least one comparison group of parents who did not have anxiety disorders; reported rates of anxiety disorders in offspring; and used validated diagnostic tools to ascertain diagnoses. We used random and mixed-effects models and evaluated study quality.

      Results

      We included 25 studies (7,285 offspring). Where parents had an anxiety disorder, offspring were significantly more likely to have anxiety (risk ratio [RR] = 1.76, 95% CI = 1.58−1.96) and depressive disorders (RR = 1.31, 95% CI = 1.13−1.52) than offspring of parents without anxiety disorders. Parent panic disorder and generalized anxiety disorder appeared to confer particular risk. Risk was greater for offspring anxiety than for depressive disorders (RR = 2.50, 95% CI = 1.50−4.16), and specifically for offspring generalized anxiety disorder, separation anxiety disorder and specific phobia, but there was no evidence that children of parents with particular anxiety disorders were at increased risk for the same particular anxiety disorders. Moderation analyses were possible only for offspring age, sex, and parental depressive disorder; none were significant.

      Conclusion

      Parent anxiety disorders pose specific risks of anxiety disorders to offspring. However, there is limited support for transmission of the same particular anxiety disorder. These results support the potential for targeted prevention of anxiety disorders.

      Key words

      Anxiety disorders are the most common psychiatric disorders among children and adolescents,
      • Polanczyk G.V.
      • Salum G.A.
      • Sugaya L.S.
      • Caye A.
      • Rohde L.A.
      Annual research review: a meta-analysis of the worldwide prevalence of mental disorders in children and adolescents.
      with a median age of onset of 11 years.
      • Kessler R.C.
      • Berglund P.
      • Demler O.
      • Jin R.
      • Merikangas K.R.
      • Walters E.E.
      Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.
      They are associated with increased risk for other psychiatric disorders, including mood disorders, substance abuse, and psychosis,
      • Beesdo K.
      • Bittner A.
      • Pine D.S.
      • et al.
      Incidence of social anxiety disorder and the consistent risk for secondary depression in the first three decades of life.
      • Chartier M.J.
      • Walker J.R.
      • Stein M.B.
      Considering comorbidity in social phobia.
      • Schutters S.I.
      • Dominguez M.
      • Knappe S.
      • et al.
      The association between social phobia, social anxiety cognitions and paranoid symptoms.
      and carry a significant global economic burden.
      • Whiteford H.A.
      • Degenhardt L.
      • Rehm J.
      • et al.
      Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010.
      Prevention of these common and serious disorders will advance with an improved understanding of risk factors.
      One risk factor for anxiety disorders in children, examined in family aggregation studies, is anxiety disorders in parents.
      • Hirshfeld-Becker D.R.
      • Micco J.A.
      • Simoes N.A.
      • Henin A.
      High risk studies and developmental antecedents of anxiety disorders.
      In the first study to examine this risk, Turner et al. reported the odds of anxiety disorders to be more than seven times greater in children of parents with anxiety disorders than in children of psychiatrically healthy parents.
      • Turner S.M.
      • Beidel D.C.
      • Costello A.
      Psychopathology in the offspring of anxiety disorders patients.
      Other studies examining risks posed by parent anxiety disorders have also found an increased risk of depression in offspring.
      • Merikangas K.R.
      • Dierker L.C.
      • Szatmari P.
      Psychopathology among offspring of parents with substance abuse and/or anxiety disorders: a high-risk study.
      • Biederman J.
      • Petty C.
      • Faraone S.V.
      • et al.
      Effects of parental anxiety disorders in children at high risk for panic disorder: a controlled study.
      However, some studies of parents with anxiety disorders have found lower, and some insignificant, odds of offspring anxiety disorders and/or depression, relative to offspring of healthy parents
      • Merikangas K.R.
      • Dierker L.C.
      • Szatmari P.
      Psychopathology among offspring of parents with substance abuse and/or anxiety disorders: a high-risk study.
      • Kaplan S.L.
      • Busner J.
      • Gallagher R.
      • Chaput F.
      • Acosta E.
      Soft signs in children of parents with agoraphobia.
      and to offspring of parents without anxiety disorders but with other psychiatric disorders.
      • Pine D.S.
      • Klein R.G.
      • Roberson-Nay R.
      • et al.
      Response to 5% carbon dioxide in children and adolescents─relationship to panic disorder in parents and anxiety disorders in subjects.
      • Warner V.
      • Mufson L.
      • Weissman M.M.
      Offspring at high and low risk for depression and anxiety: mechanisms of psychiatric disorder.
      These discrepant findings regarding risk for anxiety and depressive disorders in offspring of parents with anxiety disorders have been addressed in a single previous meta-analysis of 9 studies, including 972 offspring.
      • Micco J.A.
      • Henin A.
      • Mick E.
      • et al.
      Anxiety and depressive disorders in offspring at high risk for anxiety: a meta-analysis.
      Children of parents with anxiety disorders were found to be at increased risk for anxiety disorders generally (odds ratio [OR] = 3.91, 95% CI = 2.51–6.1), depressive disorders (OR = 2.67, 95% CI = 1.69–4.23) and agoraphobia, generalized anxiety disorder (GAD), panic disorder, separation anxiety disorder, social phobia, and specific phobias, relative to offspring of parents without psychiatric disorders. Here, we update our understanding of the issues examined by Micco et al.
      • Micco J.A.
      • Henin A.
      • Mick E.
      • et al.
      Anxiety and depressive disorders in offspring at high risk for anxiety: a meta-analysis.
      regarding risks posed by parent anxiety disorders generally for research question (RQ) 1, offspring anxiety disorders generally; RQ 2, offspring depressive disorders; and RQ 3, offspring particular anxiety disorders. Furthermore, we address 3 questions (RQ 4–RQ6) not previously addressed in the literature regarding specific risks posed by parent anxiety disorders generally and particular parent anxiety disorders.
      First, regarding disorder class, Murray et al.
      • Murray L.
      • Creswell C.
      • Cooper P.J.
      The development of anxiety disorders in childhood: an integrative review.
      raised the question of whether parent anxiety disorders are associated uniquely with offspring anxiety disorders or with child internalizing disorders more broadly. Rates of anxiety and depressive disorders have both been found to be raised in the offspring of parents with anxiety disorders, with greater odds of anxiety than of depressive disorders.
      • Micco J.A.
      • Henin A.
      • Mick E.
      • et al.
      Anxiety and depressive disorders in offspring at high risk for anxiety: a meta-analysis.
      However, the previous meta-analysis did not directly compare the rates from studies in which offspring were assessed for both anxiety and depressive disorders. So, what has not been addressed meta-analytically is whether parent anxiety disorders pose a greater risk to offspring of anxiety disorders or of depressive disorders. Thus, we ask RQ 4, which is whether offspring whose parents have anxiety disorders are at greater risk for anxiety disorders or for depressive disorders (in studies in which both are assessed).
      Our second novel question focuses on whether particular parent anxiety disorders place offspring at increased risk for anxiety disorders. Longitudinal cohort studies have examined this for parent panic disorder
      • Biederman J.
      • Petty C.
      • Faraone S.V.
      • et al.
      Effects of parental anxiety disorders in children at high risk for panic disorder: a controlled study.
      • Biederman J.
      • Rosenbaum J.F.
      • Bolduc E.A.
      • Faraone S.V.
      • Hirshfeld D.R.
      A high risk study of young children of parents with panic disorder and agoraphobia with and without comorbid major depression.
      • Biederman J.
      • Faraone S.V.
      • Hirshfeld-Becker D.R.
      • Friedman D.
      • Robin J.A.
      • Rosenbaum J.F.
      Patterns of psychopathology and dysfunction in high-risk children of parents with panic disorder and major depression.
      in the Massachusetts General Hospital at-risk study, and for parent Social Anxiety Disorder in the Reading Longitudinal Study
      • Murray L.
      • Cooper P.
      • Creswell C.
      • Schofield E.
      • Sack C.
      The effects of maternal social phobia on mother-infant interactions and infant social responsiveness.
      • Murray L.
      • De Rosnay M.
      • Pearson J.
      • et al.
      Intergenerational transmission of social anxiety: the role of social referencing processes in infancy.
      • Murray L.
      • Pella J.E.
      • De Pascalis L.
      • et al.
      Socially anxious mothers' narratives to their children and their relation to child representations and adjustment.
      and the German Early Developmental Stages of Psychopathology study, in which parental GAD was also examined.
      • Beesdo K.
      • Pine D.S.
      • Lieb R.
      • Wittchen H.-U.
      Incidence and risk patterns of anxiety and depressive disorders and categorization of generalized anxiety disorder.
      • Knappe S.
      • Beesdo K.
      • Fehm L.
      • Hofler M.
      • Lieb R.
      • Wittchen H.U.
      Do parental psychopathology and unfavorable family environment predict the persistence of social phobia?.
      • Knappe S.
      • Beesdo K.
      • Fehm L.
      • Lieb R.
      • Wittchen H.-U.
      Associations of familial risk factors with social fears and social phobia: evidence for the continuum hypothesis in social anxiety disorder?.
      • Knappe S.
      • Lieb R.
      • Beesdo K.
      • et al.
      The role of parental psychopathology and family environment for social phobia in the first three decades of life.
      Thus, we ask: RQ 5: are the rates of anxiety disorders higher in offspring of parents with particular anxiety disorders compared to offspring of nonanxious parents?
      Third, there is evidence of increased risk of first-degree relatives (for example, sibling or avuncular relatives) having the same particular anxiety disorder as each other, including social anxiety disorder
      • Reich J.
      • Yates W.
      Family history of psychiatric disorders in social phobia.
      • Stein M.B.
      • Chartier M.J.
      • Hazen A.L.
      • et al.
      A direct-interview family study of generalized social phobia.
      • Cooper P.J.
      • Fearn V.
      • Willetts L.
      • Seabrook H.
      • Parkinson M.
      Affective disorder in the parents of a clinic sample of children with anxiety disorders.
      and specific phobia.
      • Fyer A.J.
      • Mannuzza S.
      • Chapman T.F.
      • Martin L.Y.
      • Klein D.F.
      Specificity in familial aggregation of phobic disorders.
      More specifically, particular parent anxiety disorders, including social anxiety disorder and separation anxiety disorder, have been found to pose a specific risk for the same particular anxiety disorder to offspring.
      • Biederman J.
      • Petty C.
      • Faraone S.V.
      • et al.
      Effects of parental anxiety disorders in children at high risk for panic disorder: a controlled study.
      • Knappe S.
      • Beesdo K.
      • Fehm L.
      • Lieb R.
      • Wittchen H.-U.
      Associations of familial risk factors with social fears and social phobia: evidence for the continuum hypothesis in social anxiety disorder?.
      Thus, we ask RQ 6: where parents have a particular anxiety disorder, are offspring more likely to have that same particular anxiety disorder, or only different anxiety disorders?
      Longitudinal studies have shown the importance of risk factors other than parent anxiety disorder for the development of offspring anxiety disorders, of which we examine four. First, rates of anxiety disorders have repeatedly been found to be greater in females than in males.
      • McLean C.P.
      • Asnaani A.
      • Litz B.T.
      • Hofmann S.G.
      Gender differences in anxiety disorders: prevalence, course of illness, comorbidity and burden of illness.
      • Kessler R.C.
      • McGonagle K.A.
      • Zhao S.
      • et al.
      Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey.
      Second, the temperamental style of behavioral inhibition has been implicated in the development of anxiety disorders,
      • Clauss J.A.
      • Blackford J.U.
      Behavioral inhibition and risk for developing social anxiety disorder: a meta-analytic study.
      • Hudson J.L.
      • Dodd H.F.
      Informing early intervention: preschool predictors of anxiety disorders in middle childhood.
      including in the context of parent anxiety disorders.
      • Biederman J.
      • Hirshfeld-Becker D.R.
      • Rosenbaum J.F.
      • et al.
      Further evidence of association between behavioral inhibition and social anxiety in children.
      Third, age is associated with different rates of particular anxiety disorders.
      • Beesdo-Baum K.
      • Knappe S.
      • Asselmann E.
      • et al.
      The ‘Early Developmental Stages of Psychopathology (EDSP) study’: a 20-year review of methods and findings.
      • Hill C.
      • Waite P.
      • Creswell C.
      Anxiety disorders in children and adolescents.
      Fourth, parental depressive disorders have been associated with an increased risk of offspring anxiety disorders.
      • Micco J.A.
      • Henin A.
      • Mick E.
      • et al.
      Anxiety and depressive disorders in offspring at high risk for anxiety: a meta-analysis.
      • Weissman M.M.
      • Leckman J.F.
      • Merikangas K.R.
      • Gammon G.D.
      • Prusoff B.A.
      Depression and anxiety disorders in parents and children: results from the Yale Family Study.
      Here, we examine whether the presence of parental depressive disorders moderates risks to offspring of particular outcomes from different parent risk groups. In particular we ask: in nonanxious parents, as the rate of parent depressive disorder increases, does the risk of offspring anxiety disorder increase; and, in anxious parents, as the rate of depressive disorder increases, does this modify the relative risk of anxiety versus depressive disorders in offspring? Thus, we set out to sharpen the focus of our meta-analysis by examining these four potential moderators for each of the risk relationships specified in questions 1 to 6, below.
      In summary, we examine the risks posed by parent anxiety disorders generally (ie, any, but no specific, “anxiety disorder”) for (1) offspring anxiety disorders generally and (2) offspring depressive disorders. We clarify issues of specificity by asking (3) whether parent anxiety disorders place offspring at greater risk for particular anxiety disorders, and (4) whether offspring whose parents have anxiety disorders are at greater risk for anxiety disorders or for depressive disorders (in studies in which both are assessed). We examine the risk posed by particular parent anxiety disorders to offspring for (5) anxiety disorders generally and (6) the same particular anxiety disorder (see Figure 1 for diagrams of the relationships in questions 1−6). Finally, we examine whether these relationships are weaker or stronger in the presence of other risk factors.
      Figure thumbnail gr1
      Figure 1Diagrams to Show Directions of Expected Risk Relationships Examined in Research Questions (RQ) 1 to 6
      Note: Solid lines show greater risk and dotted lines shower lower risk. AD = anxiety disorder; GAD = Generalized Anxiety Disorder. Please note color figures are available online.

      Method

       Protocol

      We specified methods, inclusion and exclusion criteria, and analyses in advance, and registered them in a protocol on the International Prospective Register of Systematic Reviews (PROSPERO; protocol number: CRD42016048814). We adapted the original protocol to account for the narrower scope of this systematic review. Specifically, this report focuses only on studies reporting diagnostic outcomes for anxiety. Examining the risks of continuous features of anxiety is conceptually separate from our focus here, so those studies that met the criteria in our registered protocol but reported only continuous outcomes will be reported separately.

       Eligibility Criteria

      We included articles that met the following inclusion criteria: published in peer-reviewed journals
      • Higgins J.P.T.
      • Green S.
      ; contained at least one group of parents with anxiety disorders and at least one comparison group of parents who did not have anxiety disorders; reported rates of anxiety disorders in offspring; and used validated diagnostic tools to ascertain diagnoses.
      We excluded articles that met the following exclusion criteria: participants were identified in light of issues other than parent psychiatric disorder (eg, child anxiety disorder, parental cancer, diabetes, dental surgery); and parents had no anxiety disorder classified in DSM 5 (where neither posttraumatic stress disorder nor obsessive compulsive disorder is classified as an “anxiety disorder”).

       Information Sources and Search Terms

      The electronic databases: PsycINFO (1967 onward), PubMed (no date restriction), and Web of Science Core Collection (1970 onward) were searched in the second week of June 2016 and third week of July 2017 (this rerun yielded a single extra paper
      • Stumper A.
      • Danzig A.P.
      • Dyson M.W.
      • Olino T.M.
      • Carlson G.A.
      • Klein D.N.
      Parents' behavioral inhibition moderates association of preschoolers' BI with risk for age 9 anxiety disorders.
      ) for reports published in English in a peer-reviewed journal. The search strategies and syntax for each database are contained in the Supplement 1, available online. We also completed a hand search of references from previous reviews and papers included in this review. We contacted study authors when data in a paper were reported in a format that we could not analyze.

       Outcome Measures

      The primary outcomes for this review were offspring anxiety disorder diagnoses and depressive disorder diagnoses.

       Study Selection

      P.L. retrieved references, which were all independently screened and rated by P.L. and one of two research assistants. There was 100% agreement between raters.

       Study Quality Assessment

      P.L. and a research assistant both assessed study quality of all papers using an adapted version of the Standard Quality Assessment Criteria for Evaluating Primary Research Papers for quantitative studies.

      Kmet LM, Lee RC, Cook LS. Standard quality assessment criteria for evaluating primary research papers from a variety of fields. In: Alberta Heritage Foundation for Medical Research Edmonton; Edmonton, Alberta, Canada; 2004.

      Items on the checklist that were irrelevant to studies included in this review were removed (for example, “If interventional and random allocation was possible, was it described?”), and other items’ wording was modified for the purpose of this review (for example, from “Outcome and (if applicable) exposure measure(s) well defined and robust to measurement / misclassification bias?” to “anxiety disorder diagnostic interviews clearly defined?”). We kept items regarding study design, sample selection, sample description and the methods of assessment of anxiety disorders. The items were as follows:
      • I.
        Is the study design evident and appropriate?
      • II.
        Is the method of participant selection described and appropriate?
      • III.
        Are the participant characteristics sufficiently described?
      • IV.
        Are the anxiety disorder diagnostic interviews clearly defined?
      • V.
        Are the anxiety disorder diagnostic tools of high quality/robust?
      For all studies, each item was rated as:
      • 0.
        No—study did not resolve this item.
      • 1.
        Partial—study addressed query partially.
      • 2.
        Yes—study addressed query to high standard.

       Data Extraction and Statistical Analyses

      We extracted data for each outcome as well as relevant information about the participants, as summarized in Table 1.
      • Turner S.M.
      • Beidel D.C.
      • Costello A.
      Psychopathology in the offspring of anxiety disorders patients.
      • Biederman J.
      • Petty C.
      • Faraone S.V.
      • et al.
      Effects of parental anxiety disorders in children at high risk for panic disorder: a controlled study.
      • Kaplan S.L.
      • Busner J.
      • Gallagher R.
      • Chaput F.
      • Acosta E.
      Soft signs in children of parents with agoraphobia.
      • Pine D.S.
      • Klein R.G.
      • Roberson-Nay R.
      • et al.
      Response to 5% carbon dioxide in children and adolescents─relationship to panic disorder in parents and anxiety disorders in subjects.
      • Murray L.
      • Cooper P.
      • Creswell C.
      • Schofield E.
      • Sack C.
      The effects of maternal social phobia on mother-infant interactions and infant social responsiveness.
      • Knappe S.
      • Beesdo K.
      • Fehm L.
      • Hofler M.
      • Lieb R.
      • Wittchen H.U.
      Do parental psychopathology and unfavorable family environment predict the persistence of social phobia?.
      • Hudson J.L.
      • Dodd H.F.
      Informing early intervention: preschool predictors of anxiety disorders in middle childhood.
      • Ginsburg G.S.
      • Drake K.L.
      • Tein J.Y.
      • Teetsel R.
      • Riddle M.A.
      Preventing onset of anxiety disorders in offspring of anxious parents: a randomized controlled trial of a family-based intervention.
      • Bhat A.S.
      • Srinivasan K.
      Psychopathology in the adolescent offspring of parents with panic disorder and depression.
      • McClure E.B.
      • Brennan P.A.
      • Hammen C.
      • Le Brocque R.M.
      Parental anxiety disorders, child anxiety disorders, and the perceived parent-child relationship in an Australian high-risk sample.
      • Breslau N.
      • Davis G.C.
      • Prabucki K.
      Searching for evidence on the validity of generalized anxiety disorder: psychopathology in children of anxious mothers.
      • Buckley A.F.
      • Woodruff-Borden J.
      Maternal modeling of coping: Relation to child anxiety.
      • Capps L.
      • Sigman M.
      • Sena R.
      • Heoker B.
      • Whalen C.
      Fear, anxiety and perceived control in children of agoraphobic parents.
      • Chapman L.K.
      • Petrie J.
      • Vines L.
      • Durrett E.
      The co-occurrence of anxiety disorders in African American parents and their children.
      • Cox L.J.
      • Stanley B.H.
      • Melhem N.M.
      • et al.
      A longitudinal study of nonsuicidal self-injury in offspring at high risk for mood disorder.
      • Klein D.N.
      • Lewinsohn P.M.
      • Rohde P.
      • Seeley J.R.
      • Olino T.M.
      Psychopathology in the adolescent and young adult offspring of a community sample of mothers and fathers with major depression.
      • Kujawa A.
      • Proudfit G.H.
      • Klein D.N.
      Neural reactivity to rewards and losses in offspring of mothers and fathers with histories of depressive and anxiety disorders.
      • Manelis A.
      • Ladouceur C.D.
      • Graur S.
      • et al.
      Altered amygdala-prefrontal response to facial emotion in offspring of parents with bipolar disorder.
      • McClellan J.M.
      • Rubert M.P.
      • Reichler R.J.
      • Sylvester C.E.
      Attention deficit disorder in children at risk for anxiety and depression.
      • Biederman J.
      • Petty C.R.
      • Hirshfeld-Becker D.R.
      • et al.
      Developmental trajectories of anxiety disorders in offspring at high risk for panic disorder and major depression.
      • Mufson L.
      • Weissman M.M.
      • Warner V.
      Depresssion and anxiety in parents and children: a direct interview study.
      • Schneider S.
      • Houweling J.E.
      • Gommlich-Schneider S.
      • Klein C.
      • Nundel B.
      • Wolke D.
      Effect of maternal panic disorder on mother-child interaction and relation to child anxiety and child self-efficacy.
      • Schrock M.
      • Woodruff-Borden J.
      Parent-Child Interactions in Anxious Families.
      • Whaley S.E.
      • Pinto A.
      • Sigman M.
      Characterizing interactions between anxious mothers and their children.
      • Biederman J.
      • Petty C.
      • Hirshfeld-Becker D.R.
      • et al.
      A controlled longitudinal 5-year follow-up study of children at high and low risk for panic disorder and major depression.
      All data were extracted by both P.L. and a research assistant. Any disagreement was resolved by CC. A full list of data extracted is available from the authors.
      Table 1Characteristics of Studies Included in Meta-Analysis
      StudyOffspring (n)Age Range (mean)Sex (% F)EthnicityParent Dx ToolAD

      Parent Dxs
      Control

      Parent Dxs
      Offspring Dx ToolRecruitment
      Beesdo et al., 2010
      • Knappe S.
      • Beesdo K.
      • Fehm L.
      • Hofler M.
      • Lieb R.
      • Wittchen H.U.
      Do parental psychopathology and unfavorable family environment predict the persistence of social phobia?.
      ,
      Data provided by authors.
      3,02121−34German sampleCAPI DIA-x / M-CIDIPhobias or PD; GADDepression; Substance Use; No Psychiatric DisorderCAPI DIA-x / M-CIDICommunity
      Beidel and Turner, 1997
      • Ginsburg G.S.
      • Drake K.L.
      • Tein J.Y.
      • Teetsel R.
      • Riddle M.A.
      Preventing onset of anxiety disorders in offspring of anxious parents: a randomized controlled trial of a family-based intervention.
      1297−12 (9.6)4483% European Am

      15% African Am;

      2% E Indian
      SCID (DSM III)PD, social phobia, OCD; MDD + GAD; MDD + OCDDepression; No Psychiatric DisorderK-SADSClinical and community
      Bhat and Srinivasan, 200641,
      Data provided by authors.
      11711−1646100% IndianCIDIPDDepression; No Psychiatric disorderMAGICClinical
      Biederman et al., 1991
      • Murray L.
      • Cooper P.
      • Creswell C.
      • Schofield E.
      • Sack C.
      The effects of maternal social phobia on mother-infant interactions and infant social responsiveness.
      121(9.2)41.3100 WhiteNIMH-DISPD W Ag; PD + MDDMDD; Other Psych; No Psychiatric disorderDICA-PClinical and community
      Biederman et al., 2006
      • Biederman J.
      • Petty C.
      • Hirshfeld-Becker D.R.
      • et al.
      A controlled longitudinal 5-year follow-up study of children at high and low risk for panic disorder and major depression.
      3197−184695 WhiteSCIDPD/AG; PD/AG + MDDMDD; No PD/AG or MDDK-SADS EClinical and community
      Biederman et al., 2007
      • Biederman J.
      • Petty C.R.
      • Hirshfeld-Becker D.R.
      • et al.
      Developmental trajectories of anxiety disorders in offspring at high risk for panic disorder and major depression.
      2337−18 (10.9)95 WhiteSCIDPD/AG; PDD + MDDMDD; No PD/AG or MDDK-SADS-E (<18 y) SCID (>17 y)Clinical and community
      Breslau et al., 1987433318−2380 WhiteDISGAD; GAD + MDDNo GAD or MDDDISCProbands from control group in study of children with disabilities
      Buckley and Woodruff-Borden, 200644496−12 (8.4)5580 WhiteADIS-IVGAD, PD, social + specific phobiaNever psychiatrically illADIS-IV-P/CCommunity
      Capps et al., 199645328−146769 White

      13 African Am; 13 Asian Am; 6 Latino
      ADIS-RPD/AGNever psychiatrically illDISC-2.1Clinical and community
      Chapman et al., 2012461006−1751100 African AmADIS-IVPD/AG, social phobia, GAD, OCD, specific phobia (various); PTSD; MDDNo Psychiatric DiagnosisADIS-IV-P/CCommunity
      Cox et al., 201247
      Data provided by authors.
      35210+ (18)4966 WhiteSCID; SCID-IINot specifiedMood DisorderKSADS-PLClinical
      Hudson and Dodd, 2012
      • Hudson J.L.
      • Dodd H.F.
      Informing early intervention: preschool predictors of anxiety disorders in middle childhood.
      ,
      Data provided by authors.
      1608−95064 Oceanic; 20 European; 10 AsianADISADNo anxiety disorderADIS-P-IVCommunity
      Kaplan et al., 1996
      • Kaplan S.L.
      • Busner J.
      • Gallagher R.
      • Chaput F.
      • Acosta E.
      Soft signs in children of parents with agoraphobia.
      506−18 (9.5)67SADS-LAG; MDD; SUD; bipolar disorder, OCDNo anxiety disorderDICA-PClinical and community
      Klein et al., 2005 48,
      Data provided by authors.
      77524K-SADS; LIFEAny anxiety disorderMDD, Alcohol dependence, Drug dependenceSCID-NPCommunity
      Kujawa et al., 201449,
      Data provided by authors.
      407(9)4589.7 Causcasian; 7.6 African Am; 2.7 AsianSCIDAD; AD + MDDMDD; No maternal anxiety or depressionK-SADS-PLCommunity
      Manelis et al., 201550,
      Data provided by authors.
      817−17 (13.8)58SCID-IVAD; AD + bipolar disorderBipolar disorder; no family history of any major psychiatric diagnosisK-SADS-PLClinical and community
      McClellan et al., 1990511637−1751DISPDMDD; no major psychiatric diagnosis,DICA; DICA-PClinical and community
      Merikangas et al., 1998
      • Biederman J.
      • Petty C.
      • Faraone S.V.
      • et al.
      Effects of parental anxiety disorders in children at high risk for panic disorder: a controlled study.
      1927−1849100 WhiteSADSPD/AG; Soc and / or GADsubstance abuse, or dependence; never psychiatrically illK-SADS-EClinical and community
      Mogg et al., 2012
      • Biederman J.
      • Petty C.R.
      • Hirshfeld-Becker D.R.
      • et al.
      Developmental trajectories of anxiety disorders in offspring at high risk for panic disorder and major depression.
      1199−14 (11.8)100SCIDPDNo psychiatric diagnosisADIS-PClinical and community
      Mufson et al., 1992532146−2353SADSPD + MDDMDD; never psychiatrically illK-SADS-ECommunity
      Murray et al., 2014
      • Beesdo K.
      • Pine D.S.
      • Lieb R.
      • Wittchen H.-U.
      Incidence and risk patterns of anxiety and depressive disorders and categorization of generalized anxiety disorder.
      1364−556.7>99 WhiteSCIDSocial PhobiaNo anxiety disorderADIS?Community
      Pine et al., 2005
      • Pine D.S.
      • Klein R.G.
      • Roberson-Nay R.
      • et al.
      Response to 5% carbon dioxide in children and adolescents─relationship to panic disorder in parents and anxiety disorders in subjects.
      1429−19SCIDPD; PD+MDDMDD; Psychiatrically healthy parentsPARISClinical, dental, community
      Schneider et al., 20095410713−23German sampleMini-DIPSPD/AGNo psychiatric disorderF-DIPSClinical and community
      Schrock and Woodruff-Borden, 2010551583−1244.376 White; 16 African Am; 3 Hispanic; 1 Asian; 1 Native Am; 3 otherADISPD/AG; Social Phobia; GAD; Specific PhobiaNo anxiety disorder, no diagnosesADIS-P (3−5 y) ADIS/PC (6−12 y)Clinical and community
      Turner et al., 1987
      • Turner S.M.
      • Beidel D.C.
      • Costello A.
      Psychopathology in the offspring of anxiety disorders patients.
      597−124293 White; 7 African AmADISAG; OCDDysthymic disorder; no DSM-III diagnosesCASClinical and community
      Whaley et al., 199956367−14 (10.3)4478 White; 11 Latino; 6 Asian Am; 6 otherADIS-IVAD (inc PD/AG, OCD, GAD, social phobia, specific phobia, hypochondriasis, MDDPsychologically healthyK-SADSClinical and community
      Note: AD = anxiety disorder; AD Parents Dxs = diagnoses in parents with anxiety disorders; ADIS(-R) = Anxiety Disorders Interview Schedule (for DSM III-R); ADIS-IV = Anxiety Disorders Interview Schedule (for DSM-IV); Am, American; ASPD = Antisocial personality disorder; CAPI = computer-assisted personal interview; version of the (DIA-X / M-CIDI) Munich−Composite International Diagnostic Interview; CAS = Children’s Assessment Schedule; CD = conduct disorder; CIDI = Composite International Diagnostic Interview; Control Parent Dxs = psychiatric disorders in parents without anxiety disorders; DIA-X = Munich-Composite International Diagnostic Interview; DICA-P = Diagnostic Interview for Children and Adolescents–Parent Version; DIPS = German version of ADIS-R; DIS = Diagnostic Interview Schedule; DISC = Diagnostic Interview Schedule for Children; F-DIPS = German version of ADIS for DSM-IV; F = female; GAD = generalized anxiety disorder; Kinder DIPS = German Child version of ADIS-R; Kinder-DIPS = German version of Child ADIS-R; LIFE = Longitudinal Interval Follow-up Evaluation; MAGIC = Missouri Assessment of Genetics Interview for Children; M-CIDI = Munich−Composite International Diagnostic Interview; MDD = major depressive disorder; Mini-DIPS = German translation of ADIS-IV-L; NIMH-DIS = National Institute of Mental Health Diagnostic Interview Schedule; NYHRSFHI = New York High Risk Study Family History Interview; Offspring Dx Tool = tool used to assess psychiatric disorders in offspring; PAPA = Preschool Age Psychiatric Assessment; Parent Dx Tool = tool used to assess psychiatric disorders in parents; PARIS = Parent As Respondent Informant Schedule; SADS-L = Schedule for Affective Disorders and Schizophrenia−Lifetime Version; SCID = Structured Clinical Interview for DSM (NP−nonpatient version); SUD = substance use disorder.
      a Data provided by authors.
      We used the R statistical environment, with the metafor package for meta-analysis
      • Viechtbauer W.
      Conducting meta-analyses in R with the metafor package.
      and its “weightr” package for weighted sensitivity analyses.
      We calculated risk ratios (RR) for diagnostic outcome reports using random effects meta-analyses.
      • Higgins J.P.T.
      • Green S.
      We used the Knapp and Hartung adjustment because random-effects modeling meta-analysis is known to increase the type I error rate, especially when there is heterogeneity of variance or a small number of studies.
      • Knapp G.
      • Hartung J.
      Improved tests for a random effects meta-regression with a single covariate.
      We used the I2 statistic to calculate the impact of heterogeneity of effect sizes between studies.
      • Higgins J.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      We conducted meta-regressions (mixed effects meta-analyses) to assess for moderation of effects by continuous variables (rate of depressive disorders in parents, offspring age, proportion of female to male offspring participants).

       Publication Bias

      We used funnel plots and Egger tests to assess the risk of publication bias and used a priori weight functions for sensitivity analyses.
      • Vevea J.L.
      • Woods C.M.
      Publication bias in research synthesis: sensitivity analysis using a priori weight functions.

      Results

      In total, 53 papers met our inclusion criteria. Table 1 provides characteristics of studies retained in the analyses. (Table S1, available online, provides characteristics of studies that met inclusion criteria but did not provide data for analysis.) Figure 2 presents the PRISMA flowchart. Of these, 26 were reports from follow-up studies. We removed multiple reports from the same cohorts to retain the most recent reports. We were unable to extract analyzable data from two papers.
      • McClure E.B.
      • Brennan P.A.
      • Hammen C.
      • Le Brocque R.M.
      Parental anxiety disorders, child anxiety disorders, and the perceived parent-child relationship in an Australian high-risk sample.
      • Johnson J.G.
      • Cohen P.
      • Kasen S.
      • Brook J.S.
      Parental concordance and offspring risk for anxiety, conduct, depressive, and substance use disorders.
      Two papers reporting results from the same sample were retained because we could extract data for offspring anxiety disorders from only one of them
      • Biederman J.
      • Petty C.
      • Hirshfeld-Becker D.R.
      • et al.
      A controlled longitudinal 5-year follow-up study of children at high and low risk for panic disorder and major depression.
      and data for offspring depressive disorders from only the other.
      • Biederman J.
      • Petty C.R.
      • Hirshfeld-Becker D.R.
      • et al.
      Developmental trajectories of anxiety disorders in offspring at high risk for panic disorder and major depression.
      Thus, we retained 25 papers from 24 studies with 7,285 unique offspring. Table 2 contains a summary of the results.
      Figure thumbnail gr2
      Figure 2PRISMA Flow Diagram of Selection of Studies
      Note: AD = anxiety disorder; GAD = generalized anxiety disorder.
      Table 2Summary of Results
      Offspring OutcomeParent Risk GroupParent Gontrol GroupStudies, kRiskHeterogeneity
      RR95% CIpI2 %
      ADADWithout AD221.761.58–1.96<.00010
      Sensitivity analyses 21Lowest 1.741.57–1.93<.00010
      21Highest 1.841.55–2.18<.000126
      Depressive disorderADWithout AD171.311.13–1.52.0010
      Sensitivity analyses 16Lowest 1.291.10–1.52.0040
      16Highest 1.541.05–2.25.0324
      GADADWithout AD152.191.58–3.04<.00010
      Sensitivity analyses 4Lowest 2.030.88–4.68.090
      4Highest 2.251.59–3.19<.00010
      Panic disorderADWithout AD62.020.87–4.67.10
      Sensitivity analyses 5Lowest 1.870.81–4.35.240
      5Highest 3.310.87–12.6.180
      Separation anxiety disorderADWithout AD72.941.26–6.86.0139
      Sensitivity analyses 6Lowest 4.321.56–11.96.0144
      6Highest 2.161.07–4.36.0322
      Social anxiety disorderADWithout AD52.980.80–11.08.149
      Sensitivity analyses 4Lowest 2.170.56–8.40.2647
      4Highest 4.741.83–12.29.0010
      Specific phobiaADWithout AD42.291.11–4.75.030
      Sensitivity analyses 3Lowest 1.620.67–3.9.280
      3Highest 2.831.27–6.29.010
      AD vs. depressive disorderAD102.501.50–4.16.00488
      Sensitivity analyses 9Lowest 2.161.32–3.51.00284
      9Highest 2.771.69–4.54.00579
      ADGADWithout AD22.541.86–3.45<.00199
      Sensitivity analyses —
      ADPanic DisorderWithout AD61.821.30–2.56<.000195
      Sensitivity analyses 5Lowest 1.541.24–1.91<.00016
      5Highest 2.051.37–3.06.00555
      ADSocial ADWithout AD33.490.27–45.7.3499
      Sensitivity analyses 2Lowest 1.291.1–1.53.0020
      2Highest 19.91.12–330.0370
      GAD vs. AD without GADGAD2.390.19–0.83.01599
      Sensitivity analyses —
      Panic disorder vs. AD without panic disorderPanic Disorder4.250.17–0.36<.000176
      Sensitivity analyses 3Lowest .230.13–0.39<.00010
      3Highest .260.17–0.39<.00010
      Social AD vs. AD without social ADSocial AD3.610.35–1.09.0975
      Sensitivity analyses 2Lowest .460.31–0.69.00020
      2Highest .820.55–1.24.0350
      Note: Sensitivity analyses used the leave-one-out method. Significant results shown in boldface type. AD = anxiety disorder; GAD = generalized anxiety disorder; RR = risk ratio.
      Regarding RQ 1, children of parents with anxiety disorders were at significantly greater risk for anxiety disorders (1.76, 95% CI = 1.58−1.96, k = 22, n = 6,674), with low heterogeneity between studies (I2 = 0.01%) (Figure 3); and, regarding RQ 2), were at greater risk of depressive disorders (RR: 1.31, 95% CI = 1.13−1.52, k = 17, n = 5,009) with low heterogeneity (I2 = 28%) (Figure 4) than children of parents without anxiety disorders. Regarding RQ 3, offspring of parents with anxiety disorders were at risk for GAD (RR = 2.19, 95% CI = 1.58−3.04, k = 5, n = 3,330, I2 = 0%), separation anxiety disorder (RR = 2.94, 95% CI = 1.26−6.86, k = 7, n = 424, I2 = 39%), and specific phobia (RR = 2.29, 95% CI = 1.11−4.75, k = 4, n = 269, I2 = 0%) compared to offspring of parents without an anxiety disorder, but there were no significant differences in risks for offspring panic disorder (RR = 2.17, 95% CI = 0.97–4.87, k = 6, n = 400, I2 = 0%) and social anxiety disorder (RR = 2.98, 95% CI = 0.80–11.08, k = 5, n = 295) where heterogeneity was moderate (I2 = 49%). Regarding RQ 4, where studies assessed for both anxiety and depressive disorders, the risk for anxiety disorders was significantly greater than the risk for depressive disorders (RR = 2.50, 95% CI = 1.50–4.16, k = 13, n = 3,220) with high heterogeneity (I2 = 88 %) (Figure 5). Regarding RQ 5, there was significant risk for anxiety disorders in offspring of parents with panic disorder (RR = 1.82, 95% CI = 1.30–2.55, k = 6, n = 773) with high heterogeneity (I2 = 76%) or GAD (RR = 2.54, 95% CI = 1.86−3.45, k = 2, n = 3,614) with moderate heterogeneity (I2 = 50%), but not social anxiety disorder (RR = 3.49, 95% CI = 0.27–45.67, k = 2, n = 3,157), where heterogeneity between studies was high (I2 = 72%) compared to that in offspring of parents without an anxiety disorder. We could not examine the risk to offspring associated with parental specific phobia or separation anxiety disorder because there were no eligible studies. Finally, regarding RQ 6, for which offspring had at least one anxiety disorder and their parents had a particular anxiety disorder, there was no evidence that children were at greater risk for the same particular anxiety disorder than for all other anxiety disorders. For GAD (RR = .39, 95% CI = 0.19−0.83, k = 3, n = 792), although heterogeneity was high (I2 = 85%), and panic disorder (RR = 0.26, 95% CI = 0.18−0.39, k = 4, n = 530, I2 = 0%) there was a greater chance that offspring would have a different disorder to their parents than have the same disorder, and for social anxiety disorder there was not a significant difference in the risk of same versus other anxiety disorder (RR = 0.61, 95% CI = 0.35–1.09, k = 3, n = 730), although heterogeneity was high (I2 = 75%).
      Figure thumbnail gr3
      Figure 3Forest Plot for Meta-Analysis of Risk Posed by Parent Anxiety Disorder for Offspring Anxiety Disorder
      Note: AD = anxiety disorder.
      Figure thumbnail gr4
      Figure 4Forest Plot for Meta-Analysis of Risk Posed by Parent Anxiety Disorder for Offspring Depressive Disorder
      Note: Dep = depressive disorder.
      Figure thumbnail gr5
      Figure 5Forest Plot for Meta-Analysis of Risk Posed by Parent Anxiety Disorder for Offspring Anxiety and Depressive Disorders
      Note: AD = anxiety disorder; Dep = depressive disorder.
      Regarding rating study quality, interrater reliability was good (Cohen’s κ = 0.779, 95% CI = 0.632−0.925). Studies were generally highly rated in four domains: evident and appropriate designs; descriptions of participant characteristics; definitions of anxiety disorder diagnostic tools; and quality of diagnostic tools (Figure S1, available online). The main area of concern was that 11 studies were scored as only “partially addressing” their methods of participant selection.
      Funnel plots (Figures S2 and S3, available online) and Egger test results were consistent with publication bias for studies reporting offspring anxiety (z = 3.36, p < .0001) and for those reporting offspring depressive disorders (z =2.15, p = .003). The bias appears to reflect studies with medium or larger standard errors (ie, those with a smaller n), with null results being underreported in the published literature. We used Vevea and Woods’ weight-function model to analyze sensitivity.
      • Vevea J.L.
      • Woods C.M.
      Publication bias in research synthesis: sensitivity analysis using a priori weight functions.
      The estimates for offspring anxiety (RR = 1.75–1.78) and depressive disorders (RR = 1.26–1.32) proved robust. This is consistent with publication bias being an unlikely influence on results.
      There was no support for offspring mean age moderating the risk for any outcome. Temperament was reported in too few studies to examine it as a moderator. There was limited evidence of moderation by (1) offspring gender of the risk posed by parent anxiety disorders for offspring anxiety disorders, and (2) the presence of parent depressive disorders of the risk posed by parent anxiety disorder for offspring separation anxiety disorder in particular (Figures S4 and S5, available online). The association between anxiety disorders in parents and offspring was higher when there was a greater proportion of female offspring in the study (QM1 = 5.63, p = .02). This finding appeared to be accounted for by one study with only female participants,
      • Mogg K.
      • Wilson K.A.
      • Hayward C.
      • Cunning D.
      • Bradley B.P.
      Attentional biases for threat in at-risk daughters and mothers with lifetime panic disorder.
      and the moderation effect was no longer significant when this study was excluded (QM1 = 2.93, p = .09). The relationship between anxiety disorders in parents and separation anxiety disorder in offspring was weaker when parents also had depressive disorders. However, when two outlying studies, which included no psychiatrically healthy parents, were removed, the moderation effect became nonsignificant (p = .20).

      Discussion

      Consistent with the previous meta-analysis by Micco et al.,
      • Micco J.A.
      • Henin A.
      • Mick E.
      • et al.
      Anxiety and depressive disorders in offspring at high risk for anxiety: a meta-analysis.
      we found that children of parents with anxiety disorders are at increased risk for both anxiety and depressive disorders. We extended the findings of the previous meta-analysis by demonstrating that the risk for offspring anxiety disorders is higher than the risk for offspring depression (RR = 2.50). The effect sizes that we obtained for risk for offspring anxiety (RR = 1.76) and depressive disorders (RR = 1.31) are smaller than those reported in the previous meta-analysis (anxiety; OR = 3.91; depression; OR = 2.67). This is likely to reflect the greater number of included studies (an additional 11 studies with 5,393 offspring). Indeed the effect sizes reported in many of these more recent studies are smaller than those in earlier studies, consistent with Ioannidis’ concept of the “decline effect.”
      • Ioannidis J.P.
      Why science is not necessarily self-correcting.
      As well as identifying this general risk, it is scientifically and clinically important to examine the specific risks posed (1) for particular child anxiety disorders, and (2) by particular parent anxiety disorders, to inform prevention programs for at-risk offspring. Regarding particular child anxiety disorders, Micco et al. found that, compared to children of psychiatrically healthy parents, children of parents with anxiety disorders were at increased risk for all particular anxiety disorders. However, when compared to children of psychiatric control parents, children of parents with anxiety disorders were at increased risk for no particular anxiety disorders.
      • Micco J.A.
      • Henin A.
      • Mick E.
      • et al.
      Anxiety and depressive disorders in offspring at high risk for anxiety: a meta-analysis.
      We found that offspring of parents with anxiety disorders, compared to offspring of parents without anxiety disorders, were at increased risk for GAD, separation anxiety disorder, and specific phobia, but not social anxiety disorder or panic disorder, irrespective of whether the parents had depressive disorders. The important implication for prevention of anxiety disorders in offspring at risk in light of parent anxiety disorders generally is that prevention programs could focus on targeting specific mechanisms implicated in the development of GAD, separation anxiety disorder, and specific phobia, but may not necessarily need to focus specifically on the prevention of social anxiety disorder or panic disorder.
      In terms of the risks posed by particular parent anxiety disorders rather than parent anxiety disorders generally, we were able to examine the risks posed by three particular parent anxiety disorders: GAD, panic disorder, and social anxiety disorder. Our meta-analyses indicated that two of these, parent GAD, and panic disorder, when compared to no parent anxiety disorder, place offspring at increased risk for anxiety disorders in general, whereas parent social anxiety disorder did not significantly increase this risk. This is surprising, because previous studies of familial aggregation of anxiety disorders have found increased rates of anxiety disorders in first-degree relatives of probands with social phobia.
      • Reich J.
      • Yates W.
      Family history of psychiatric disorders in social phobia.
      • Stein M.B.
      • Chartier M.J.
      • Hazen A.L.
      • et al.
      A direct-interview family study of generalized social phobia.
      • Cooper P.J.
      • Fearn V.
      • Willetts L.
      • Seabrook H.
      • Parkinson M.
      Affective disorder in the parents of a clinic sample of children with anxiety disorders.
      • Fyer A.J.
      • Mannuzza S.
      • Chapman T.F.
      • Liebowitz M.R.
      • Klein D.F.
      A direct interview family study of social phobia.
      We could include data from only two studies in this analysis, yielding a large confidence interval around the point risk estimate of 3.49, which may explain this discrepancy. (Although many more than two studies included parents with social phobia in their high risk groups, we were unable to ascertain the rates of anxiety disorders in their offspring, so we could not calculate the risk associated with parent social phobia in these studies.) Furthermore, for parent GAD and panic disorder, offspring were significantly less likely to have the same particular anxiety disorder as their parent (ie, GAD or panic disorder) than to have different anxiety disorders. For parent social anxiety disorder, offspring were not significantly more likely to have any of the other anxiety disorders than to have social anxiety disorder. These results are also surprising, given the significant associations found between particular parent anxiety disorders and the same particular anxiety disorders in their offspring in some previous studies.
      • Biederman J.
      • Petty C.
      • Faraone S.V.
      • et al.
      Effects of parental anxiety disorders in children at high risk for panic disorder: a controlled study.
      • Murray L.
      • Pella J.E.
      • De Pascalis L.
      • et al.
      Socially anxious mothers' narratives to their children and their relation to child representations and adjustment.
      • Mancini C.
      • Van Ameringen M.
      • Szatmari P.
      • Fugere C.
      • Boyle M.
      A high-risk pilot study of the children of adults with social phobia.
      It is possible that we failed to find a significant risk for the same particular disorder in offspring and parents because we had to set a higher bar for conclusions to be drawn about this than in individual studies. We required the risk for the same particular anxiety disorder in offspring to be greater than the combined risk for all other anxiety disorders. This is a higher bar than is typically set in individual studies in which the risk for having the same particular anxiety disorder as a parent is compared to the risk for having another individual particular anxiety disorder. We were unable to assess for specificity of risk in this same way, because we had only group level data, not individual participant level data. As highlighted by Bloch,
      • Bloch M.H.
      Meta-analysis and moderator analysis: can the field develop further?.
      such individual participant level data are essential to clarifying meta-analyses, allowing finer-grained analyses to be conducted. Without these data, we cannot conclude whether or not particular parent anxiety disorders increase the risk for the same particular anxiety disorder in their offspring compared to any other particular anxiety disorder.
      Our findings must be considered in light of the following limitations. The included studies did not report the age of onset of anxiety disorders in offspring, but the age of participation at the time of assessment. In particular, our analyses of risks for particular anxiety disorders could have failed to identify true moderation effects, because particular anxiety disorders have different median ages of onset.
      • Hill C.
      • Waite P.
      • Creswell C.
      Anxiety disorders in children and adolescents.
      Second, few studies have reported the rates of diagnoses of the full range of anxiety disorders so we were unable to examine which particular anxiety disorder is most commonly seen in the offspring of parents with a given particular anxiety disorder. Third, samples varied in terms of whether one or multiple children and one or two parents per family were included in study samples. This is problematic, because including siblings or more than one parent might lead to increased estimates of risk, due to both sibling and parent similarities.
      • Nordsletten A.E.
      • Larsson H.
      • Crowley J.J.
      • Almqvist C.
      • Lichtenstein P.
      • Mataix-Cols D.
      Patterns of nonrandom mating within and across 11 major psychiatric disorders.
      Furthermore, where only one parent was included, we were not always able to establish whether this was a mother or a father. Although studies have found anxiety disorders in mothers and fathers to be equally important in explaining transmission of toddlers’ observed anxious behaviors,
      • Aktar E.
      • Majdandzic M.
      • de Vente W.
      • Bogels S.M.
      Parental social anxiety disorder prospectively predicts toddlers' fear/avoidance in a social referencing paradigm.
      to our knowledge, top-down studies have not reported differential risks for offspring anxiety disorders posed by maternal versus paternal anxiety disorders. Fourth, we were unable to assess whether offspring temperament moderated risk because it was reported in too few studies. Fifth, although we examined four particular moderators of the associations between parent and child disorders, we did not examine potential influences of a broader range of environmental factors (eg, adversity, trauma, cultural factors). Furthermore, none of the studies that we identified reported parent physical illness, so we were unable to examine how this context may influence risks to offspring. The generalizability of our findings is limited by differences among studies in whether families were recruited from clinics or the community, what diagnostic system was used, and whether current or lifetime disorder was assessed. Where lifetime anxiety disorders were not assessed, this would likely make our effects sizes more conservative estimates of the risks.
      We chose to examine risk for anxiety disorders based on studies using a family design, not twin designs, so we are unable to conclude anything about the extent to which transmission of risk for anxiety disorders from parents to offspring might be genetically or environmentally mediated. However, notably, a recent and pioneering children of twins study found that the transmission of risk for anxiety symptoms in adolescents was mediated solely by environmental factors.
      • Eley T.C.
      • McAdams T.A.
      • Rijsdijk F.V.
      • et al.
      The intergenerational transmission of anxiety: a children-of-twins study.
      This is consistent with other studies that have found shared and nonshared environmental factors to be important in the development of anxiety disorders.
      • Spatola C.A.
      • Fagnani C.
      • Pesenti-Gritti P.
      • Ogliari A.
      • Stazi M.A.
      • Battaglia M.
      A general population twin study of the CBCL/6-18 DSM-oriented scales.
      We focused here on categorical diagnoses of anxiety and depression, as predictor, moderator, and outcome variables. Anxiety and depression can also be examined via dimensional constructs, such as symptom/trait measures and broader domains as highlighted by the United States of America National Institute for Mental Health Research Domain Criteria (RDoC).
      • Insel T.
      • Cuthbert B.
      • Garvey M.
      • et al.
      Research Domain Criteria (RDoC): toward a new classification framework for research on mental disorders.
      It will be important to establish whether the patterns of risk that we have found here for categorical diagnoses are similar for dimensional features of anxiety and depression. Further investigation of specific dimensions will be important, because evidence currently suggests that different dimensional features of anxiety and depression might be explained by different mechanisms. For example, twin studies examining dimensional features of anxiety and depression have found that stable genetic effects account for the stability of anxiety sensitivity, fear, and negative affect from childhood to adolescence, whereas environmental factors account for changes in anxiety and depression symptoms over time.
      • Waszczuk M.A.
      • Zavos H.M.S.
      • Gregory A.M.
      • Eley T.C.
      The phenotypic and genetic structure of depression and anxiety disorder symptoms in childhood, adolescence, and young adulthood.
      • Trzaskowski M.
      • Zavos H.M.S.
      • Haworth C.M.A.
      • Plomin R.
      • Eley T.C.
      Stable genetic influence on anxiety-related behaviours across middle childhood.
      • Zavos H.M.S.
      • Rijsdijk F.V.
      • Eley T.C.
      A longitudinal, genetically informative, study of associations between anxiety sensitivity, anxiety and depression.
      In summary, our meta-analyses found that parent anxiety disorders pose a greater risk for anxiety than depressive disorders to offspring; and that the risk was significant for some particular anxiety disorders in offspring (GAD, separation anxiety disorder, and specific phobia), but not others (panic disorder or social anxiety disorder). Parent GAD and panic disorder, but not social anxiety disorder, posed a risk for anxiety disorders in offspring, but not for the same particular anxiety disorder. These findings build on those from a recent meta-analysis
      • Lawrence P.J.
      • Rooke S.M.
      • Creswell C.
      Review: prevention of anxiety among at-risk children and adolescents─a systematic review and meta-analysis.
      in which the only prevention program that effectively lowered the rate of onset of child anxiety disorders was one in which at-risk offspring were targeted in light of parent anxiety disorders.
      • Ginsburg G.S.
      • Drake K.L.
      • Tein J.Y.
      • Teetsel R.
      • Riddle M.A.
      Preventing onset of anxiety disorders in offspring of anxious parents: a randomized controlled trial of a family-based intervention.
      Although this does not establish a causal mechanism, it does demonstrate that targeting children at risk for anxiety disorders in light of parent anxiety disorders can be effective. Our findings suggest that there may be value in developing prevention programs that identify offspring in light of particular parent anxiety disorders, and that target the prevention of particular anxiety disorders in offspring.

      Supplemental Material

      References

        • Polanczyk G.V.
        • Salum G.A.
        • Sugaya L.S.
        • Caye A.
        • Rohde L.A.
        Annual research review: a meta-analysis of the worldwide prevalence of mental disorders in children and adolescents.
        J Child Psychol Psychiatry. 2015; 56: 345-365
        • Kessler R.C.
        • Berglund P.
        • Demler O.
        • Jin R.
        • Merikangas K.R.
        • Walters E.E.
        Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.
        Arch Gen Psychiatry. 2005; 62: 593-602
        • Beesdo K.
        • Bittner A.
        • Pine D.S.
        • et al.
        Incidence of social anxiety disorder and the consistent risk for secondary depression in the first three decades of life.
        Arch Gen Psychiatry. 2007; 64: 903-912
        • Chartier M.J.
        • Walker J.R.
        • Stein M.B.
        Considering comorbidity in social phobia.
        Soc Psychiatry Psychiatr Epidemiol. 2003; 38: 728-734
        • Schutters S.I.
        • Dominguez M.
        • Knappe S.
        • et al.
        The association between social phobia, social anxiety cognitions and paranoid symptoms.
        Acta Psychiatr Scand. 2012; 125: 213-227
        • Whiteford H.A.
        • Degenhardt L.
        • Rehm J.
        • et al.
        Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010.
        Lancet. 2013; 382: 1575-1586
        • Hirshfeld-Becker D.R.
        • Micco J.A.
        • Simoes N.A.
        • Henin A.
        High risk studies and developmental antecedents of anxiety disorders.
        Am J Med Genet Part C Semin Med Genet. 2008; 148C: 99-117
        • Turner S.M.
        • Beidel D.C.
        • Costello A.
        Psychopathology in the offspring of anxiety disorders patients.
        J Consult Clin Psychol. 1987; 55: 229-235
        • Merikangas K.R.
        • Dierker L.C.
        • Szatmari P.
        Psychopathology among offspring of parents with substance abuse and/or anxiety disorders: a high-risk study.
        J Child Psychol Psychiatry Allied Discip. 1998; 39: 711-720
        • Biederman J.
        • Petty C.
        • Faraone S.V.
        • et al.
        Effects of parental anxiety disorders in children at high risk for panic disorder: a controlled study.
        J Affect Disord. 2006; 94: 191-197
        • Kaplan S.L.
        • Busner J.
        • Gallagher R.
        • Chaput F.
        • Acosta E.
        Soft signs in children of parents with agoraphobia.
        J Am Acad Child Adolesc Psychiatry. 1996; 35: 516-522
        • Pine D.S.
        • Klein R.G.
        • Roberson-Nay R.
        • et al.
        Response to 5% carbon dioxide in children and adolescents─relationship to panic disorder in parents and anxiety disorders in subjects.
        Arch Gen Psychiatry. 2005; 62: 73-80
        • Warner V.
        • Mufson L.
        • Weissman M.M.
        Offspring at high and low risk for depression and anxiety: mechanisms of psychiatric disorder.
        J Am Acad Child Adolesc Psychiatry. 1995; 34: 786-797
        • Micco J.A.
        • Henin A.
        • Mick E.
        • et al.
        Anxiety and depressive disorders in offspring at high risk for anxiety: a meta-analysis.
        J Anxiety Disord. 2009; 23: 1158-1164
        • Murray L.
        • Creswell C.
        • Cooper P.J.
        The development of anxiety disorders in childhood: an integrative review.
        Psychol Med. 2009; 39: 1413-1423
        • Biederman J.
        • Rosenbaum J.F.
        • Bolduc E.A.
        • Faraone S.V.
        • Hirshfeld D.R.
        A high risk study of young children of parents with panic disorder and agoraphobia with and without comorbid major depression.
        Psychiatry Res. 1991; 37: 333-348
        • Biederman J.
        • Faraone S.V.
        • Hirshfeld-Becker D.R.
        • Friedman D.
        • Robin J.A.
        • Rosenbaum J.F.
        Patterns of psychopathology and dysfunction in high-risk children of parents with panic disorder and major depression.
        Am J Psychiatry. 2001; 158: 49-57
        • Murray L.
        • Cooper P.
        • Creswell C.
        • Schofield E.
        • Sack C.
        The effects of maternal social phobia on mother-infant interactions and infant social responsiveness.
        J Child Psychol Psychiatry Allied Discip. 2007; 48: 45-52
        • Murray L.
        • De Rosnay M.
        • Pearson J.
        • et al.
        Intergenerational transmission of social anxiety: the role of social referencing processes in infancy.
        Child Dev. 2008; 79: 1049-1064
        • Murray L.
        • Pella J.E.
        • De Pascalis L.
        • et al.
        Socially anxious mothers' narratives to their children and their relation to child representations and adjustment.
        Dev Psychopathol. 2014; 26: 1531-1546
        • Beesdo K.
        • Pine D.S.
        • Lieb R.
        • Wittchen H.-U.
        Incidence and risk patterns of anxiety and depressive disorders and categorization of generalized anxiety disorder.
        Arch Gen Psychiatry. 2010; 67: 47-57
        • Knappe S.
        • Beesdo K.
        • Fehm L.
        • Hofler M.
        • Lieb R.
        • Wittchen H.U.
        Do parental psychopathology and unfavorable family environment predict the persistence of social phobia?.
        J Anxiety Disord. 2009; 23: 986-994
        • Knappe S.
        • Beesdo K.
        • Fehm L.
        • Lieb R.
        • Wittchen H.-U.
        Associations of familial risk factors with social fears and social phobia: evidence for the continuum hypothesis in social anxiety disorder?.
        J Neur Transm. 2009; 116: 639-648
        • Knappe S.
        • Lieb R.
        • Beesdo K.
        • et al.
        The role of parental psychopathology and family environment for social phobia in the first three decades of life.
        Depress Anxiety. 2009; 26: 363-370
        • Reich J.
        • Yates W.
        Family history of psychiatric disorders in social phobia.
        Comprehens Psychiatry. 1988; 29: 72-75
        • Stein M.B.
        • Chartier M.J.
        • Hazen A.L.
        • et al.
        A direct-interview family study of generalized social phobia.
        Am J Psychiatry. 1998; 155: 90-97
        • Cooper P.J.
        • Fearn V.
        • Willetts L.
        • Seabrook H.
        • Parkinson M.
        Affective disorder in the parents of a clinic sample of children with anxiety disorders.
        J Affect Disord. 2006; 93: 205-212
        • Fyer A.J.
        • Mannuzza S.
        • Chapman T.F.
        • Martin L.Y.
        • Klein D.F.
        Specificity in familial aggregation of phobic disorders.
        Arch Gen Psychiatry. 1995; 52: 564-573
        • McLean C.P.
        • Asnaani A.
        • Litz B.T.
        • Hofmann S.G.
        Gender differences in anxiety disorders: prevalence, course of illness, comorbidity and burden of illness.
        J Psychiatr Res. 2011; 45: 1027-1035
        • Kessler R.C.
        • McGonagle K.A.
        • Zhao S.
        • et al.
        Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey.
        Arch Gen Psychiatry. 1994; 51: 8-19
        • Clauss J.A.
        • Blackford J.U.
        Behavioral inhibition and risk for developing social anxiety disorder: a meta-analytic study.
        J Am Acad Child Adolesc Psychiatry. 2012; 51: 1066-1075
        • Hudson J.L.
        • Dodd H.F.
        Informing early intervention: preschool predictors of anxiety disorders in middle childhood.
        PLoS One. 2012; 7: e42359
        • Biederman J.
        • Hirshfeld-Becker D.R.
        • Rosenbaum J.F.
        • et al.
        Further evidence of association between behavioral inhibition and social anxiety in children.
        Am J Psychiatry. 2001; 158: 1673-1679
        • Beesdo-Baum K.
        • Knappe S.
        • Asselmann E.
        • et al.
        The ‘Early Developmental Stages of Psychopathology (EDSP) study’: a 20-year review of methods and findings.
        Soc Psychiatry Psychiatr Epidemiol. 2015; 50: 851-866
        • Hill C.
        • Waite P.
        • Creswell C.
        Anxiety disorders in children and adolescents.
        Paediatr Child Health. 2016; 26: 548-553
        • Weissman M.M.
        • Leckman J.F.
        • Merikangas K.R.
        • Gammon G.D.
        • Prusoff B.A.
        Depression and anxiety disorders in parents and children: results from the Yale Family Study.
        Arch Gen Psychiatry. 1984; 41: 845-852
        • Higgins J.P.T.
        • Green S.
        Cochrane Handbook for Systematic Reviews of Interventions. Vol 4. John Wiley and Sons, Chichester, UK2011
        • Stumper A.
        • Danzig A.P.
        • Dyson M.W.
        • Olino T.M.
        • Carlson G.A.
        • Klein D.N.
        Parents' behavioral inhibition moderates association of preschoolers' BI with risk for age 9 anxiety disorders.
        J Affect Disord. 2017; 210: 35-42
      1. Kmet LM, Lee RC, Cook LS. Standard quality assessment criteria for evaluating primary research papers from a variety of fields. In: Alberta Heritage Foundation for Medical Research Edmonton; Edmonton, Alberta, Canada; 2004.

        • Ginsburg G.S.
        • Drake K.L.
        • Tein J.Y.
        • Teetsel R.
        • Riddle M.A.
        Preventing onset of anxiety disorders in offspring of anxious parents: a randomized controlled trial of a family-based intervention.
        Am J Psychiatry. 2015; 172: 1207-1214
        • Bhat A.S.
        • Srinivasan K.
        Psychopathology in the adolescent offspring of parents with panic disorder and depression.
        J Indian Assoc Child Adolesc Ment Heal. 2006; 2: 100-107
        • McClure E.B.
        • Brennan P.A.
        • Hammen C.
        • Le Brocque R.M.
        Parental anxiety disorders, child anxiety disorders, and the perceived parent-child relationship in an Australian high-risk sample.
        J Abnorm Child Psychol. 2001; 29: 1-10
        • Breslau N.
        • Davis G.C.
        • Prabucki K.
        Searching for evidence on the validity of generalized anxiety disorder: psychopathology in children of anxious mothers.
        Psychiatry Res. 1987; 20: 285-297
        • Buckley A.F.
        • Woodruff-Borden J.
        Maternal modeling of coping: Relation to child anxiety.
        Child Fam Behav Ther. 2006; 28: 59-80
        • Capps L.
        • Sigman M.
        • Sena R.
        • Heoker B.
        • Whalen C.
        Fear, anxiety and perceived control in children of agoraphobic parents.
        J Child Psychol Psychiatry. 1996; 37: 445-452
        • Chapman L.K.
        • Petrie J.
        • Vines L.
        • Durrett E.
        The co-occurrence of anxiety disorders in African American parents and their children.
        J Anxiety Disord. 2012; 26: 65-70
        • Cox L.J.
        • Stanley B.H.
        • Melhem N.M.
        • et al.
        A longitudinal study of nonsuicidal self-injury in offspring at high risk for mood disorder.
        J Clin Psychiatry. 2012; 73: 821-828
        • Klein D.N.
        • Lewinsohn P.M.
        • Rohde P.
        • Seeley J.R.
        • Olino T.M.
        Psychopathology in the adolescent and young adult offspring of a community sample of mothers and fathers with major depression.
        Psychol Med. 2005; 35: 353-365
        • Kujawa A.
        • Proudfit G.H.
        • Klein D.N.
        Neural reactivity to rewards and losses in offspring of mothers and fathers with histories of depressive and anxiety disorders.
        J Abnorm Psychol. 2014; 123: 287-297
        • Manelis A.
        • Ladouceur C.D.
        • Graur S.
        • et al.
        Altered amygdala-prefrontal response to facial emotion in offspring of parents with bipolar disorder.
        Brain. 2015; 138: 2777-2790
        • McClellan J.M.
        • Rubert M.P.
        • Reichler R.J.
        • Sylvester C.E.
        Attention deficit disorder in children at risk for anxiety and depression.
        J Am Acad Child Adolesc Psychiatry. 1990; 29: 534-539
        • Biederman J.
        • Petty C.R.
        • Hirshfeld-Becker D.R.
        • et al.
        Developmental trajectories of anxiety disorders in offspring at high risk for panic disorder and major depression.
        Psychiatry Res. 2007; 153: 245-252
        • Mufson L.
        • Weissman M.M.
        • Warner V.
        Depresssion and anxiety in parents and children: a direct interview study.
        J Anxiety Disord. 1992; 6: 1-13
        • Schneider S.
        • Houweling J.E.
        • Gommlich-Schneider S.
        • Klein C.
        • Nundel B.
        • Wolke D.
        Effect of maternal panic disorder on mother-child interaction and relation to child anxiety and child self-efficacy.
        Arch Womens Ment Heal. 2009; 12: 251-259
        • Schrock M.
        • Woodruff-Borden J.
        Parent-Child Interactions in Anxious Families.
        Child Fam Behav Ther. 2010; 32: 291-310
        • Whaley S.E.
        • Pinto A.
        • Sigman M.
        Characterizing interactions between anxious mothers and their children.
        J Consult Clin Psychol. 1999; 67: 826-836
        • Viechtbauer W.
        Conducting meta-analyses in R with the metafor package.
        J Stat Softw. 2010; 36: 1-48
        • Knapp G.
        • Hartung J.
        Improved tests for a random effects meta-regression with a single covariate.
        Stat Med. 2003; 22: 2693-2710
        • Higgins J.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        Br Med J. 2003; 327: 557-560
        • Vevea J.L.
        • Woods C.M.
        Publication bias in research synthesis: sensitivity analysis using a priori weight functions.
        Psychol Methods. 2005; 10: 428
        • Johnson J.G.
        • Cohen P.
        • Kasen S.
        • Brook J.S.
        Parental concordance and offspring risk for anxiety, conduct, depressive, and substance use disorders.
        Psychopathology. 2008; 41: 124-128
        • Biederman J.
        • Petty C.
        • Hirshfeld-Becker D.R.
        • et al.
        A controlled longitudinal 5-year follow-up study of children at high and low risk for panic disorder and major depression.
        Psychol Med. 2006; 36: 1141-1152
        • Mogg K.
        • Wilson K.A.
        • Hayward C.
        • Cunning D.
        • Bradley B.P.
        Attentional biases for threat in at-risk daughters and mothers with lifetime panic disorder.
        J Abnorm Psychol. 2012; 121: 852-862
        • Ioannidis J.P.
        Why science is not necessarily self-correcting.
        Perspect Psychol Sci. 2012; 7: 645-654
        • Fyer A.J.
        • Mannuzza S.
        • Chapman T.F.
        • Liebowitz M.R.
        • Klein D.F.
        A direct interview family study of social phobia.
        Arch Gen Psychiatry. 1993; 50: 286-293
        • Mancini C.
        • Van Ameringen M.
        • Szatmari P.
        • Fugere C.
        • Boyle M.
        A high-risk pilot study of the children of adults with social phobia.
        J Am Acad Child Adolesc Psychiatry. 1996; 35: 1511-1517
        • Bloch M.H.
        Meta-analysis and moderator analysis: can the field develop further?.
        J Am Acad Child Adolesc Psychiatry. 2014; 53: 135
        • Nordsletten A.E.
        • Larsson H.
        • Crowley J.J.
        • Almqvist C.
        • Lichtenstein P.
        • Mataix-Cols D.
        Patterns of nonrandom mating within and across 11 major psychiatric disorders.
        JAMA Psychiatry. 2016; 73: 354-361
        • Aktar E.
        • Majdandzic M.
        • de Vente W.
        • Bogels S.M.
        Parental social anxiety disorder prospectively predicts toddlers' fear/avoidance in a social referencing paradigm.
        J Child Psychol Psychiatry Allied Discip. 2014; 55: 77-87
        • Eley T.C.
        • McAdams T.A.
        • Rijsdijk F.V.
        • et al.
        The intergenerational transmission of anxiety: a children-of-twins study.
        Am J Psychiatry. 2015; 172: 630-637
        • Spatola C.A.
        • Fagnani C.
        • Pesenti-Gritti P.
        • Ogliari A.
        • Stazi M.A.
        • Battaglia M.
        A general population twin study of the CBCL/6-18 DSM-oriented scales.
        J Am Acad Child Adolesc Psychiatry. 2007; 46: 619-627
        • Insel T.
        • Cuthbert B.
        • Garvey M.
        • et al.
        Research Domain Criteria (RDoC): toward a new classification framework for research on mental disorders.
        Am J Psychiatry. 2010; 167: 748-751
        • Waszczuk M.A.
        • Zavos H.M.S.
        • Gregory A.M.
        • Eley T.C.
        The phenotypic and genetic structure of depression and anxiety disorder symptoms in childhood, adolescence, and young adulthood.
        JAMA Psychiatry. 2014; 71: 905-916
        • Trzaskowski M.
        • Zavos H.M.S.
        • Haworth C.M.A.
        • Plomin R.
        • Eley T.C.
        Stable genetic influence on anxiety-related behaviours across middle childhood.
        J Abnorm Child Psychol. 2012; 40: 85-94
        • Zavos H.M.S.
        • Rijsdijk F.V.
        • Eley T.C.
        A longitudinal, genetically informative, study of associations between anxiety sensitivity, anxiety and depression.
        Behav Genet. 2012; 42: 592-602
        • Lawrence P.J.
        • Rooke S.M.
        • Creswell C.
        Review: prevention of anxiety among at-risk children and adolescents─a systematic review and meta-analysis.
        Child Adolesc Ment Health. 2017; 22: 118-130