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Cited by 19Grief, Bereavement, and Mental HealthChild Abuse and TraumaBirth, Development, and Health

Early-Life Adversity Due to Bereavement and Inflammatory Diseases in the Next Generation: A Population Study in Transgenerational Stress Exposure

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Brew, Bronwyn K, Lundholm, Cecilia, Caffrey Osvald, Emma, Chambers, Georgina, Öberg, Sara, Fang, Fang, Almqvist, Catarina·2022·American Journal of Epidemiology
DOI 10.1093/aje/kwab236PMC PMC8751780
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Abstract

Emerging evidence suggests that trauma experienced in childhood has negative transgenerational implications for offspring mental and physical health. We aimed to investigate whether early-life adversity experienced as bereavement is associated with chronic inflammatory health in offspring. The study population included 3 generations of Swedish families with a base population of 453,516 children (generation 3) born in 2001–2012. Exposure was defined as the middle generation’s (generation 2) experiencing bereavement in childhood due to the death of a parent (generation 1). Outcomes in generation 3 included 2 diagnoses of inflammatory diseases, including asthma, allergic diseases, eczema, and autoimmune diseases. Survival analysis was used to identify causal pathways, including investigation of mediation by generation 2 mood disorders and socioeconomic status (SES). We found that early-life bereavement experienced by women was associated with early-onset offspring asthma (hazard ratio = 1.15, 95% confidence interval: 1.08, 1.23); mediation analysis revealed that 28%–33% of the association may be mediated by SES and 9%–20% by mood disorders. Early-life bereavement experienced by men was associated with autoimmune diseases in offspring (hazard ratio = 1.31, 95% confidence interval: 1.06, 1.62), with no evidence of mediation. In conclusion, adversity experienced early in life may contribute to an increased risk of inflammatory diseases which is partly mediated by mood disorders and SES.

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  • Multigenerational cohort data indicate parental bereavement corresponds with immune-related outcomes in offspring, including increased risk of asthma, allergic disease, and autoimmune conditions.

    “Multigenerational cohort data indicate parental bereavement corresponds with immune-related outcomes in offspring, including increased risk of asthma, allergic disease, and autoimmune conditions (45).”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [45]

    The Results report increased early-onset asthma risk in offspring of women bereaved in childhood and increased autoimmune-disease risk in offspring of men bereaved in childhood. They do not support a general increase in allergic disease: other outcomes were largely unassociated, and the subgroup finding for atopic disease was not supported by further analyses of eczema and allergic rhinitis. Page numbers were not provided in our copy. (LLM, conf=0.90)

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  • Grief exposure has been linked to dysregulated HPA axis activity, altered glucocorticoid feedback, and increased pro-inflammatory cytokine signaling, alongside downstream changes in gene expression.

    “Grief exposure has been linked to dysregulated HPA axis activity, altered glucocorticoid feedback, and increased pro-inflammatory cytokine signaling, alongside downstream changes in gene expression (45).”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [45]

    The Discussion (page not provided) describes a possible link between early-life stress, altered HPA-axis activity, a proinflammatory immune response, and epigenetic changes. It does not specifically link bereavement to altered glucocorticoid feedback, increased cytokine signaling, or downstream changes in gene expression; those mechanisms are more specific than the passage supports. (LLM, conf=0.88)

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Research works printed but not linked: 38

  1. [1]Barker DJP, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet. 1986; 1(8489): 1077– 1081. 2871345
  2. [2]Gluckman PD, Hanson MA, Cooper C, et al. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008; 359(1): 61– 73. 18596274 PMC3923653
  3. [3]Chang HY, Suh DI, Yang SI, et al. Prenatal maternal distress affects atopic dermatitis in offspring mediated by oxidative stress. J Allergy Clin Immunol. 2016; 138(2): 468– 475.e5. 27016803
  4. [5]Brew BK, Gong T, Williams DM, et al. Using fathers as a negative control exposure to test the developmental origins of health and disease hypothesis: a case study on maternal distress and offspring asthma using Swedish register data. Scand J Public Health. 2017; 45(17 suppl): 36– 40. 28683663
  5. [6]Flanigan C, Sheikh A, DunnGalvin A, et al. Prenatal maternal psychosocial stress and offspring’s asthma and allergic disease: a systematic review and meta-analysis. Clin Exp Allergy. 2018; 48(4): 403– 414. 29331049
  6. [8]Tomfohr-Madsen LM, Bayrampour H, Tough S. Maternal history of childhood abuse and risk of asthma and allergy in 2-year-old children. Psychosom Med. 2016; 78(9): 1031– 1042. 27763990
  7. [9]Lê-Scherban F, Wang X, Boyle-Steed K, et al. Intergenerational associations of parent adverse childhood experiences and child health outcomes. Pediatrics. 2018; 141(6): e20174274. 29784755
  8. [10]Taouk L, Schulkin J. Transgenerational transmission of pregestational and prenatal experience: maternal adversity, enrichment, and underlying epigenetic and environmental mechanisms. J Dev Orig Health Dis. 2016; 7(6): 588– 601. 27488022
  9. [11]Mørkve Knudsen T, Rezwan FI, Jiang Y, et al. Transgenerational and intergenerational epigenetic inheritance in allergic diseases. J Allergy Clin Immunol. 2018; 142(3): 765– 772. 30040975 PMC6167012
  10. [12]Blaze J, Roth TL. Evidence from clinical and animal model studies of the long-term and transgenerational impact of stress on DNA methylation. Semin Cell Dev Biol. 2015; 43: 76– 84. 25917771 PMC4618788
  11. [13]Vågerö D, Rajaleid K. Does childhood trauma influence offspring’s birth characteristics? Int J Epidemiol. 2017; 46(1): 219– 229. 27150254 PMC5407175
  12. [14]Hõrak P. Commentary: transgenerational effects of parental death—a life history perspective. Int J Epidemiol. 2017; 46(1): 230– 232. 28201756
  13. [15]Küffer AL, Thoma MV, Maercker A. Transgenerational aspects of former Swiss child laborers: do second generations suffer from their parents’ adverse early-life experiences? Eur J Psychotraumatol. 2016; 7: 30804. 27784510 PMC5081486
  14. [16]Gapp K, Jawaid A, Sarkies P, et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci. 2014; 17(5): 667– 669. 24728267 PMC4333222
  15. [19]Zaidan H, Gaisler-Salomon I. Prereproductive stress in adolescent female rats affects behavior and corticosterone levels in second-generation offspring. Psychoneuroendocrinology. 2015; 58: 120– 129. 25973567
  16. [20]Zaidan H, Leshem M, Gaisler-Salomon I. Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring. Biol Psychiatry. 2013; 74(9): 680– 687. 23726318
  17. [21]Moog NK, Buss C, Entringer S, et al. Maternal exposure to childhood trauma is associated during pregnancy with placental-fetal stress physiology. Biol Psychiatry. 2016; 79(10): 831– 839. 26444076 PMC4777678
  18. [22]Luecken LJ, Roubinov DS. Pathways to lifespan health following childhood parental death. Soc Personal Psychol Compass. 2012; 6(3): 243– 257. 23555319 PMC3613285
  19. [23]Stroebe M, Schut H, Stroebe W. Health outcomes of bereavement. Lancet. 2007; 370(9603): 1960– 1973. 18068517
  20. [24]McEwen CA, McEwen BS. Social structure, adversity, toxic stress, and intergenerational poverty: an early childhood model. Annu Rev Sociol. 2017; 43: 445– 472.
  21. [25]Fang F, Höglund CO, Arck P, et al. Maternal bereavement and childhood asthma—analyses in two large samples of Swedish children. PLoS One. 2011; 6(11): e27202. 22087265 PMC3210147
  22. [26]Örtqvist AK, Lundholm C, Wettermark B, et al. Validation of asthma and eczema in population-based Swedish drug and patient registers. Pharmacoepidemiol Drug Saf. 2013; 22(8): 850– 860. 23754713
  23. [27]Henriksen L, Simonsen J, Haerskjold A, et al. Incidence rates of atopic dermatitis, asthma, and allergic rhinoconjunctivitis in Danish and Swedish children. J Allergy Clin Immunol. 2015; 136(2): 360– 366.e2. 25828267
  24. [28]Shrier I, Platt RW. Reducing bias through directed acyclic graphs. BMC Med Res Methodol. 2008; 8: 70. 18973665 PMC2601045
  25. [29]Valeri L, VanderWeele TJ. SAS macro for causal mediation analysis with survival data. Epidemiology. 2015; 26(2): e23– e24. 25643116
  26. [30]VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med. 2017; 167(4): 268– 274. 28693043
  27. [31]Knackstedt M, Hamelmann E, Arck PC. Mothers in stress: consequences for the offspring. Am J Reprod Immunol. 2005; 54(2): 63– 69. 16105097
  28. [32]Wright RJ. Stress and childhood asthma risk: overlapping evidence from animal studies and epidemiologic research. Allergy Asthma Clin Immunol. 2008; 4(1): 29– 36. 20525123 PMC2869338
  29. [33]Silverman MN, Sternberg EM. Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. Ann N Y Acad Sci. 2012; 1261: 55– 63. 22823394 PMC3572859
  30. [35]Dreger LC, Kozyrskyj AL, HayGlass KT, et al. Lower cortisol levels in children with asthma exposed to recurrent maternal distress from birth. J Allergy Clin Immunol. 2010; 125(1): 116– 122. 19962747
  31. [36]Trump S, Bieg M, Gu Z, et al. Prenatal maternal stress and wheeze in children: novel insights into epigenetic regulation. Sci Rep. 2016; 6: 28616. 27349968 PMC4923849
  32. [37]Lehto K, Pedersen NL, Almqvist C, et al. Asthma and affective traits in adults: a genetically informative study. Eur Respir J. 2019; 53(5): 1802142. 30956207
  33. [38]Williams DR, Sternthal M, Wright RJ. Social determinants: taking the social context of asthma seriously. Pediatrics. 2009; 123(suppl 3): S174– S184. 19221161 PMC3489274
  34. [39]Chen E, Shalowitz MU, Story RE, et al. Parents’ childhood socioeconomic circumstances are associated with their children’s asthma outcomes. J Allergy Clin Immunol. 2017; 140(3): 828– 835.e2. 28089871 PMC5509526
  35. [40]Ekström S, Magnusson J, Kull I, et al. Maternal body mass index in early pregnancy and offspring asthma, rhinitis and eczema up to 16 years of age. Clin Exp Allergy. 2015; 45(1): 283– 291. 24807420 PMC4296237
  36. [41]Brew BK, Chiesa F, Lundholm C, et al. A modern approach to identifying and characterizing child asthma and wheeze phenotypes based on clinical data. PLoS One. 2019; 14(12): e0227091. 31887128 PMC6936778
  37. [42]Lytje M, Dyregrov A. The price of loss—a literature review of the psychosocial and health consequences of childhood bereavement. Bereave Care. 2019; 38(1): 13– 22.
  38. [44]Narayan AJ, Kalstabakken AW, Labella MH, et al. Intergenerational continuity of adverse childhood experiences in homeless families: unpacking exposure to maltreatment versus family dysfunction. Am J Orthopsychiatry. 2017; 87(1): 3– 14. 26752439

Cited by

Sorted by citations

Authors
Brew, B. K., Lundholm, C., Caffrey Osvald, E., Chambers, G., Öberg, S., Fang, F., & Almqvist, C.
Affiliations
Karolinska Institutet (SE)
Corresponding author
Brew, Bronwyn K
ORCID
Venue
American Journal of Epidemiology
Publisher
Oxford University Press (OUP)
Published
2021-09-22
Volume
191
Issue
1
Pages
38-48
ISSN
  • 0002-9262 (ISSN-L)
  • 1476-6256
DOI
10.1093/aje/kwab236
PMC
PMC8751780
OpenAlex
W3199998819
Cited by
19
References
6
Citations by year
2026: 4 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 2 · 2021: 1
FWCI
1.88
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal of Epidemiology (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
Funders
  • Karolinska Institutet
  • Forskningsrådet om Hälsa, Arbetsliv och Välfärd (2015-00289, 2015-01208)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Grief, Bereavement, and Mental Health
  • Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
Keywords
childhood adversity, bereavement, parental death, inflammatory diseases, asthma, autoimmune disease, allergic diseases, atopic dermatitis, mood disorders, socioeconomic status, mediation, offspring health
MeSH terms
Adverse Childhood Experiences, Adolescent, Adult, Aged, Aged, 80 and over, Asthma, Autoimmune Diseases, Bereavement, Child, Child, Preschool, Chronic Disease, Female, Humans, Hypersensitivity, Infant, Inflammation, Male, Middle Aged, Pregnancy, Prenatal Exposure Delayed Effects, Sex Factors, Socioeconomic Factors, Sweden, Age of Onset, Mood Disorders, Young Adult, Parental Death

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