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No effect of preterm birth on the risk of multiple sclerosis: a population based study Ramagopalan, Sreeram V; Valdar, William; Dyment, David A; DeLuca, Gabriele C; Orton, Sarah-Michelle; Yee, Irene M; Criscuoli, Maria; Ebers, George C; Sadovnick, A D Aug 1, 2008

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ralssBioMed CentBMC NeurologyOpen AcceResearch articleNo effect of preterm birth on the risk of multiple sclerosis: a population based studySreeram V Ramagopalan1,2, William Valdar1, David A Dyment1,2, Gabriele C DeLuca1,2, Sarah-Michelle Orton1,2, Irene M Yee3, Maria Criscuoli3, George C Ebers1,2, A Dessa Sadovnick*3,4 and for the Canadian Collaborative Study GroupAddress: 1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK, 2Department of Clinical Neurology, University of Oxford, Level 3, The West Wing, The John Radcliffe Hospital, Oxford, OX3 9DU, UK, 3Department of Medical Genetics, University of British Columbia, G920, Detwiller Pavilion, VCHA – UBC Hospital, 2211 Wesbrook Mall, Vancouver, British Columbia, V6T 2B5, Canada and 4Faculty of Medicine, Division of Neurology, University of British Columbia, G920, Detwiller Pavilion, VCHA – UBC Hospital, 2211 Wesbrook Mall, Vancouver, British Columbia, V6T 2B5, CanadaEmail: Sreeram V Ramagopalan - sramagopalan@gmail.com; William Valdar - valdar@well.ox.ac.uk; David A Dyment - ddyment@well.ox.ac.uk; Gabriele C DeLuca - gcdeluca@gmail.com; Sarah-Michelle Orton - ortons@well.ox.ac.uk; Irene M Yee - iyee@helix.medgen.ubc.ca; Maria Criscuoli - mcriscuoli@helix.medgen.ubc.ca; George C Ebers - george.ebers@clneuro.ox.ac.uk; A Dessa Sadovnick* - dessa.sadovnick@gmail.com; for the Canadian Collaborative Study Group - sramagopalan@gmail.com* Corresponding author    AbstractBackground: Genetic and environmental factors have important roles in multiple sclerosis (MS)susceptibility. A clear parent of origin effect has been shown in several populations, perhapsresulting from factors operating during gestation. Preterm birth (birth at less than 37 weeksgestational age) has been shown to result in long-term health problems, including impairedneurological development. Here, in a population-based cohort, we investigate whether pretermbirth increases the risk to subsequently develop MS.Methods: We identified 6585 MS index cases and 2509 spousal controls with preterm birthinformation from the Canadian Collaborative Project on Genetic Susceptibility to MS. Rates ofindividuals born preterm were compared for index cases and controls.Results: There were no significant differences between cases and controls with respect topreterm births. 370 (5.6%) MS index cases and 130 (5.2%) spousal controls were born preterm, p= 0.41.Conclusion: Preterm birth does not appear to contribute to MS aetiology. Other factors involvedin foetal and early development need to be explored to elucidate the mechanism of the increasedrisk conferred by the apparent maternal effect.Published: 1 August 2008BMC Neurology 2008, 8:30 doi:10.1186/1471-2377-8-30Received: 19 May 2008Accepted: 1 August 2008This article is available from: http://www.biomedcentral.com/1471-2377/8/30© 2008 Ramagopalan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 5(page number not for citation purposes)BMC Neurology 2008, 8:30 http://www.biomedcentral.com/1471-2377/8/30BackgroundMultiple sclerosis (MS) is a chronic inflammatory diseaseof the central nervous system (CNS) characterized bymyelin loss, varying degrees of axonal pathology and pro-gressive neurological dysfunction [1]. With a prevalenceof about 1/1000, MS is the most common cause ofacquired neurological disability in young adults of North-ern European descent [1] other than trauma. The aetiol-ogy of MS remains elusive. However, like most common,complex traits, it is clear that genetic and environmentalcomponents play important roles, both independentlyand interactively [2].A parent-of-origin effect (maternal) has been repeatedlyobserved in MS, based on data from studies of half-sib-lings [3], sibships including dizygotic twins [4], a largeextended Dutch pedigree [5] and avuncular pairs [6] aswell as a documented timing of birth effect [7]. The bio-logical basis of this parent-of-origin effect is as yetunknown, but may arise from environmental compo-nents, gene-environment interactions and/or epigeneticmodifications.A "preterm" birth is defined as occurring at less than 37weeks gestational age [8]. Preterm birth has been increas-ing in frequency over the last few decades in Western soci-eties, now accounting for some 7% of all births in Canada[9]. Although the cause of preterm labour has no preciseaetiology, several maternal risk factors have been impli-cated, including smoking, stress, infection and nutritionalstatus [8]. Additionally, preterm birth has been observedto vary seasonally [10]. With improvements in perinatalcare, such as surfactant therapy and ventilator strategies,survival has steadily improved [8]. This however has beenaccompanied by concerns about a higher risk of long termhealth problems among survivors [11]. Although mostorgans are immature, the brain and lungs are especiallysusceptible to the consequences of preterm birth, leadingto high rates of neurological complications including cer-ebral palsy, cognitive deficits and neuro-sensory impair-ments [11]. Preterm birth has been shown to alter brainstructure with reduced total cerebral tissue volume anddelayed myelination compared to term births [12].In MS, plaque load does not correlate with axonal loss[13], the accumulation of axonal loss is associated withirreversible disability [14] and natural history data showthat the progressive phase is an age-dependent degenera-tive process [15]. Taken together, these data suggest that apossible mechanism affecting neurodegeneration/neu-rodevelopment may be involved in MS pathogenesis.Here, in a population-based cohort, we investigatedevelop MS. To the best of our knowledge, this is the firststudy on this specific topic.MethodsCases and controls were identified through the popula-tion-based, longitudinal Canadian Collaborative Projecton Genetic Susceptibility to Multiple Sclerosis(CCPGSMS), the methodology of which has been previ-ously described [16,17]. Briefly, specialist MS clinics in 11cities across Canada use standardised, personally admin-istered questionnaires to screen individuals with MS (MSindex cases) and to collect data about themselves andtheir families. Each participating CCPGSMS site hasobtained ethical approval from the relevant institutionalreview board. The entire project was reviewed andapproved by the University of British Columbia. TheCCPGSMS combines both genetic epidemiology andmolecular genetics to investigate the aetiology of MS. Akey strength of the CCPGSMS is that the MS study popu-lation is derived from 14 regional clinics that have apatient pool representative of the Canadian MS popula-tion. This minimizes ascertainment biases inherent ingenetic epidemiological investigations and generates asufficiently large sample size from which significantresults from both molecular and epidemiological studiescan be attained. To date over 30,000 MS patients and theirfamilies have been screened.Specific to this study, preterm data was collected by tele-phone interview with mothers of MS index cases andspouse controls (the term "spouse" is used generically torefer to legal spouse, same-sex partner or common lawpartner). Each CCPGSMS index case and spouse control(if available) was asked if he/she had a biological motherwho could provide information on the individual's earlylife. If a positive answer was received the biologicalmother of the case/control was contacted by a CCPGSMSsite research nurse and administered a standardised ques-tionnaire, details of which are described in [16].CCPGSMS site research nurses have all been trained bypersonnel from the central CCPGSMS centre at the Uni-versity of British Columbia. An individual was classed asbeing born preterm if born at under 37 weeks gestationalage. It is well known that maternal recall of preterm birthis sufficiently accurate for clinical and epidemiological use[18], but the validity of this information was corroboratedby further information asked for on the standardisedquestionnaire, including data about birth weight (lessthan 5 pounds), length of hospital stay (average 5 to 7days between 1940–1965, the peak time of birth of ourcases and controls), and the use of an incubator, as thesefactors are known to be associated with preterm birth[11,19]. If a mother could not remember exact detailsPage 2 of 5(page number not for citation purposes)whether preterm birth increases the risk to subsequently and/or the supporting data did not fit criteria for a pre-BMC Neurology 2008, 8:30 http://www.biomedcentral.com/1471-2377/8/30term birth, the offspring was not classed as being bornpreterm.Statistical analysesThe Chi squared test was used to assess significance whencomparing index cases and controls for the rate of pretermbirths. The Student's t-test was used to look for differencesin average gestational age. Logistic regression (using the Rstatistical package) was used to assess the effect of pretermbirth, gender and the interaction thereof.ResultsComplete information from maternal informants onweeks gestation at birth as well as birth weight, durationof hospital stay, and the use of an incubator was availablefor 6585 index cases and 2509 spousal controls. The clin-ical and demographic details of the index cases and con-trols are shown in Table 1.Three hundred and seventy (5.6%) MS index cases and130 (5.2%) spousal controls were born preterm. Thesevalues were not significantly different; p = 0.41 (see Table2). Given the marked yet expected difference between sexratios of index cases versus spousal controls because of thefemale preponderance in MS [20], a sex-stratified compar-ison was also carried out. No significant differences (p =0.67 and p = 0.31 respectively) in the rates of pretermbirth were observed when comparing female cases (280;5.6%) and controls (46; 6.0%) – or male cases (90; 5.6%)and controls (84; 4.8%) (Table 2). This was confirmed bylogistic regression analysis, which showed an effect of sexon the risk of MS (p < 1 × 10-16) but no effect of being bornpreterm (p = 0.65), or an interaction effect between sexand preterm birth (p = 0.31) on the likelihood of develop-ing the disease.The average gestational age of preterm MS index cases was34.6 weeks compared to 34.2 weeks for controls (p = 0.25)– see Table 2. No significant differences were also foundwhen stratifying by sex (average gestational age femaleindex cases born preterm = 34.7 weeks, average gesta-tional age female controls born preterm = 34.8 weeks, p =0.82; average gestational age male index cases born pre-term = 34.2 weeks, average gestational age male controlsborn preterm = 33.9 weeks, p = 0.52).There were no differences in the number of individualsborn preterm between MS index cases and controls whenstratifying by month of birth or when stratifying MS indexcases by clinical course (data not shown).DiscussionMS is a complex neurological trait with a parent-of-origin(maternal) effect shown by several studies [3,5,6]. Intrau-terine factors may potentially affect susceptibility to dis-ease [4,7]. Preterm birth may have a seasonal basis [10]and a timing of birth effect has been observed in MS [7].Consequences of preterm birth may be detrimental neu-rologically [11,12]. Taken together, it is possible thatbeing born prematurely may affect the risk to develop MS.However, our data do not support this hypothesis.Here, we observed no significant differences in pretermbirths for cases or controls, even when stratifying by sex.The mean gestational age for preterm cases and controlswas also similar (Table 2). Furthermore, stratification bymonth of birth or clinical course found no significant dif-ferences, however this analysis may have been underpow-ered due to the sample size reduction upon stratification.The clinical definition of preterm birth may not take intoaccount detrimental aspects of foetal development associ-ated with premature birth measured in days rather thanweeks that may contribute to the onset of MS in adult-hood. Development of gyri and sulci has been shown totake place well into 40 weeks of gestational age [21], andhence premature birth by even a few days may result insmall changes in brain structure. However, even whenanalysing the data as above and including only individu-als born up to and including 39 weeks gestational age,there were no differences between MS cases and spousalcontrols (data not shown). Greater understanding of foetaldevelopment and early maternal influences on the foetusand child is needed before the early origins of multiplesclerosis can be assessed to a greater extent.This study does not rule out maternal risk factors associ-ated with preterm birth, for example smoking and infec-tion, from MS disease pathogenesis, as these factors maystill have a role independent of any effect they may haveon premature birth.Table 1: Clinical and demographic details of MS index cases and controlsMS Index Cases Spousal controlsn 6585 2509Present mean age in years (SD) 49.0 (9.6) 50.9 (9.2)Sex Ratio (f:m) 3.1:1 0.4:1% Relapsing Remitting MS 67.9 /Page 3 of 5(page number not for citation purposes)SD = standard deviation, (f:m) = female to male sex ratioBMC Neurology 2008, 8:30 http://www.biomedcentral.com/1471-2377/8/30Our study may be limited in that maternal recall of datamay not be as accurate as data from clinical records etc.Additionally, as we erred on the side of caution when clas-sifying individuals as preterm, we may have missed thosewho were born borderline preterm and hence we may beunderestimating the number of preterm births in ourcohort. However, this will apply equally to cases and con-trols and maternal recall of preterm birth has been shownto be accurate enough for epidemiological use [18].ConclusionIt should be remembered that parent of origin effects canarise in a number of ways, and likely also by other meansas yet undiscovered. These mechanisms include genomicimprinting [22] and microchimerism [23]. We have previ-ously shown that the rate of microchimerism is signifi-cantly higher in affected MS twins than in unaffected co-twins [24]. As a maternal influence in disease risk does notappear to act via preterm birth, the mechanism of theincreased risk conferred maternally needs to be uncoveredby exploring all possible avenues.AbbreviationsCCPGSMS: Canadian Collaborative Study Group on theGenetic Susceptibility to Multiple Sclerosis, MS- MultipleSclerosisCompeting interestsThe authors declare that they have no competing interests.Authors' contributionsGCE and ADS conceived and designed the experiments.SVR, WV, DAD, GCD, SMO, IMY, MC, GCE and ADS ana-lyzed the data and wrote the paper. All authors read andapproved the final manuscript.AcknowledgementsThis work was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation. S.V.R. is funded by the Medical Research Council of the United Kingdom. G.C.E. is the Action Research Professor of Clinical Neurology at the University of Oxford. The authors would like to thank all patients who generously participated in this study. The sponsor of the study had no role in study design, data collection, data analysis, data interpreta-tion, or writing of the report. The corresponding author had full access to all the data in the study and final responsibility for the decision to submit Vancouver, BC (V Devonshire, P Rieckmann, S A Hashimoto, J Hooge, L Kastrukoff, J J F Oger, J P Smythe, A Traboulsee, P Smyth); Calgary, AB (L Metz); Edmonton, AB (S Warren); Saskatoon, SK (W Hader, K Knox); Lon-don, ON (G Rice, M Kremenchutzky); Ottawa, ON (M Freedman); King-ston, ON (D Brunet); Toronto, ON (P O'Connor, T Gray, M Hohol); Montreal, QC (P Duquette, Y Lapierre); Halifax, NS (T J Murray, V Bhan, C Maxner); and St John's, NL (M Stefanelli).References1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG: Mul-tiple sclerosis.  N Engl J Med 2000, 343(13):938-952.2. Dyment DA, Ebers GC, Sadovnick AD: Genetics of multiple scle-rosis.  Lancet Neurol 2004, 3(2):104-110.3. 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Lancet 2008, 371(9606):75-84.9. Joseph KS, Kramer MS, Marcoux S, Ohlsson A, Wen SW, Allen A,Platt R: Determinants of preterm birth rates in Canada from1981 through 1983 and from 1992 through 1994.  N Engl J Med1998, 339(20):1434-1439.10. Cooperstock M, Wolfe RA: Seasonality of preterm birth in theCollaborative Perinatal Project: demographic factors.  Am JEpidemiol 1986, 124(2):234-241.11. Saigal S, Doyle LW: An overview of mortality and sequelae ofpreterm birth from infancy to adulthood.  Lancet 2008,371(9608):261-269.12. Inder TE, Warfield SK, Wang H, Huppi PS, Volpe JJ: Abnormal cer-ebral structure is present at term in premature infants.  Pedi-atrics 2005, 115(2):286-294.13. DeLuca GC, Williams K, Evangelou N, Ebers GC, Esiri MM: The con-tribution of demyelination to axonal loss in multiple sclero-sis.  Brain 2006, 129(Pt 6):1507-1516.14. 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Ramagopalan SV, Dyment DA, Valdar W, Herrera BM, Criscuoli M,Table 2: Number of individuals born preterm and their average gestational age in MS index cases and controlsMS Index Cases Spousal Controls p valueNo. of individuals born preterm (%) 370 (5.6%) 130 (5.2%) 0.41No. of females born preterm (%) 280 (5.6%) 46 (6.0%) 0.67No. of males born preterm (%) 90 (5.6%) 84 (4.8%) 0.31Average gestational age for preterm individuals 34.6 weeks 34.2 weeks 0.25Page 4 of 5(page number not for citation purposes)for publication.Canadian Collaborative Study Group membersYee IM, Sadovnick AD, Ebers GC: Autoimmune disease in fami-lies with multiple sclerosis: a population-based study.  LancetNeurol 2007, 6(7):604-610.Publish with BioMed Central   and  every scientist can read your work free of charge"BioMed Central will be the most significant development for disseminating the results of biomedical research in our lifetime."Sir Paul Nurse, Cancer Research UKYour research papers will be:available free of charge to the entire biomedical communitypeer reviewed and published immediately upon acceptancecited in PubMed and archived on PubMed Central BMC Neurology 2008, 8:30 http://www.biomedcentral.com/1471-2377/8/3018. Adegboye AR, Heitmann B: Accuracy and correlates of mater-nal recall of birthweight and gestational age.  Bjog 2008,115(7):886-893.19. Gilbert WM, Nesbitt TS, Danielsen B: The cost of prematurity:quantification by gestational age and birth weight.  ObstetGynecol 2003, 102(3):488-492.20. Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV,Sadovnick AD, Ebers GC: Sex ratio of multiple sclerosis in Can-ada: a longitudinal study.  Lancet Neurol 2006, 5(11):932-936.21. Chi JG, Dooling EC, Gilles FH: Gyral development of the humanbrain.  Ann Neurol 1977, 1(1):86-93.22. Reik W, Walter J: Genomic imprinting: parental influence onthe genome.  Nat Rev Genet 2001, 2(1):21-32.23. Nelson JL, Gillespie KM, Lambert NC, Stevens AM, Loubiere LS,Rutledge JC, Leisenring WM, Erickson TD, Yan Z, Mullarkey ME,Boespflug ND, Bingley PJ, Gale EA: Maternal microchimerism inperipheral blood in type 1 diabetes and pancreatic islet betacell microchimerism.  Proc Natl Acad Sci U S A 2007,104(5):1637-1642.24. Willer CJ, Herrera BM, Morrison KM, Sadovnick AD, Ebers GC:Association between microchimerism and multiple sclerosisin Canadian twins.  J Neuroimmunol 2006, 179(1-2):145-151.Pre-publication historyThe pre-publication history for this paper can be accessedhere:http://www.biomedcentral.com/1471-2377/8/30/prepubyours — you keep the copyrightSubmit your manuscript here:http://www.biomedcentral.com/info/publishing_adv.aspBioMedcentralPage 5 of 5(page number not for citation purposes)

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