Maternal and perinatal factors associated with hospitalised infectious mononucleosis in children, adolescents and young adults
Maternal and perinatal factors associated with hospitalised infectious mononucleosis in children, adolescents and young adults: record linkage study
Imran Mahmud1, Omar A Abdel-Mannan2, Clare J Wotton3, Michael J Goldacre3*
Background: There is current interest in the role of perinatal factors in the aetiology of diseases that occur later in life. Infectious mononucleosis (IM) can follow late primary infection with Epstein-Barr virus (EBV), and has been shown to increase the risk of multiple sclerosis and Hodgkin’s disease. Little is known about maternal or perinatal factors associated with IM or its sequelae.
Methods: We investigated perinatal risk factors for hospitalised IM using a prospective record-linkage study in a population in the south of England. The dataset used, the Oxford record linkage study (ORLS), includes abstracts of birth registrations, maternities and in-patient hospital records, including day case care, for all subjects in a defined geographical area. From these sources, we identified cases of hospitalised IM up to the age of 30 years in people for whom the ORLS had a maternity record; and we compared perinatal factors in their pregnancy with those in the pregnancy of children who had no hospital record of IM.
Results: Our data showed a significant association between hospitalised IM and lower social class (p = 0.02), a higher risk of hospitalised IM in children of married rather than single mothers (p < 0.001), and, of marginal statistical significance, an association with singleton birth (p = 0.06). The ratio of observed to expected cases of hospitalised IM in each season was 0.95 in winter, 1.02 in spring, 1.02 in summer and 1.00 in autumn. The chi-square test for seasonality, with a value of 0.8, was not significant.
Other factors studied, including low birth weight, short gestational age, maternal smoking, late age at motherhood, did not increase the risk of subsequent hospitalised IM.
Conclusions: Because of the increasing tendency of women to postpone childbearing, it is useful to know that older age at motherhood is not associated with an increased risk of hospitalised IM in their children. We have no explanation for the finding that children of married women had a higher risk of IM than those of single mothers. Though highly significant, it may nonetheless be a chance finding. We found no evidence that such perinatal factors as birth weight and gestational age, or season of birth, were associated with the risk of hospitalised IM.
Over many years, the linked datafiles were built by Leicester Gill, Glenys Bettley and Myfanwy Griffith. The Unit of Health-Care Epidemiology is funded by the English National Institute for Health Research. The views expressed in this paper do not necessarily reflect those of the funding body.
1Clinical Medicine, Somerville College, University of Oxford, Oxford, OX2 6HD, UK. 2Clinical Medicine, St John’s College, University of Oxford, Oxford, OX1 3JP, UK. 3Unit of Health-Care Epidemiology, Department of Public Health, University of Oxford, Old Road Campus, Old Road, Oxford OX3 7LF, UK.
MJG designed the study, with input from IM and OA-M. CJW undertook the analyses. All authors contributed to the interpretation and discussion of findings. IM wrote the first draft and all authors contributed to the final manuscript.
The authors declare that they have no competing interests.
Received: 25 June 2010 Accepted: 28 February 2011 Published: 28 February 2011
1.Nye FJ, Lambert HP: Epstein-Barr virus antibody in cases and contacts of infectious mononucleosis; a family study. J Hyg (Lond) 1973, 71(1):151-161.
2.Pattle SB, Farrell PJ: The role of Epstein-Barr virus in cancer. Expert Opin Biol Ther 2006, 6(11):1193-1205.
3.Crawford DH: Biology and disease associations of Epstein-Barr virus. Philos Trans R Soc Lond B Biol Sci 2001, 356(1408):461-473.
4.Crawford DH, Macsween KF, Higgins CD, Thomas R, McAulay K, Williams H, Harrison N, Reid S, Conacher M, Douglas J, et al: A cohort study among university students: identification of risk factors for Epstein-Barr virus seroconversion and infectious mononucleosis. Clin Infect Dis 2006, 43(3):276-282.
5.Magrath I: The pathogenesis of Burkitt’s lymphoma. Adv Cancer Res 1990, 55:133-270.
6.Wolf H, zur Hausen H, Becker V: EB viral genomes in epithelial nasopharyngeal carcinoma cells. Nat New Biol 1973, 244(138):245-247.
7.Diepstra A, Niens M, Vellenga E, van Imhoff GW, Nolte IM, Schaapveld M, van der Steege G, van den Berg A, Kibbelaar RE, te Meerman GJ, et al: Association with HLA class I in Epstein-Barr-virus-positive and with HLA class III in Epstein-Barr-virus-negative Hodgkin’s lymphoma. Lancet 2005, 365(9478):2216-2224.
8.Evans AS, Comstock GW: Presence of elevated antibody titres to Epstein-Barr virus before Hodgkin’s disease. Lancet 1981, 1(8231):1183-1186.
9.Gutensohn N, Cole P: Epidemiology of Hodgkin’s disease. Semin Oncol 1980, 7(2):92-102.
10.Ascherio A, Munger KL: Epstein-barr virus infection and multiple sclerosis: a review. J Neuroimmune Pharmacol 2010, 5(3):271-277.
11.Pohl D: Epstein-Barr virus and multiple sclerosis. JNeurolSci 2009, 286(1-2):62-64.
12.Thacker EL, Mirzaei F, Ascherio A: Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann Neurol 2006, 59(3):499-503.
13.Warner HB, Carp RI: Multiple sclerosis and Epstein-Barr virus. Lancet 1981, 2(8258):1290.
14.Barker D: Fetal and infant origins of adult disease. London: British Medical Journal; 1992.
15.Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ: Weight in infancy and death from ischaemic heart disease. Lancet 1989, 2(8663):577-580.
16.Cardwell CR, Stene LC, Joner G, Bulsara MK, Cinek O, Rosenbauer J, Ludvigsson J, Jane M, Svensson J, Goldacre MJ, et al: Maternal age at birth and childhood type 1 diabetes: a pooled analysis of 30 observational studies. Diabetes 2010, 59(2):486-494.
17.Law CM, de Swiet M, Osmond C, Fayers PM, Barker DJ, Cruddas AM, Fall CH: Initiation of hypertension in utero and its amplification throughout life. BMJ 1993, 306(6869):24-27.
18.Purtilo DT, Sakamoto K: Reactivation of Epstein-Barr virus in pregnant women: social factors, and immune competence as determinants of lymphoproliferative diseases-a hypothesis. Med Hypotheses 1982, 8(4):401-408.
19.Dean G, Kurtzke JF: On the risk of multiple sclerosis according to age at immigration to South Africa. Br Med J 1971, 3(5777):725-729.
20.Elian M, Nightingale S, Dean G: Multiple sclerosis among United Kingdom-born children of immigrants from the Indian subcontinent, Africa and the West Indies. J Neurol Neurosurg Psychiatry 1990, 53(10):906-911.
21.Bayes HK, Weir CJ, O’Leary C: Timing of birth and risk of multiple sclerosis in the Scottish population. Eur Neurol 2010, 63(1):36-40.
22.Willer CJ, Dyment DA, Sadovnick AD, Rothwell PM, Murray TJ, Ebers GC, Canadian Collaborative Study G: Timing of birth and risk of multiple sclerosis: population based study. BMJ 2005, 330(7483):120.
23.Langagergaard V, Norgard B, Mellemkjaer L, Pedersen L, Rothman KJ, Sorensen HT: Seasonal variation in month of birth and diagnosis in children and adolescents with Hodgkin disease and non-Hodgkin lymphoma. J Pediatr Hematol Oncol 2003, 25(7):534-538.
24.Davidson R, Roberts SE, Wotton CJ, Goldacre MJ: Influence of maternal and perinatal factors on subsequent hospitalisation for asthma in children: evidence from the Oxford record linkage study. BMC Pulm Med 2010, 10:14.
25.Ievins R, Roberts SE, Goldacre MJ: Perinatal factors associated with subsequent diabetes mellitus in the child: record linkage study. Diabet Med 2007, 24(6):664-670.
26.Roberts SE, Williams JG, Meddings D, Davidson R, Goldacre MJ: Perinatal risk factors and coeliac disease in children and young adults: a record linkage study. Aliment Pharmacol Ther 2009, 29(2):222-231.
27.Goldacre MJ, Wotton CJ, Seagroatt V, Yeates D: Multiple sclerosis after infectious mononucleosis: record linkage study. J Epidemiol Community Health 2004, 58(12):1032-1035.
28.Goldacre MJ, Wotton CJ, Yeates DG: Associations between infectious mononucleosis and cancer: record-linkage studies. Epidemiol Infect 2009, 137(5):672-680.
29.Kutok JL, Wang F: Spectrum of Epstein-Barr virus-associated diseases. Annu Rev Pathol 2006, 1:375-404.
30.Williams H, Macsween K, McAulay K, Higgins C, Harrison N, Swerdlow A, Britton K, Crawford D: Analysis of immune activation and clinical events in acute infectious mononucleosis. J Infect Dis 2004, 190(1):63-71.
31.Crawford DH, Swerdlow AJ, Higgins C, McAulay K, Harrison N, Williams H, Britton K, Macsween KF: Sexual history and Epstein-Barr virus infection. J Infect Dis 2002, 186(6):731-736.
32.McAulay KA, Higgins CD, Macsween KF, Lake A, Jarrett RF, Robertson FL, Williams H, Crawford DH: HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection. J Clin Invest 2007, 117(10):3042-3048.
33.Hjalgrim H, Askling J, Rostgaard K, Hamilton-Dutoit S, Frisch M, Zhang JS, Madsen M, Rosdahl N, Konradsen HB, Storm HH, et al: Characteristics of Hodgkin’s lymphoma after infectious mononucleosis. N Engl J Med 2003, 349(14):1324-1332.
34.Larsen PD, Bloomer LC, Bray PF: Epstein-Barr nuclear antigen and viral capsid antigen antibody titers in multiple sclerosis. Neurology 1985, 35(3):435-438.
35.Ponsonby AL, van der Mei I, Dwyer T, Blizzard L, Taylor B, Kemp A, Simmons R, Kilpatrick T: Exposure to infant siblings during early life and risk of multiple sclerosis. JAMA 2005, 293(4):463-469.
36.Nye FJ: Social class and infectious mononucleosis. J Hyg (Lond) 1973, 71(1):145-149.
37.Bager P, Nielsen NM, Bihrmann K, Frisch M, Hjalgrim H, Wohlfart J, Koch-Henriksen N, Melbye M, Westergaard T: Childhood infections and risk of multiple sclerosis. Brain 2004, 127(Pt 11):2491-2497.
38.Montgomery SM, Lambe M, Olsson T, Ekbom A: Parental age, family size, and risk of multiple sclerosis. Epidemiology 2004, 15(6):717-723.
39.Sleckman BG, Mauch PM, Ambinder RF, Mann R, Pinkus GS, Kadin ME, Sherburne B, Perez-Atayde A, Thior I, Mueller N: Epstein-Barr virus in Hodgkin’s disease: correlation of risk factors and disease characteristics with molecular evidence of viral infection. Cancer Epidemiol Biomarkers Prev 1998, 7(12):1117-1121.
40.Wong DI, Dockerty JD: Birth characteristics and the risk of childhood leukaemias and lymphomas in New Zealand: a case-control study. BMC Blood Disord 2006, 6:5.
41.Flavell K, Constandinou C, Lowe D, Scott K, Newey C, Evans D, Dutton A, Simmons S, Smith R, Crocker J, et al: Effect of material deprivation on Epstein-Barr virus infection in Hodgkin’s disease in the West Midlands. Br J Cancer 1999, 80(3-4):604-608.