# paper.pdf ## Metadata - PDFFormatVersion=1.6 - IsLinearized=false - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - CreationDate=D:20260415080537Z - ModDate=D:20260415091454+01'00' - Producer=macOS Version 15.7.4 (Build 24G517) Quartz PDFContext - xmp:createdate=2026-04-15T08:05:37Z - xmp:modifydate=2026-04-15T09:14:54+01:00 - xmp:metadatadate=2026-04-15T09:14:54+01:00 - pdf:producer=macOS Version 15.7.4 (Build 24G517) Quartz PDFContext - dc:format=application/pdf - xmpmm:documentid=uuid:9d1aa5e7-0c63-274d-9794-d8e09bc12f1e - xmpmm:instanceid=uuid:6f505393-bb6e-4b4e-8641-1ec2647385e3 ## Contents ### Page 1 1Supplementary data.Supplementary Box S1. Case and control selection criteria (CPRD initialidentification plus additional inclusion/exclusion criteria applied in this study).MS cases selection criteria (obtained cases from CPRD had achieved 1-4):(1) CPRD initially identified potential cases who had more than or equal to one MSdiagnostic code based on a pre-developed CPRD Aurum MS diagnostic codes list(Supplementary Box S2).(2) Patients had their first ever record of MS between 1st January 1990 and 1st March2022.(3) Patients had at least 5 years of prior GP registration at the index date.(4) Patients were aged more than or equal to 18 years old at the index date.(5) To improve the accuracy of case selection, we additionally excluded patients whoonly had diagnostic codes suggestive of other inflammatory/demyelinatingconditions (probable/possible MS diagnostic codes) or only had one definite MSdiagnostic code (1). The MS diagnostic code list and confidence informationwere developed by neurologists (RD, BJ) and are presented in SupplementaryBox S2.(6) In 2001, the first McDonald MS criteria published, which was revolutionary forMS diagnosis (1, 2). The patients who could be diagnosed changed substantiallywith the MacDonald revisions (1, 2). Therefore, to keep the populationhomogenous, we additionally excluded patients who had the index date before ### Page 2 22001.Controls selection criteria (obtained controls from CPRD had achieved 1-2):(1) CPRD initially identified potential controls who did not have any CPRD codesfor MS, matched to selected cases by year of birth in a 1:10 ratio.(2) Participants were aged more than or equal to 18 years old at the index date.(3) Some CPRD-selected controls mistakenly had MS diagnostic codes in CPRD andwere therefore excluded.(4) Participants who had an index date before 2001 were excluded.(5) Only included controls whose matched cases were retained in the final casecohort.(6) Patients had at least 5 years of prior GP registration at the index date. ### Page 3 3Supplementary Box S3. Prescription categoriesPrescription type Medication category in British National Formulary(BNF), and examplesAnti-depressants/anxietymedicationsSSRIs – e.g. citalopramSNRIs – e.g. duloxetineTCA – e.g. amitriptylineMAOI – e.g. phenetzineRIMA – e.g. manerixSMS – e.g. brintellixAtypical – e.g. mirtazapineMigraine/cluster headachespecific medicationsTriptans – e.g. sumatriptanLower urinary tract symptomsrelated medicationsAlpha-blockers – e.g. tamsulosin, doxazosin, alfuzosinBeta-agonists – e.g. mirabegronAlpha-reductase – e.g. finasterideAntimuscarinics – e.g. oxybutynin, tolterodineUTI treatments relatedmedicationsAntibiotics listed in BNF as a treatment for urinary tractinfection or pyelonephritis — for example, nitrofurantoinand trimethoprimAlkalysing agents used in the treatment of cystitisSleeping disorder relatedmedicationsBenzodiazepines – e.g. diazepamSedatives – e.g. zolpidemOther – e.g. melatoninGI medications Antidiarrheals – e.g. loperamideLaxatives – e.g. sennaAntispasmodics – e.g. hyoscine butylbromideMedications for erectiledysfunctionPhosphodisterase inhibitors – e.g. sildenafilAbbreviation：BNF= British National Formulary.; MAOI = Monoamine oxidase inhibitors; RIMA =Reversible inhibitors of monoamine oxidase A; SSRI = Selective serotonin reuptake inhibitors;Serotonin and norepinephrine reuptake inhibitors; SMS= serotonin modulator and stimulator; TCA =Tricyclic antidepressants. ### Page 4 4Supplementary Table S2. Proportion of cases and controls with a prescription record in each prescription category byage, sex and IMD (all prescriptions, 5-year registration).Anti-anxiety/depressionprescriptionsMigraine / clusterheadache specificmedicationsLUTS relatedmedicationsUTI treatmentsrelatedmedicationsMedications forsleeping disorderGI medications Medications forEDControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)Allparticipants10136(17.95)5088(52.66)1651(2.92)889(9.20)1353(2.40)1106(11.45)18820(33.34)6608(68.39)5710(10.11)2690(27.84)6349(11.25)2964(30.68)794(2.83)379(13.36)Age at theindex date(years)<30 505(9.15)429(40.66)150(2.72)121(11.47)27(0.49)26(2.46)1602(29.03)713(67.58)226(4.10)173(16.40)493(8.93)287(27.20)8(0.29)6(1.91)30-39 1776(13.73)1085(50.75)295(2.28)224(10.48)83(0.64)109(5.10)3563(27.55)1499(70.11)933(7.21)552(25.82)1214(9.39)649(30.36)47(0.77)32(5.48)40-49 3684(17.80)1690(54.78)559(2.70)254(8.23)317(1.53)279(9.04)6520(31.50)2146(69.56)2103(10.16)929(30.11)2080(10.05)869(28.17)181(1.75)111(13.77)50-59 2870(23.55)1244(55.86)475(3.90)205(9.21)453(3.72)316(14.19)4727(38.78)1455(65.33)1617(13.27)688(30.89)1541(12.64)664(29.82)321(5.06)141(19.89)60-69 974(25.52)490(55.24)145(3.80)75(8.46)302(7.91)264(29.76)1739(45.57)600(67.64)602(15.78)273(30.78)649(17.01)358(40.36)174(9.02)70(21.15)>70 327 150 27 10 171 112 669 195 229 75 372 137 63 19 ### Page 5 5(25.10) (55.56) (2.07) (3.70) (13.12) (41.48) (51.34) (72.22) (17.57) (27.78) (28.55) (50.74) (9.97) (20.65)SexMale 3905(13.92)1223(43.12)363(1.29)108(3.81)732(2.61)388(13.68)7773(27.71)1564(55.15)2318(8.26)629(22.18)2174(7.75)613(21.61)794(2.83)379(13.36)Female 6231(21.94)3865(56.62)1288(4.53)781(11.44)621(2.19)718(10.52)11047(38.89)5044(73.89)3392(11.94)2061(30.19)4175(14.70)2351(34.44)NA NAIMDQuintile11923(17.39)1071(49.33)318(2.88)184(8.48)259(2.34)244(11.24)3938(35.61)1472(67.80)1112(10.06)605(27.87)1144(10.34)584(26.90)151(2.76)73(12.50)Quintile21895(17.43)1092(51.73)338(3.11)184(8.72)262(2.41)252(11.94)3867(35.57)1421(67.31)1064(9.79)578(27.38)1194(10.98)620(29.37)155(2.87)91(13.60)Quintile31906(17.90)989(51.89)309(2.90)178(9.34)283(2.66)217(11.39)3558(33.41)1304(68.42)1067(10.02)530(27.81)1217(11.43)568(29.80)171(3.24)78(13.27)Quintile41993(18.01)927(53.28)332(3.00)164(9.43)261(2.36)192(11.03)3634(32.84)1204(69.20)1108(10.01)465(26.72)1255(11.34)582(33.45)143(2.61)56(11.97)Quintile52135(21.89)885(59.00)303(3.11)156(10.40)267(2.74)177(11.80)3331(34.15)1051(70.07)1207(12.37)442(29.47)1364(13.98)532(35.47)163(3.27)73(15.97)Missing 284(9.29)124(52.99)51(1.67)23(9.83)21(0.69)24(10.26)492(16.09)156(66.67)152(4.97)70(29.91)175(5.72)78(33.33)11(0.76)8(11.43)ED= erectile dysfunction, GI= Gastrointestinal, LUTS= Lower urinary tract symptoms, UTI= Urinary tract infection, IMD= index of multiple deprivation,N=number, %=proportion, Quintile 1 (least deprived), Quintile 5 (most deprived). ### Page 6 6Supplementary Table S3. Proportion of cases and controls with a prescription record in each prescription category byage, sex and IMD (first prescription, 5-year registration).Anti-anxiety/depressionprescriptionsMigraine / clusterheadache specificmedicationsLUTS relatedmedicationsUTI treatmentsrelatedmedicationsMedications forsleeping disorderGI medications Medications forEDControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)All participants 8203(14.53)3836(39.70)1411(2.50)748(7.74)1270(2.25)1023(10.59)13804(24.45)3903(40.40)4932(8.74)2222(23.00)5425(9.61)2283(23.63)747(2.66)352(12.41)Age at the indexdate (years)<30 487(8.83)409(38.77)134(2.43)112(10.62)24(0.43)26(2.46)965(17.49)369(34.98)213(3.86)169(16.02)437(7.92)245(23.22)8(0.29)6(1.91)30-39 1513(11.70)888(41.53)266(2.06)195(9.12)81(0.63)105(4.91)2796(21.62)982(45.93)865(6.69)505(23.62)1070(8.27)540(25.26)46(0.76)32(5.48)40-49 2947(14.24)1256(40.71)466(2.25)220(7.13)299(1.44)269(8.72)4830(23.34)1295(41.98)1835(8.87)796(25.80)1757(8.49)657(21.30)173(1.67)105(13.03)50-59 2264(18.58)873(39.20)405(3.32)163(7.32)424(3.48)293(13.16)3455(28.35)812(36.46)1366(11.21)513(23.04)1293(10.61)492(22.09)303(4.77)134(18.90)60-69 741(19.42)309(34.84)117(3.07)51(5.75)283(7.42)232(26.16)1298(34.01)342(38.56)475(12.45)193(21.76)572(14.99)252(28.41)160(8.30)56(16.92)>70 251(19.26)101(37.41)23(1.77)7(2.59)159(12.20)98(36.30)460(35.30)103(38.15)178(13.66)46(17.04)296(22.72)97(35.93)57(9.02)19(20.65) ### Page 7 7SexMale 3279(11.69)982(34.63)325(1.16)94(3.31)697(2.48)364(12.83)6019(21.46)1027(36.21)2047(7.30)537(18.94)1936(6.90)517(18.23)747(2.66)352(12.41)Female 4924(17.33)2854(41.81)1086(3.82)654(9.58)573(2.02)659(9.65)7785(27.41)2876(42.13)2885(10.16)1685(24.69)3489(12.28)1766(25.87)NA NAIMDQuintile11557(14.08)792(36.48)274(2.48)150(6.91)252(2.28)224(10.32)2864(25.90)807(37.17)959(8.67)493(22.71)986(8.92)436(20.08)140(2.56)69(11.82)Quintile21540(14.17)836(39.60)282(2.59)162(7.67)240(2.21)234(11.08)2804(25.80)879(41.64)933(8.58)485(22.97)1015(9.34)471(22.31)148(2.74)82(12.26)Quintile31546(14.52)758(39.77)271(2.54)146(7.66)267(2.51)201(10.55)2599(24.40)766(40.19)906(8.51)441(23.14)1038(9.75)449(23.56)160(3.03)73(12.41)Quintile41612(14.57)695(39.94)278(2.51)141(8.10)242(2.19)180(10.34)2682(24.24)721(41.44)958(8.66)388(22.30)1079(9.75)459(26.38)137(2.50)54(11.54)Quintile51709(17.52)652(43.47)261(2.68)128(8.53)249(2.55)161(10.73)2478(25.40)621(41.40)1043(10.69)358(23.87)1154(11.83)404(26.93)153(3.07)67(14.66)Missing 239(7.82)103(44.02)45(1.47)21(8.97)20(0.65)23(9.83)377(12.33)109(46.58)133(4.35)57(24.36)153(5.00)64(27.35)9(0.63)7(10.00)ED= erectile dysfunction, GI= Gastrointestinal, LUTS= Lower urinary tract symptoms, UTI= Urinary tract infection, IMD= index of multiple deprivation,N=number, %=proportion, Quintile 1 (least deprived), Quintile 5 (most deprived). ### Page 8 9Supplementary Table S4. Full results of multivariable conditionallogistic regression models (all prescriptions, 5-year registration).Full results of multivariable conditional logistic regression model for Anxiety/depressionprescriptionsYears before the index date 0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PAnti-anxiety/depressionprescriptions6.68[ 6.31, 7.08]<0.001 3.69[ 3.49, 3.91]<0.001 2.51[ 2.38, 2.66]<0.001Sex(Male as reference)2.06[ 1.96, 2.17]<0.001 2.16[ 2.05, 2.27]<0.001 2.24[ 2.13, 2.36]<0.001IMD(IMD-1 as reference)IMD-2 0.98[ 0.91, 1.06]0.601 0.99[ 0.93, 1.07]0.849 0.99[ 0.92, 1.06]0.741IMD-3 0.90[ 0.83, 0.97]0.004 0.92[ 0.85, 0.98]0.017 0.91[ 0.85, 0.98]0.010IMD-4 0.77[ 0.72, 0.84]<0.001 0.78[ 0.73, 0.84]<0.001 0.78[ 0.73, 0.84]<0.001IMD-5 0.71[ 0.66, 0.77]<0.001 0.74[ 0.69, 0.80]<0.001 0.75[ 0.70, 0.81]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, the lowest value isthe year closest to the index date. ### Page 9 10Full results of multivariable conditional logistic regression model for Migraine relatedprescriptionsYears before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PMigraineprescriptions3.51[ 3.06, 4.02]<0.001 2.70[ 2.39, 3.07]<0.001 2.15[ 1.90, 2.43]<0.001Sex(Male as reference)2.35[ 2.24, 2.47]<0.001 2.36[ 2.25, 2.48]<0.001 2.37[ 2.26, 2.49]<0.001IMD(IMD-1 as reference)IMD-2 1.00[ 0.93, 1.07]0.894 1.00[ 0.94, 1.07]0.941 1.00[ 0.93, 1.07]0.974IMD-3 0.92[ 0.86, 0.99]0.019 0.92[ 0.86, 0.99]0.026 0.92[ 0.86, 0.99]0.020IMD-4 0.80[ 0.74, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001IMD-5 0.79[ 0.73, 0.85]<0.001 0.79[ 0.74, 0.86]<0.001 0.79[ 0.74, 0.86]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, the lowestvalue is the year closest to the index date. ### Page 10 11Full results of multivariable conditional logistic regression model for Lower urinary tractsymptoms related prescriptionYears before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PLower urinarytract symptomsrelatedprescriptions7.47[ 6.64, 8.41]<0.001 4.71[ 4.15, 5.34]<0.001 3.42[ 2.96, 3.95]<0.001Sex(Male as reference)2.48[ 2.36, 2.61]<0.001 2.45[ 2.33, 2.58]<0.001 2.43[ 2.32, 2.55]<0.001IMD(IMD-1 asreference)IMD-2 1.00[ 0.93, 1.07]0.982 0.99[ 0.93, 1.07]0.875 1.00[ 0.93, 1.07]0.915IMD-3 0.92[ 0.85, 0.98]0.015 0.91[ 0.85, 0.98]0.012 0.92[ 0.86, 0.99]0.021IMD-4 0.79[ 0.74, 0.85]<0.001 0.79[ 0.74, 0.85]<0.001 0.80[ 0.74, 0.86]<0.001IMD-5 0.78[ 0.73, 0.85]<0.001 0.79[ 0.73, 0.85]<0.001 0.79[ 0.74, 0.86]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, the lowestvalue is the year closest to the index date. ### Page 11 12Full results of multivariable conditional logistic regression model for Urinary tract infectionstreatments related prescriptionsYears before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PUrinary tractinfectionstreatments relatedprescriptions3.71[ 3.52, 3.92]<0.001 3.08[ 2.93, 3.23]<0.001 2.49[ 2.38, 2.62]<0.001Sex(Male as reference)2.11[ 2.01, 2.22]<0.001 2.13[ 2.02, 2.24]<0.001 2.17[ 2.06, 2.28]<0.001IMD(IMD-1 asreference)IMD-2 1.00[ 0.93, 1.07]0.963 1.00[ 0.93, 1.07]0.947 1.00[ 0.93, 1.07]0.960IMD-3 0.93[ 0.86, 1.00]0.037 0.93[ 0.86, 0.99]0.036 0.93[ 0.87, 1.00]0.043IMD-4 0.80[ 0.74, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001 0.81[ 0.75, 0.87]<0.001IMD-5 0.78[ 0.72, 0.84]<0.001 0.78[ 0.72, 0.84]<0.001 0.80[ 0.74, 0.86]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, the lowestvalue is the year closest to the index date. ### Page 12 13Full results of multivariable conditional logistic regression model for Sleeping disorderrelated prescriptionsYears before the indexdate0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PSleeping disorderprescriptions4.37[ 4.04, 4.72]<0.001 2.75[ 2.55, 2.97]<0.001 2.22[ 2.06, 2.39]<0.001Sex (Male as reference) 2.30[ 2.19, 2.42]<0.001 2.34[ 2.23, 2.46]<0.001 2.37[ 2.25, 2.49]<0.001IMD(IMD-1 as reference)IMD-2 1.00[ 0.94, 1.08]0.913 1.01[ 0.94, 1.08]0.873 1.00[ 0.93, 1.07]1.000IMD-3 0.91[ 0.85, 0.98]0.013 0.92[ 0.86, 0.99]0.020 0.92[ 0.86, 0.99]0.023IMD-4 0.80[ 0.74, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001IMD-5 0.77[ 0.72, 0.83]<0.001 0.78[ 0.72, 0.84]<0.001 0.78[ 0.72, 0.84]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, the lowest value isthe year closest to the index date. ### Page 13 14Full results of multivariable conditional logistic regression model for Gastrointestinalprescriptions.Years before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PGastrointestinalprescriptions4.21[ 3.90, 4.55]<0.001 3.01[ 2.80, 3.23]<0.001 2.17[ 2.03, 2.33]<0.001Sex(Male as reference)2.28[ 2.17, 2.39]<0.001 2.27[ 2.16, 2.39]<0.001 2.31[ 2.20, 2.43]<0.001IMD(IMD-1 asreference)IMD-2 0.99[ 0.93, 1.06]0.823 0.99[ 0.92, 1.06]0.767 0.99[ 0.92, 1.06]0.708IMD-3 0.91[ 0.85, 0.98]0.009 0.91[ 0.85, 0.98]0.011 0.91[ 0.85, 0.98]0.009IMD-4 0.78[ 0.72, 0.84]<0.001 0.79[ 0.73, 0.85]<0.001 0.79[ 0.73, 0.85]<0.001IMD-5 0.75[ 0.69, 0.81]<0.001 0.76[ 0.70, 0.82]<0.001 0.77[ 0.72, 0.83]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, the lowest value isthe year closest to the index date. ### Page 14 15Full results of multivariable conditional logistic regression model for Erectile dysfunctionprescriptions.Years before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PErectile dysfunctionprescriptions6.38[ 4.99, 8.15]<0.001 3.69[ 2.89, 4.72]<0.001 2.79[ 2.10, 3.69]<0.001IMD(IMD-1 as reference)IMD-2 1.26[ 1.09, 1.46]0.001 1.24[ 1.07, 1.43]0.003 1.26[ 1.09, 1.45]0.002IMD-3 1.15[ 0.99, 1.33]0.061 1.13[ 0.98, 1.31]0.093 1.15[ 0.99, 1.32]0.064IMD-4 0.82[ 0.70, 0.95]0.009 0.82[ 0.71, 0.96]0.011 0.83[ 0.72, 0.97]0.017IMD-5 0.86[ 0.73, 1.00]0.054 0.87[ 0.74, 1.01]0.066 0.87[ 0.75, 1.01]0.077OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, the lowest value isthe year closest to the index date. ### Page 15 8Supplementary Table S5. Results of multivariable conditional logisticregression models for 7 prescriptions (first prescription, 5-yearregistration)Years before the index date 0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PAnti-anxiety/depressionprescriptions5.93[ 5.40, 6.51]<0.001 2.84[ 2.62, 3.08]<0.001 1.90[ 1.78, 2.03]<0.001Migraine prescriptions 3.95[ 3.19, 4.88]<0.001 2.82[ 2.38, 3.34]<0.001 2.03[ 1.76, 2.33]<0.001Lower urinary tractsymptoms relatedprescriptions7.27[ 6.16, 8.58]<0.001 4.50[ 3.83, 5.30]<0.001 3.26[ 2.79, 3.81]<0.001Urinary tract infectionstreatments relatedprescriptions2.45[ 2.20, 2.72]<0.001 1.73[ 1.61, 1.87]<0.001 1.52[ 1.43, 1.60]<0.001Sleeping disorderprescriptions4.32[ 3.86, 4.84]<0.001 2.57[ 2.32, 2.84]<0.001 1.98[ 1.82, 2.15]<0.001Gastrointestinalprescriptions3.75[ 3.33, 4.23]<0.001 2.47[ 2.24, 2.72]<0.001 1.77[ 1.63, 1.92]<0.001Erectile dysfunctionprescriptions7.91[ 5.50,11.39]<0.001 4.00[ 2.93, 5.45]<0.001 2.69[ 1.99, 3.65]<0.001OR: Odds ratio, P: P-value, CI: confidence interval, IMD= index of multiple deprivation, the lowest value is theyear closest to the index date. ### Page 16 16Supplementary Table S6. Full results of multivariable conditionallogistic regression models (first prescription, 5-year registration).Full results of multivariable conditional logistic regression model for Anxiety/depressionprescriptionsYears before the indexdate0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PAnti-anxiety/depressionprescriptions5.93[ 5.40, 6.51]<0.001 2.84[ 2.62, 3.08]<0.001 1.90[ 1.78, 2.03]<0.001Sex(Male as reference)2.40[ 2.28, 2.52]<0.001 2.36[ 2.25, 2.48]<0.001 2.35[ 2.24, 2.47]<0.001IMD(IMD-1 as reference)IMD-2 1.00[ 0.93, 1.07]0.895 1.00[ 0.93, 1.07]0.998 0.99[ 0.93, 1.06]0.843IMD-3 0.92[ 0.86, 0.99]0.023 0.92[ 0.86, 0.99]0.029 0.91[ 0.85, 0.98]0.012IMD-4 0.80[ 0.74, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001 0.79[ 0.74, 0.85]<0.001IMD-5 0.79[ 0.73, 0.85]<0.001 0.79[ 0.73, 0.85]<0.001 0.78[ 0.72, 0.84]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 17 17Full results of multivariable conditional logistic regression model for Migraine relatedprescriptionsYears before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PMigraineprescriptions3.95[ 3.19, 4.88]<0.001 2.82[ 2.38, 3.34]<0.001 2.03[ 1.76, 2.33]<0.001Sex(Male as reference)2.39[ 2.28, 2.52]<0.001 2.39[ 2.28, 2.51]<0.001 2.39[ 2.28, 2.51]<0.001IMD(IMD-1 as reference)IMD-2 1.00[ 0.93, 1.07]0.907 1.00[ 0.94, 1.07]0.954 1.00[ 0.93, 1.07]0.977IMD-3 0.92[ 0.86, 0.99]0.020 0.93[ 0.86, 0.99]0.029 0.92[ 0.86, 0.99]0.020IMD-4 0.80[ 0.75, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001IMD-5 0.79[ 0.74, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 18 18Full results of multivariable conditional logistic regression model for Lower urinary tractsymptoms related prescriptionYears before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PLower urinary tractsymptoms relatedprescriptions7.27[ 6.16, 8.58]<0.001 4.50[ 3.83, 5.30]<0.001 3.26[ 2.79, 3.81]<0.001Sex(Male as reference)2.45[ 2.34, 2.58]<0.001 2.44[ 2.32, 2.56]<0.001 2.44[ 2.32, 2.56]<0.001IMD(IMD-1 as reference)IMD-2 1.01[ 0.94, 1.08]0.845 1.00[ 0.93, 1.07]0.931 1.00[ 0.93, 1.07]0.958IMD-3 0.92[ 0.86, 0.99]0.024 0.92[ 0.85, 0.98]0.015 0.92[ 0.86, 0.99]0.023IMD-4 0.80[ 0.74, 0.86]<0.001 0.79[ 0.74, 0.85]<0.001 0.80[ 0.75, 0.86]<0.001IMD-5 0.80[ 0.74, 0.86]<0.001 0.79[ 0.73, 0.85]<0.001 0.80[ 0.74, 0.86]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 19 19Full results of multivariable conditional logistic regression model for Urinary tract infectionstreatments related prescriptionsYears before the indexdate0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PUrinary tract infectionstreatments relatedprescriptions2.45[ 2.20, 2.72]<0.001 1.73[ 1.61, 1.87]<0.001 1.52[ 1.43, 1.60]<0.001Sex(Male as reference)2.42[ 2.30, 2.54]<0.001 2.41[ 2.29, 2.53]<0.001 2.38[ 2.26, 2.50]<0.001IMD(IMD-1 as reference)IMD-2 1.00[ 0.94, 1.07]0.960 1.00[ 0.93, 1.07]0.917 1.00[ 0.93, 1.07]0.965IMD-3 0.92[ 0.86, 0.99]0.022 0.92[ 0.86, 0.99]0.025 0.92[ 0.86, 0.99]0.024IMD-4 0.80[ 0.75, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001IMD-5 0.80[ 0.74, 0.86]<0.001 0.79[ 0.74, 0.85]<0.001 0.80[ 0.74, 0.86]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 20 20Full results of multivariable conditional logistic regression model for Sleeping disorderrelated prescriptionsYears before the indexdate0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PSleeping disorderprescriptions4.32[ 3.86, 4.84]<0.001 2.57[ 2.32, 2.84]<0.001 1.98[ 1.82, 2.15]<0.001Sex(Male as reference)2.39[ 2.27, 2.51]<0.001 2.39[ 2.28, 2.51]<0.001 2.40[ 2.28, 2.52]<0.001IMD(IMD-1 as reference)IMD-2 1.00[ 0.93, 1.07]0.983 1.00[ 0.94, 1.07]0.945 1.00[ 0.93, 1.07]0.996IMD-3 0.92[ 0.86, 0.99]0.024 0.92[ 0.86, 0.99]0.030 0.92[ 0.86, 0.99]0.024IMD-4 0.80[ 0.75, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001 0.80[ 0.74, 0.86]<0.001IMD-5 0.80[ 0.74, 0.86]<0.001 0.79[ 0.73, 0.85]<0.001 0.79[ 0.73, 0.85]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 21 21Full results of multivariable conditional logistic regression model for Gastrointestinalprescriptions.Years before the indexdate0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PGastrointestinalprescriptions3.75[ 3.33, 4.23]<0.001 2.47[ 2.24, 2.72]<0.001 1.77[ 1.63, 1.92]<0.001Sex(Male as reference)2.40[ 2.29, 2.53]<0.001 2.37[ 2.26, 2.49]<0.001 2.37[ 2.26, 2.49]<0.001IMD(IMD-1 as reference)IMD-2 1.00[ 0.93, 1.07]0.995 1.00[ 0.93, 1.07]0.916 0.99[ 0.93, 1.06]0.823IMD-3 0.92[ 0.86, 0.99]0.022 0.92[ 0.86, 0.99]0.019 0.92[ 0.85, 0.98]0.014IMD-4 0.79[ 0.74, 0.85]<0.001 0.80[ 0.74, 0.86]<0.001 0.79[ 0.74, 0.85]<0.001IMD-5 0.79[ 0.73, 0.85]<0.001 0.78[ 0.73, 0.84]<0.001 0.78[ 0.73, 0.85]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 22 22Full results of multivariable conditional logistic regression model for Erectile dysfunctionprescriptions.Years before the indexdate0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PErectile dysfunctionprescriptions7.91[ 5.50, 11.39]<0.001 4.00[ 2.93, 5.45]<0.001 2.69[ 1.99, 3.65]<0.001IMD(IMD-1 as reference)IMD-2 1.28[ 1.11, 1.47]<0.001 1.24[ 1.07, 1.43]0.003 1.26[ 1.09, 1.45]0.001IMD-3 1.16[ 1.00, 1.34]0.049 1.13[ 0.98, 1.31]0.099 1.15[ 0.99, 1.32]0.064IMD-4 0.83[ 0.72, 0.97]0.018 0.82[ 0.70, 0.95]0.008 0.83[ 0.71, 0.97]0.016IMD-5 0.88[ 0.75, 1.02]0.099 0.87[ 0.75, 1.02]0.082 0.87[ 0.75, 1.02]0.085OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, the lowestvalue is the year closest to the index date. ### Page 23 44Supplementary Information S1. Translated Poisson results (5-yearregistration)All prescriptions:Anxiety/depression: 9-12 months (95% CI = 3 to 18)Migraine: 63-66 months (95% CI = 27 to 102)Lower urinary tract symptoms: 69-72 months (95% CI = 30 to 111)Urinary tract infection: 66-69 months (95% CI = 45 to 90)Sleep disorder: 6-9 months (95% CI = -12 to 27)Gastrointestinal symptoms: 69-72 months (95% CI = 51 to 90)Erectile dysfunction: 60-63 months (95% CI = 30 to 93)First prescription:Anxiety/depression: 6-9 months (95% CI = 3 to 12)Migraine: 9-12 months (95% CI = -54 to 75)Lower urinary tract symptoms: 6-9 months (95% CI = 0 to 15)Urinary tract infection: 63-66 months (95% CI = 54 to 75)Sleep disorder: 6-9 months (95% CI = 3 to 12)Gastrointestinal symptoms: 3-6 months (95% CI = -45 to 54)Erectile dysfunction: 3-6 months (95% CI = -66 to 75) ### Page 24 23Supplementary Table S7. Demographic characteristics incases/controls (10-year registration).AllparticipantsCases ControlsCharacteristics N % N % N %Total participants 42765 100 7018 16.41 35747 83.59Age at the index date (years)<30 4241 9.92 751 10.70 3490 9.7630-39 8424 19.70 1249 17.80 7175 20.0740-49 16010 37.44 2226 31.72 13784 38.5650-59 9919 23.19 1815 25.86 8104 22.6760-69 3086 7.22 751 10.70 2335 6.53≥70 1085 2.54 226 3.22 859 2.40SexMale 19738 46.15 2104 29.98 17634 49.33Female 23027 53.85 4914 70.02 18113 50.67IMDQuintile 1 (lowest quintile ofdeprivation)8659 20.25 1553 22.13 7106 19.88Quintile 2 8359 19.55 1516 21.60 6843 19.14Quintile 3 8029 18.77 1411 20.11 6618 18.51Quintile 4 8081 18.90 1278 18.21 6803 19.03Quintile 5 7167 16.76 1089 15.52 6078 17.00Missing (highest quintile ofdeprivation)2470 5.78 171 2.44 2299 6.43IMD= index of multiple deprivation, N=number, %=proportion. ### Page 25 24Supplementary Table S8. Proportion of cases and controls with a prescription record in each prescription category byage, sex and IMD (all prescriptions, 10-year registration).Anti-anxiety/depression prescriptionsMigraine / clusterheadache specificmedicationsLUTS relatedmedicationsUTI treatmentsrelatedmedicationsMedications forsleeping disorderGI medications Medications forEDControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)All participants 5626(15.74)3750(53.43)958(2.68)656(9.35)781(2,18)876(12.48)10818(30.26)4857(69.21)3188(8.92)1966(28.01)3575(10.00)2207(31.45)424(2.40)293(13.93)Age at the indexdate (years)<30 288(8.25)302(40.21)89(2.55)88(11.72)14(0.40)21(2.80)1037(29.71)525(69.91)135(3.87)114(15.18)307(8.80)202(26.90)5(0.27)5(2.09)30-39 796(11.09)646(51.72)133(1.85)146(11.69)31(0.43)67(5.36)1614(22.49)900(72.06)401(5.59)321(25.70)564(7.86)394(31.55)19(0.56)21(5.63)40-49 2069(15.01)1234(55.44)342(2.48)180(8.09)187(1.36)209(9.39)3767(27.33)1566(70.35)1185(8.60)675(30.32)1171(8.50)646(29.02)95(1.42)77(13.85)50-59 1724(21.27)1028(56.64)287(3.54)172(9.48)274(3.38)254(13.99)2938(36.25)1190(65.56)960(11.85)560(30.85)949(11.71)545(30.03)178(4.29)116(20.39)60-69 549(23.51)416(55.39)91(3.90)62(8.26)177(7.58)227(30.23)1034(44.28)511(68.04)362(15.50)233(31.03)357(15.29)305(40.61)95(7.95)56(19.65)>70 200(23.28)124(54.87)16(1.86)8(3.54)98(11.41)98(43.36)428(49.83)165(73.01)145(16.88)63(27.88)227(26.43)115(50.88)32(7.62)18(21.95)Sex ### Page 26 25Male 2050(11.63)916(43.54)208(1.18)80(3.80)402(2.28)326(15.49)4436(25.16)1186(56.37)1230(6.98)475(22.58)1199(6.80)478(22.72)424(2.40)293(13.93)Female 3576(19.74)2834(57.67)750(4.14)576(11.72)379(2.09)550(11.19)6382(35.23)3671(74.70)1958(10.81)1491(30.34)2376(13.12)1729(35.19)NA NAIMDQuintile11136(15.99)801(51.58)188(2.65)128(8.24)158(2.22)196(12.62)2331(32.80)1074(69.16)650(9.15)453(29.17)660(9.29)428(27.56)85(2.43)53(12.77)Quintile21097(16.03)788(51.98)191(2.79)132(8.71)162(2.37)200(13.19)2249(32.87)1020(67.28)631(9.22)421(27.77)713(10.42)457(30.15)95(2.79)73(14.81)Quintile31049(15.85)752(53.30)191(2.89)138(9.78)161(2.43)179(12.69)2005(30.30)982(69.60)592(8.95)388(27.50)677(10.23)423(29.98)84(2.57)60(13.67)Quintile41107(16.27)678(53.05)171(2.51)121(9.47)134(1.97)155(12.13)2081(30.59)890(69.64)604(8.88)337(26.37)700(10.29)444(34.74)68(2.04)43(12.18)Quintile51106(18.20)643(59.04)191(3.14)122(11.20)156(2.57)131(12.03)1877(30.88)782(71.81)632(10.40)321(29.48)741(12.19)396(36.36)87(2.84)57(16.43)Missing 131(5.70)88(51.46)26(1.13)15(8.77)10(0.43)15(8.77)275(11.96)109(63.74)79(3.44)46(26.90)84(3.65)59(34.50)5(0.47)7(12.28)ED= erectile dysfunction, GI= Gastrointestinal, LUTS= Lower urinary tract symptoms, UTI= Urinary tract infection, IMD= index of multiple deprivation,N=number, %=proportion, Quintile 1 (least deprived), Quintile 5 (most deprived). ### Page 27 26Supplementary Table S9. Proportion of cases and controls with a prescription record in each prescription category byage, sex and IMD (first prescription, 10-year registration).Anti-anxiety/depression prescriptionsMigraine / clusterheadache specificmedicationsLUTS relatedmedicationsUTI treatmentsrelatedmedicationsMedications forsleeping disorderGI medications Medications forEDControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)ControlsN (%)CasesN (%)All participants 3964(11.09)2580(36.76)750(2.10)521(7.42)706(1.97)798(11.37)6423(17.97)2328(33.17)2528(7.07)1526(21.74)2746(7.68)1567(22.33)385(2.18)267(12.69)Age at the indexdate (years)<30 275(7.88)289(38.48)74(2.12)81(10.79)12(0.34)21(2.80)482(13.81)213(28.36)125(3.58)111(14.78)259(7.42)164(21.84)5(0.27)5(2.09)30-39 582(8.11)476(38.11)111(1.55)118(9.45)29(0.40)64(5.12)982(13.69)453(36.27)351(4.89)279(22.34)440(6.13)300(24.02)18(0.53)21(5.63)40-49 1424(10.33)827(37.15)261(1.89)148(6.65)171(1.24)199(8.94)2263(16.42)755(33.92)954(6.92)551(24.75)876(6.36)441(19.81)89(1.33)72(12.95)50-59 1198(14.78)672(37.02)223(2.75)130(7.16)245(3.02)231(12.73)1806(22.29)566(31.18)741(9.14)395(21.76)721(8.90)379(20.88)163(3.93)109(19.16)60-69 354(15.16)240(31.96)68(2.91)39(5.19)161(6.90)198(26.36)644(27.58)266(35.42)258(11.05)154(20.51)289(12.38)206(27.43)84(7.03)42(14.74)>70 131(15.25)76(33.63)13(1.51)5(2.21)88(10.24)85(37.61)246(28.64)75(33.19)99(11.53)36(15.93)161(18.74)77(34.07)26(6.19)18(21.95) ### Page 28 27SexMale 1524(8.64)690(32.79)174(0.99)66(3.14)372(2.11)303(14.40)2905(16.47)668(31.75)1007(5.71)387(18.39)994(5.64)384(18.25)385(2.18)267(12.69)Female 2440(13.47)1890(38.46)576(3.18)455(9.26)334(1.84)495(10.07)3518(19.42)1660(33.78)1521(8.40)1139(23.18)1752(9.67)1183(24.07)NA NAIMDQuintile1820(11.54)542(34.90)150(2.11)94(6.05)151(2.12)177(11.40)1383(19.46)454(29.23)523(7.36)350(22.54)518(7.29)284(18.29)78(2.23)49(11.81)Quintile2786(11.49)547(36.08)146(2.13)111(7.32)143(2.09)183(12.07)1327(19.39)513(33.84)527(7.70)331(21.83)551(8.05)321(21.17)88(2.59)65(13.18)Quintile3748(11.30)537(38.06)158(2.39)107(7.58)147(2.22)165(11.69)1161(17.54)479(33.95)452(6.83)308(21.83)517(7.81)313(22.18)75(2.30)55(12.53)Quintile4777(11.42)456(35.68)126(1.85)101(7.90)117(1.72)144(11.27)1252(18.40)436(34.12)475(6.98)262(20.50)543(7.98)327(25.59)62(1.86)41(11.61)Quintile5736(12.11)431(39.58)150(2.47)95(8.72)139(2.29)115(10.56)1125(18.51)379(34.80)487(8.01)242(22.22)550(9.05)275(25.25)78(2.54)51(14.70)Missing 97(4.22)67(39.18)20(0.87)13(7.60)9(0.39)14(8.19)175(7.61)67(39.18)64(2.78)33(19.30)67(2.91)47(27.49)4(0.37)6(10.53)ED= erectile dysfunction, GI= Gastrointestinal, LUTS= Lower urinary tract symptoms, UTI= Urinary tract infection, IMD= index of multiple deprivation,N=number, %=proportion, Quintile 1 (least deprived), Quintile 5 (most deprived). ### Page 29 28Supplementary Table S10. Results of multivariable conditional logisticregression models for 7 prescriptions (all prescriptions, 10-yearregistration)OR: Odds ratio, P: P-value, CI: confidence interval, IMD= index of multiple deprivation, the lowestvalue is the year closest to the index date.Years before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PAnti-anxiety/depressionprescriptions6.85[ 6.33, 7.41]<0.001 4.20[ 3.89, 4.54]<0.001 2.89[ 2.69, 3.11]<0.001Migraineprescriptions3.65[ 3.03, 4.39]<0.001 2.96[ 2.49, 3.53]<0.001 2.38[ 2.04, 2.79]<0.001Lower urinary tractsymptoms relatedprescriptions7.18[ 6.15, 8.40]<0.001 4.96[ 4.19, 5.87]<0.001 3.65[ 3.02, 4.40]<0.001Urinary tractinfections treatmentsrelated prescriptions3.64[ 3.39, 3.92]<0.001 3.32[ 3.11, 3.55]<0.001 2.80[ 2.63, 2.98]<0.001Sleeping disorderprescriptions4.43[ 3.98, 4.92]<0.001 2.95[ 2.66, 3.28]<0.001 2.46[ 2.24, 2.71]<0.001Gastrointestinalprescriptions4.34[ 3.91, 4.81]<0.001 3.48[ 3.16, 3.85]<0.001 2.45[ 2.24, 2.67]<0.001Erectile dysfunctionprescriptions7.82[ 5.59, 10.93]<0.001 4.02[ 2.90, 5.59]<0.001 3.74[ 2.56, 5.46]<0.001 ### Page 30 29Supplementary Table S11. Results of multivariable conditional logisticregression models for 7 prescriptions (first prescription, 10-yearregistration)Years before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PAnti-anxiety/depressionprescriptions5.98[ 5.25, 6.80]<0.001 3.32[ 2.95, 3.73]<0.001 2.33[ 2.13, 2.55]<0.001Migraineprescriptions4.43[ 3.29, 5.98]<0.001 3.16[ 2.45, 4.07]<0.001 2.37[ 1.96, 2.86]<0.001Lower urinary tractsymptoms relatedprescriptions7.26[ 5.84, 9.01]<0.001 4.88[ 3.91, 6.09]<0.001 3.71[ 3.02, 4.56]<0.001Urinary tractinfections treatmentsrelated prescriptions2.73[ 2.33, 3.18]<0.001 2.02[ 1.80, 2.27]<0.001 1.68[ 1.55, 1.81]<0.001Sleeping disorderprescriptions4.48[ 3.83, 5.25]<0.001 2.91[ 2.52, 3.37]<0.001 2.32[ 2.07, 2.59]<0.001Gastrointestinalprescriptions3.91[ 3.31, 4.62]<0.001 3.03[ 2.63, 3.49]<0.001 2.10[ 1.89, 2.34]<0.001Erectile dysfunctionprescriptions11.05[ 6.37, 19.17]<0.001 4.29[ 2.81, 6.53]<0.001 4.16[ 2.74, 6.31]<0.001OR: Odds ratio, P: P-value, CI: confidence interval, IMD= index of multiple deprivation, the lowestvalue is the year closest to the index date. ### Page 31 30Supplementary Table S12. Full results of multivariable conditionallogistic regression models (all prescriptions, 10-year registration).Full results of multivariable conditional logistic regression model for Anxiety/depressionprescriptionsYears before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PAnti-anxiety/depressionprescriptions6.85[ 6.33, 7.41]<0.001 4.20[ 3.89, 4.54]<0.001 2.89[ 2.69, 3.11]<0.001Sex(Male as reference)2.03[ 1.90, 2.17]<0.001 2.11[ 1.98, 2.25]<0.001 2.18[ 2.04, 2.32]<0.001IMD(IMD-1 as reference)IMD-2 1.02[ 0.92, 1.12]0.742 1.03[ 0.94, 1.13]0.501 1.02[ 0.93, 1.12]0.671IMD-3 0.98[ 0.89, 1.08]0.747 1.01[ 0.92, 1.11]0.756 1.01[ 0.92, 1.10]0.908IMD-4 0.85[ 0.77, 0.94]0.001 0.87[ 0.79, 0.95]0.003 0.87[ 0.79, 0.95]0.003IMD-5 0.77[ 0.70, 0.86]<0.001 0.79[ 0.72, 0.88]<0.001 0.80[ 0.73, 0.89]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 32 31Full results of multivariable conditional logistic regression model for Migraine relatedprescriptionsYears before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PMigraineprescriptions3.65[ 3.03, 4.39]<0.001 2.96[ 2.49, 3.53]<0.001 2.38[ 2.04, 2.79]<0.001Sex(Male as reference)2.34[ 2.20, 2.49]<0.001 2.35[ 2.21, 2.50]<0.001 2.36[ 2.21, 2.51]<0.001IMD(IMD-1 asreference)IMD-2 1.03[ 0.95, 1.13]0.460 1.04[ 0.95, 1.13]0.405 1.03[ 0.94, 1.13]0.513IMD-3 1.02[ 0.93, 1.11]0.744 1.02[ 0.93, 1.11]0.695 1.01[ 0.93, 1.11]0.779IMD-4 0.88[ 0.81, 0.97]0.007 0.89[ 0.81, 0.97]0.009 0.88[ 0.80, 0.96]0.005IMD-5 0.84[ 0.76, 0.92]<0.001 0.84[ 0.77, 0.93]<0.001 0.84[ 0.76, 0.92]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 33 32Full results of multivariable conditional logistic regression model for Lower urinary tractsymptoms related prescriptionYears before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PLower urinary tractsymptoms relatedprescriptions7.18[ 6.15, 8.40]<0.001 4.96[ 4.19, 5.87]<0.001 3.65[ 3.02, 4.40]<0.001Sex(Male as reference)2.46[ 2.31, 2.62]<0.001 2.43[ 2.29, 2.59]<0.001 2.41[ 2.26, 2.56]<0.001IMD(IMD-1 as reference)IMD-2 1.03[ 0.94, 1.13]0.481 1.03[ 0.94, 1.12]0.570 1.03[ 0.94, 1.13]0.489IMD-3 1.01[ 0.92, 1.10]0.871 1.01[ 0.92, 1.10]0.875 1.02[ 0.93, 1.11]0.694IMD-4 0.87[ 0.80, 0.96]0.004 0.88[ 0.80, 0.96]0.005 0.88[ 0.81, 0.97]0.008IMD-5 0.84[ 0.76, 0.92]<0.001 0.84[ 0.76, 0.92]<0.001 0.85[ 0.77, 0.93]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 34 33Full results of multivariable conditional logistic regression model for Urinary tractinfections treatments related prescriptionsYears before the indexdate0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PUrinary tractinfections treatmentsrelated prescriptions3.64[ 3.39, 3.92]<0.001 3.32[ 3.11, 3.55]<0.001 2.80[ 2.63, 2.98]<0.001Sex(Male as reference)2.09[ 1.96, 2.23]<0.001 2.09[ 1.96, 2.22]<0.001 2.10[ 1.97, 2.24]<0.001IMD(IMD-1 as reference)IMD-2 1.04[ 0.95, 1.14]0.386 1.03[ 0.94, 1.13]0.543 1.04[ 0.95, 1.14]0.401IMD-3 1.03[ 0.94, 1.13]0.514 1.02[ 0.93, 1.12]0.697 1.03[ 0.94, 1.12]0.586IMD-4 0.87[ 0.79, 0.95]0.003 0.87[ 0.80, 0.96]0.005 0.89[ 0.81, 0.97]0.012IMD-5 0.83[ 0.75, 0.91]<0.001 0.83[ 0.75, 0.91]<0.001 0.86[ 0.78, 0.95]0.003OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 35 34Full results of multivariable conditional logistic regression model for Sleeping disorderrelated prescriptionsYears before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PSleeping disorderprescriptions4.43[ 3.98, 4.92]<0.001 2.95[ 2.66, 3.28]<0.001 2.46[ 2.24, 2.71]<0.001Sex(Male as reference)2.31[ 2.17, 2.46]<0.001 2.31[ 2.17, 2.46]<0.001 2.34[ 2.20, 2.49]<0.001IMD(IMD-1 as reference)IMD-2 1.04[ 0.95, 1.13]0.438 1.04[ 0.95, 1.14]0.378 1.04[ 0.95, 1.14]0.364IMD-3 1.00[ 0.92, 1.10]0.916 1.02[ 0.93, 1.11]0.725 1.03[ 0.94, 1.12]0.588IMD-4 0.88[ 0.81, 0.97]0.009 0.89[ 0.81, 0.97]0.009 0.89[ 0.81, 0.97]0.012IMD-5 0.83[ 0.75, 0.91]<0.001 0.83[ 0.75, 0.91]<0.001 0.84[ 0.76, 0.92]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, the lowestvalue is the year closest to the index date. ### Page 36 35Full results of multivariable conditional logistic regression model for Gastrointestinalprescriptions.Years before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PGastrointestinalprescriptions4.34[ 3.91, 4.81]<0.001 3.48[ 3.16, 3.85]<0.001 2.45[ 2.24, 2.67]<0.001Sex(Male as reference)2.27[ 2.13, 2.41]<0.001 2.26[ 2.12, 2.41]<0.001 2.26[ 2.13, 2.41]<0.001IMD(IMD-1 as reference)IMD-2 1.04[ 0.95, 1.14]0.386 1.01[ 0.93, 1.11]0.765 1.02[ 0.93, 1.12]0.644IMD-3 1.01[ 0.92, 1.11]0.838 1.00[ 0.91, 1.10]0.992 1.01[ 0.92, 1.10]0.850IMD-4 0.86[ 0.78, 0.94]0.001 0.86[ 0.78, 0.94]0.001 0.87[ 0.79, 0.95]0.003IMD-5 0.81[ 0.74, 0.89]<0.001 0.81[ 0.73, 0.89]<0.001 0.82[ 0.74, 0.90]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, the lowestvalue is the year closest to the index date. ### Page 37 36Full results of multivariable conditional logistic regression model for Erectile dysfunctionprescriptions.Years before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PErectile dysfunctionprescriptions7.82[ 5.59, 10.93]<0.001 4.02[ 2.90, 5.59]<0.001 3.74[ 2.56, 5.46]<0.001IMD(IMD-1 as reference)IMD-2 1.33[ 1.10, 1.61]0.004 1.31[ 1.09, 1.58]0.005 1.32[ 1.10, 1.60]0.004IMD-3 1.27[ 1.05, 1.55]0.016 1.25[ 1.04, 1.52]0.021 1.25[ 1.04, 1.52]0.020IMD-4 0.89[ 0.73, 1.09]0.273 0.90[ 0.74, 1.10]0.312 0.91[ 0.74, 1.10]0.327IMD-5 0.91[ 0.74, 1.12]0.374 0.94[ 0.76, 1.15]0.529 0.93[ 0.76, 1.14]0.501OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 38 37Supplementary Table S13. Full results of multivariable conditionallogistic regression models (first prescription, 10-year registration).Full results of multivariable conditional logistic regression model for Anxiety/depressionprescriptionsYears before the indexdate0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PAnti-anxiety/depressionprescriptions5.98[ 5.25, 6.80]<0.001 3.32[ 2.95, 3.73]<0.001 2.33[ 2.13, 2.55]<0.001Sex(Male as reference)2.40[ 2.26, 2.56]<0.001 2.36[ 2.22, 2.51]<0.001 2.33[ 2.19, 2.48]<0.001IMD(IMD-1 as reference)IMD-2 1.03[ 0.94, 1.13]0.495 1.03[ 0.94, 1.13]0.495 1.03[ 0.94, 1.13]0.518IMD-3 1.01[ 0.92, 1.11]0.843 1.02[ 0.94, 1.12]0.597 1.01[ 0.92, 1.10]0.900IMD-4 0.88[ 0.80, 0.96]0.006 0.88[ 0.80, 0.97]0.007 0.88[ 0.80, 0.96]0.006IMD-5 0.85[ 0.77, 0.93]<0.001 0.84[ 0.77, 0.93]<0.001 0.84[ 0.76, 0.92]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, the lowestvalue is the year closest to the index date. ### Page 39 38Full results of multivariable conditional logistic regression model for Migraine relatedprescriptionsYears before the indexdate0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PMigraineprescriptions4.43[ 3.29, 5.98]<0.001 3.16[ 2.45, 4.07]<0.001 2.37[ 1.96, 2.86]<0.001Sex(Male as reference)2.38[ 2.24, 2.53]<0.001 2.39[ 2.24, 2.54]<0.001 2.38[ 2.23, 2.53]<0.001IMD(IMD-1 as reference)IMD-2 1.03[ 0.95, 1.13]0.450 1.04[ 0.95, 1.14]0.376 1.03[ 0.94, 1.12]0.532IMD-3 1.02[ 0.93, 1.11]0.743 1.02[ 0.93, 1.12]0.641 1.01[ 0.93, 1.11]0.786IMD-4 0.88[ 0.81, 0.97]0.008 0.89[ 0.81, 0.97]0.008 0.88[ 0.80, 0.96]0.005IMD-5 0.84[ 0.77, 0.93]<0.001 0.85[ 0.77, 0.93]<0.001 0.84[ 0.76, 0.92]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 40 39Full results of multivariable conditional logistic regression model for Lower urinary tractsymptoms related prescriptionYears before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PLower urinary tractsymptoms relatedprescriptions7.26[ 5.84, 9.01]<0.001 4.88[ 3.91, 6.09]<0.001 3.71[ 3.02, 4.56]<0.001Sex(Male as reference)2.45[ 2.30, 2.61]<0.001 2.43[ 2.29, 2.59]<0.001 2.42[ 2.27, 2.57]<0.001IMD(IMD-1 as reference)IMD-2 1.04[ 0.95, 1.14]0.388 1.03[ 0.94, 1.13]0.516 1.03[ 0.95, 1.13]0.457IMD-3 1.02[ 0.93, 1.11]0.702 1.01[ 0.93, 1.11]0.797 1.02[ 0.93, 1.12]0.651IMD-4 0.88[ 0.81, 0.97]0.008 0.88[ 0.80, 0.96]0.005 0.89[ 0.81, 0.97]0.009IMD-5 0.84[ 0.77, 0.93]<0.001 0.84[ 0.76, 0.92]<0.001 0.85[ 0.77, 0.94]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 41 40Full results of multivariable conditional logistic regression model for Urinary tract infectionstreatments related prescriptionsYears before the indexdate0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PUrinary tractinfections treatmentsrelated prescriptions2.73[ 2.33, 3.18]<0.001 2.02[ 1.80, 2.27]<0.001 1.68[ 1.55, 1.81]<0.001Sex(Male as reference)2.42[ 2.27, 2.57]<0.001 2.41[ 2.27, 2.57]<0.001 2.38[ 2.23, 2.53]<0.001IMD(IMD-1 as reference)IMD-2 1.04[ 0.95, 1.13]0.439 1.02[ 0.94, 1.12]0.585 1.03[ 0.95, 1.13]0.476IMD-3 1.01[ 0.93, 1.11]0.753 1.02[ 0.93, 1.11]0.743 1.02[ 0.93, 1.11]0.729IMD-4 0.88[ 0.80, 0.96]0.006 0.88[ 0.80, 0.96]0.004 0.88[ 0.80, 0.96]0.005IMD-5 0.85[ 0.77, 0.93]<0.001 0.84[ 0.76, 0.92]<0.001 0.85[ 0.77, 0.93]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 42 41Full results of multivariable conditional logistic regression model for Sleeping disorderrelated prescriptionsYears before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PSleeping disorderprescriptions4.48[ 3.83, 5.25]<0.001 2.91[ 2.52, 3.37]<0.001 2.32[ 2.07, 2.59]<0.001Sex(Male as reference)2.39[ 2.25, 2.55]<0.001 2.38[ 2.23, 2.53]<0.001 2.38[ 2.24, 2.53]<0.001IMD(IMD-1 as reference)IMD-2 1.03[ 0.94, 1.12]0.533 1.04[ 0.95, 1.13]0.437 1.04[ 0.95, 1.14]0.366IMD-3 1.01[ 0.92, 1.11]0.819 1.02[ 0.93, 1.12]0.632 1.03[ 0.94, 1.12]0.573IMD-4 0.88[ 0.80, 0.96]0.006 0.88[ 0.81, 0.97]0.008 0.89[ 0.81, 0.97]0.012IMD-5 0.85[ 0.77, 0.94]<0.001 0.84[ 0.77, 0.93]<0.001 0.85[ 0.77, 0.93]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, the lowestvalue is the year closest to the index date. ### Page 43 42Full results of multivariable conditional logistic regression model for Gastrointestinalprescriptions.Years before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PGastrointestinalprescriptions3.91[3.31, 4.62]<0.001 3.03[ 2.63, 3.49]<0.001 2.10[ 1.89, 2.34]<0.001Sex(Male as reference)2.40[ 2.26, 2.56]<0.001 2.38[ 2.24, 2.54]<0.001 2.34[ 2.20, 2.49]<0.001IMD(IMD-1 as reference)IMD-2 1.04[ 0.95, 1.13]0.412 1.02[ 0.93, 1.12]0.640 1.03[ 0.94, 1.12]0.575IMD-3 1.02[ 0.93, 1.11]0.743 1.01[ 0.92, 1.10]0.899 1.01[ 0.93, 1.11]0.792IMD-4 0.87[ 0.80, 0.96]0.004 0.87[ 0.80, 0.95]0.003 0.87[ 0.80, 0.96]0.003IMD-5 0.84[ 0.76, 0.93]<0.001 0.83[ 0.76, 0.92]<0.001 0.83[ 0.76, 0.92]<0.001OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 44 43Full results of multivariable conditional logistic regression model for Erectile dysfunctionprescriptions.Years before theindex date0–2 years 2–5 years 5–10 yearsVariable OR [95%CI] P OR [95%CI] P OR [95%CI] PErectile dysfunctionprescriptions11.05[ 6.37, 19.17]<0.001 4.29[ 2.81, 6.53]<0.001 4.16[ 2.74, 6.31]<0.001IMD(IMD-1 as reference)IMD-2 1.34[ 1.11, 1.63]0.002 1.31[ 1.09, 1.58]0.005 1.33[ 1.10, 1.61]0.003IMD-3 1.27[ 1.05, 1.55]0.014 1.26[ 1.04, 1.52]0.019 1.26[ 1.04, 1.52]0.018IMD-4 0.92[ 0.75, 1.12]0.414 0.90[ 0.74, 1.10]0.324 0.91[ 0.74, 1.11]0.335IMD-5 0.94[ 0.77, 1.16]0.587 0.95[ 0.78, 1.16]0.614 0.94[ 0.77, 1.15]0.536OR: Odds ratio, P: P-value, CI: 95% confidence interval, IMD= index of multiple deprivation, thelowest value is the year closest to the index date. ### Page 45 45Supplementary Figure S1. Proportions of participants with aprescription in the 10 years before the index date for cases/controls(10-year registration).Years before index date: the lowest value is the year closest to the index date. ### Page 46 46Supplementary Figure S2. Rates of recordings, inflection points, and 95% CIfor infection points of each prescription category in the 10 years leading up todiagnosis (all prescriptions, 10-year registration)Inflection point is indicated by a solid vertical line, shaded area indicates 95% confidence interval.Each period covers 3-months. The lowest value is the period closest to diagnosis. CI: confidenceinterval.Period:Anxiety/depression: period 5 (95% CI = 3.30 to 6.70)Migraine: period 9 (95% CI = -13.98 to 31.98)Lower urinary tract symptoms: period 32 (95% CI = 3.93 to 60.07)Urinary tract infection: period 2 (95% CI = -1.86 to 5.86)Sleep disorder: period 8 (95% CI = -1.50 to 17.50)Gastrointestinal symptoms: period 24 (95% CI = 5.60 to 42.40)Erectile dysfunction: period 22 (95% CI = 10.63 to 33.37)Month:Anxiety/depression: 12-15 months (95% CI = 6 to 21)Migraine: 24-27 months (95% CI = -45 to 96)Lower urinary tract symptoms: 93-96 months (95% CI = 6 to 183) ### Page 47 47Urinary tract infection: 3-6 months (95% CI = -9 to 18)Sleep disorder: 21-24 months (95% CI = -9 to 54)Gastrointestinal symptoms: 69-72 months (95% CI = 12 to 129)Erectile dysfunction: 63-66 months (95% CI = 27 to 102) ### Page 48 48Supplementary Figure S3. Rates of recordings, inflection points, and 95%CI for infection points of each prescription category in the 10 years leading up todiagnosis (first prescription, 10-year registration)Inflection point is indicated by a solid vertical line, shaded area indicates 95% confidence interval.Each period covers 3-months. The lowest value is the period closest to diagnosis. CI: confidenceinterval.Period:Anxiety/depression: period 4 (95% CI = 3.00 to 5.00)Migraine: period 4 (95% CI = -12.23 to 20.23)Lower urinary tract symptoms: period 5 (95% CI = 0.81 to 9.19)Urinary tract infection: period 2 (95% CI = -19.54 to 23.54)Sleep disorder: period 6 (95% CI = 2.15 to 9.85)Gastrointestinal symptoms: period 4 (95% CI = 1.75 to 6.25)Erectile dysfunction: period 39 (95% CI = 12.32 to 65.68)Month:Anxiety/depression: 9-12 months (95% CI = 6 to 15)Migraine: 9-12 months (95% CI = -42 to 63)Lower urinary tract symptoms: 12-15 months (95% CI = -3 to 30) ### Page 49 49Urinary tract infection: 3-6 months (95% CI = -63 to 72)Sleep disorder: 15-18 months (95% CI = 3 to 30)Gastrointestinal symptoms: 9-12 months (95% CI = 0 to 21)Erectile dysfunction: 114-117 months (95% CI = 33 to 198) ### Page 50 50References1. Jacobs BM, Tank P, Bestwick JP, et al. Modifiable risk factors for multiplesclerosis have consistent directions of effect across diverse ethnic backgrounds: anested case–control study in an English population-based cohort. J Neurol 2024;271(1):241-253. doi: 10.1007/s00415-023-11971-0.2. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria formultiple sclerosis: guidelines from the International Panel on the diagnosis of multiplesclerosis. Ann Neurol 2001; 50(1):121-127. doi: 10.1002/ana.1032.