. 2021 Nov 22;2021(11):CD004407. doi: 10.1002/14651858.CD004407.pub5

19. Safety: idiopathic thrombocytopenic purpura.

Study ID and design	Population	Outcome definition	Exposure MMR/MMRV vaccine	Findings	Crude data	Estimate (95% CI)
bb‐Black 2003 Nested case‐control study	Cases: n = 23 children with outcome of interest at 12 to 23 months, between 1988 and 1999, GPRD members. Controls: n = 116 participants matching for index date (age), sex, practice. Nested case–control analysis to evaluate whether there was any relationship between recent MMR vaccination and the risk of ITP. Because the data were sparse, the authors grouped case–control sets by 3‐month age bands (13 to 15 months, 16 to 18 months, and so on). In addition, they included boys and girls in sets together because childhood ITP is reported to occur with equal frequency amongst both sexes, and because preliminary analysis of their data showed no evidence for a predominance of cases amongst either sex. The risk ratio of ITP during the specified time periods after MMR vaccination was estimated as the odds ratio using conditional logistic regression.	Idiopathic thrombocytopenic purpura GPRD electronic records with first‐time diagnosis of thrombocytopenia (ICD‐9 code 287.1)	MMR vaccine: not reported. Data about MMR vaccination were presumably obtained from GPRD records (type and composition not reported). The authors referred to ITP cases that occurred within 6 weeks after an MMR vaccine as "possible vaccine‐related"; this is a plausible period of risk related to a primary immune response. They also evaluated the risk of ITP during a longer period after MMR vaccination (7 to 26 weeks). Risk time following MMR immunisation (a) 0 to 6 weeks (b) 7 to 26 weeks (c) 0 to 26 weeks Reference time unexposed MMR or > 26 weeks after MMR	Authors' conclusion: "Although ITP is one of the most frequently diagnosed haematological disorders amongst young children, it is an uncommon condition. The risk of ITP occurring within the 6 weeks after vaccination with MMR is significantly increased. However, the attributable risk of ITP within 6 weeks after MMR vaccination remains low at 1 in 25,000" (95% CI 21,300 to 89,400) "vaccinated children. Complications or long‐term consequences of ITP in this age group are rare. For the majority of children less than 6 years of age, the illness is self‐limiting."	N cases vaccinated/ N cases versus N controls vaccinated/ N controls Data reported in the study: (a) 8/17 versus 19/84 (b) 6/15 versus 32/97 (c) 14/23 versus 51/116	OR (95% CI) unadjusted estimates (a) 3.04 (1.03 to 8.96) (b) 1.35 (0.44 to 4.14) (c) 1.98 (0.79 to 4.95) computed from the data reported in the study. ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ adjusted estimates() (a) 6.3 (1.3 to 30.1) (b) 1.5 (0.4 to 4.8) () logistic regresson
bb‐Bertuola 2010 Case‐control study	Cases: n = 387 children aged 1 month to 18 years, hospitalised at emergency department with outcome of interest between November 1999 and September 2007, with outcome of interest. Controls: n = 1924 children of same age interval hospitalised at emergency department for acute neurological disorders or endoscopically confirmed gastroduodenal lesions	Acute immune thrombocytopenia Platelets count < 100,000/μL at admission. Participants with following conditions were excluded: cancer, immunodeficiency, chronic renal and hepatic failure, so as acute events related to a reactivation of an underlying chronic disease or a congenital anomaly Hospitalisation (emergency department) records review	Not reported. Exposure to the vaccine (and other drugs) was assessed during hospital admission by means of interview with parents. 0 to 6 weeks following MMR immunisation	Authors' conclusion: the study confirms an association between MMR vaccination and ITP. As the risk of ITP after vaccination is smaller than after natural infection with these viruses, it is clear that the benefit of vaccination programmes greatly exceed the significance of this possible adverse effect. Although thrombocytopenia is initially severe, the subsequent course is generally benign and short‐lasting.	N cases vaccinated/ N cases versus N controls vaccinated/ N controls 14/387 versus 27/1924	*OR (95% CI)()** 2.4 (1.2 to 4.7) (*) adjusted estimates by logistic regression
db‐France 2008 Self‐controlled case series	Children (n = 63) aged 12 to 23 months with ITP identified from versusD database for the years 1991 to 2000, who had been vaccinated with MMR whilst actively enrolled in their respective MCOs. For each child, follow‐up time was limited to the 365 days before and after MMR vaccination. Vaccinated children with ITP that occurred outside this follow‐up window were excluded.	Immune thrombocytopenia purpura Participants with 2 platelet counts ≤ 50,000/μL within 6‐week period or with 1 platelets count ≤ 50,000/μL associated with ICD‐9 diagnosis codes 287.0 to 287.9 within 6 weeks, with exclusion of: cases of thrombocytopenia from a known condition (neonatal thrombocytopenia, aplastic anaemia, defibrination syndrome, acquired haemolytic anaemia, chronic liver disease, malignant neoplasm), thrombocytopenia diagnosed within the 30th day of life. By subsequent patient chart reviews, participants who did not have not have ITP, who had drug exposure, with acute illness, or with serendipitous finding during routine care were further excluded.	MMR vaccine: not reported MMR vaccination date assessed by means of separate audit of patient charts. Exposed period: 42 days after MMR vaccination Unexposed period: defined as the time periods before and after the exposed period. Period of 6 weeks immediately preceding MMR vaccination was excluded from analysis (because this represents a period when a child is most likely to be healthy (the healthy‐vaccinee) and may underestimate the background incidence of ITP)	Authors' conclusion: since its introduction in the 1960s, the MMR vaccine has reduced the incidence of wild‐type measles by nearly 100% in the USA. Although this vaccine is associated with an increased incidence of ITP, the attributable risk is low (1 case per 40,000 doses of MMR), and the disease associated with MMR vaccination is mild and resolves, on average, within 7 days. Our results, therefore, do not suggest a need to alter current immunisation policies.	Age groups (a) 12 to 23 months (b) 12 to 15 months	*rr (95% CI)() Self‐controlled case series** (a) 5.38 (2.72 to 10.62) (b) 7.06 (1.95 to 25.88) () conditional Poisson regression controlled by age in three 4‐month age groupings (12 to 15, 16 to 19, 20 to 23 months) and excluding fixed covariate from the model (gender, MCO, MMR dose number) ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ Person‐time cohort()* (a) 3.94 (2.01 to 7.69) (b) 7.10 (2.03 to 25.03) (**) Poisson regression model controlled for age, MMR dose number, MCO site, and gender
db‐Farrington 1995 Self‐controlled case series	Children aged 12 to 24 months discharged from hospital in 5 districts in England (Ashford, Leicester, Nottingham, Preston, and Chorley & Ribble) for varying periods between October 1988, and February 1993. Readmissions within 72 h with the same diagnosis were counted as 1 episode. n = 952 children	Idiopatric thrombocytopenic purpura (ICD 287.3) children aged between 366 and 730 days	MMR vaccine: Urabe mumps strain Jeryl Lynn mumps strain Rubella strain not specified Exposure risk period: (a1) 6 to 11 days (1 to 2 weeks after vaccination) (a2) 15 to 35 days (3 to 5 weeks after vaccination) Control period: (b) for each vaccine was defined as the time not included in a risk period. The analyses were adjusted for age and were grouped in 6 equal intervals of about 2 months.	Authors' conclusion: we demonstrated a causal association between ITP and MMR vaccination, with an absolute risk of 1 in 24,000 doses and an attributable risk of 1 in 29,000 doses.	Any strain (a1) 0 cases (a2) 4 cases	*rr (95% CI)()** (a2) 6.44 (1.94 to 21.4) (*) Poisson regression
db‐Andrews 2012 Self‐controlled case series	Multicountry collaboration (England and Denmark) study. The chosen study population was children aged 12 to 23 months (365 to 732 days).	Thrombocytopenic purpura The case definition for TP was based only on the presence of a relevant ICD‐10 code (D69.3) or ICD‐8 code (287.10) in 1 of the diagnostic discharge fields. First episodes were defined as the earliest record found for an individual, further episodes were initially required to be at least 14 days since a previous episode (to prevent double counting of episodes). In England cases (based on ICD‐10) occurring between 1 April 1996 and 31 March 2007 were linked using NHS number or gender/date of birth/postcode to immunisation records. In Denmark the Central Person Registry (CPR) was used to construct a nationwide cohort consisting of all Danish children born in the period 1 January 1990 to 31 December 2007 (∼1.2 million children).	MMR vaccine: not described Risk periods: (post‐MMR) (a) 0 to 13 days (b) 14 to 27 days (c) 28 to 42 days (d) 0 to 42 days Reference period pre‐vaccination (e) −7 to −1 days (to allow for a vaccination being delayed if the child was ill)	Authors' conclusion: this study gave consistent estimates of the relative incidence of TP following MMR vaccination in 1‐year‐olds. The 95% CI for the attributable risk of TP can be calculated based on the 95% CI for the relative incidence and gives an interval of 1 in 74,000 to 1 in 40,000 doses.	(a) 12 cases (b) 26 cases (c) 17 cases (d) 55 cases	*rr (95% CI)()** (a) 1.30 (0.71 to 2.38) (b) 2.87 (1.85 to 4.46) (c) 1.81 (1.07 to 3.05) (d) 1.98 (1.41 to 2.78) (*) adjusting for age, period, country, and country‐age interaction
db‐O'Leary 2012 Self‐controlled case series	Children < 18 years old (confirmed ITP cases) who had been vaccinated while actively enrolled in their respective health plans. This investigation was conducted in 5 healthcare systems (Kaiser Permanente: Colorado, Hawaii, Georgia, Northern California, and Harvard Vanguard Medical Associates) by using data from the years 2000 to 2009.	Thrombocytopenic purpura Case was defined as a child aged 6 weeks to 18 years with a platelet count of ≤ 50,000/μL, with normal red and white blood cell indices, and the presence of clinical signs and symptoms of ITP, such as petechiae, significant bruising, or spontaneous bleeding.	MMR, MMRV vaccine: not described Follow‐up time: 365 days before and after vaccination. Exposed period: 1 to 42 days after vaccination for all vaccines. Unexposed period: defined as the time before and after the exposed period within 365 days of follow‐up before or after vaccination. Day 0 (the day of vaccination) was excluded, because any cases occurring at this time were most likely coincidental.	Authors' conclusion: none of the routine childhood vaccines given in the first year of life was significantly associated with an increased risk of ITP. For vaccines routinely administered at 12 to 19 months of age, there was a significant association of ITP with MMR. There was no increased risk of ITP (calculated when not given simultaneously with MMR or MMRV). There were 1.9 cases of ITP per 100,000 doses of MMR.	Exposed cases versus unexposed cases (a) 12 to 19 months (a1) MMR: 6 versus 5 (a2) MMRV: 4 versus 6 (b) 4 to 6 years (b1) MMR: 2 versus 7 (b2) MMRV: 0 versus 5 (c) 11 to 17 years (c1) MMR: 0 versus 1	rr (95% CI) (a1) 5.48 (1.61 to 18.64) (a2) 2.87 (0.78 to 10.56) (b1) 3.06 (0.42 to 22.30) (b2) not estimable (c1) not estimable
db‐Perez‐Vilar 2018 Self‐controlled case series	For this study, WHO selected 26 sentinel sites (49 hospitals) distributed in 16 countries of the 6 WHO regions. The study population included children aged 9 to 23 months admitted to a network‐participating hospital during January 2010 to March 2014, with a discharge diagnosis of either aseptic menigitis or immune thrombocytopenic purpura.	Immune thrombocytopenia ICD‐9 codes in first discharge diagnosis position: 287.30 to 287.39 Primary thrombocytopenia 287.41 to 287.49 Secondary thrombocytopenia 287.5 Thrombocytopenia, unspecified ICD‐10 codes in first discharge diagnosis position: D69.3, D69.4 (D69.41 to D69.43) Primary thrombocytopenia D69.5 (D69.51, D69.59) Secondary thrombocytopenia D69.6 Thrombocytopenia, unspecified	Vaccine (measle strain) (mumps strain) Priorix, GSK (Schwarz) (RIT 4385a) Priorix Tetra, GSK (Schwarz) (RIT 4385a) MMR Shanghai Institute (Shanghai‐191) (S79) Measles, Lanzhou Institute (Shanghai‐191) (–) Measles‐Rubella, Beijing Tiantan (Shanghai‐191) (–) M‐M‐R‐II, MSD (Enders’ Edmonston) (Jeryl Lynn (Level B)) MMR, Razi Vaccine and Serum Research (AIK‐C) (Hoshino) M‐M‐RVAXPRO, Sanofi Pasteur‐MSD (Enders’ Edmonston) (Jeryl Lynn (Level B)) Trimovax, Sanofi Pasteur (Schwarz) (Urabe AM9) Measles, Serum Institute of India Pvt. (Edmonston‐Zagreb) (–) Measles‐Rubella, Serum Institute of India Pvt. (Edmonston‐Zagreb) (–) MMR, Serum Institute of India (Edmonston‐Zagreb) (Leningrad‐Zagreb) Tresivac, Serum Institute of India (Edmonston‐Zagreb) (Leningrad‐Zagreb) Rouvax, Sanofi Pasteur (Schwarz) (–) Risk period 8 to 35 days Washout periods 1 to 7 days 36 to 42 days Control period 43 to 84 days	The elevated risk of ITP following measles‐containing vaccination is consistent with the literature (db‐O'Leary 2012: db‐France 2008). Our strain‐specific unadjusted analysis showed a significantly elevated ITP risk for measles vaccines containing the Schwarz, Edmonston‐Zagreb, and Enders’ Edmonston strains. No risk of ITP was identified in Iran, which reported the concurrent distribution of 3 vaccine products including the AIK‐C, Edmonston‐Zagreb, and Schwarz strains, without distinguishing between them.	In 16 countries n = 183 ITP cases ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ (risk versus control) period (a) overall (36 versus 12) (b) overall (excluding Iran) (36 versus 8) (c) AIK‐C/Edmonston‐Zagreb/Schwarz (2 versus 5) (d) Edmonston‐Zagreb (7 versus 1) (e) Enders' Edmonston (11 versus 3) (f) Schwarz (14 versus 1) (g) Shanghai‐191 (0 versus 1)	rr (95% CI) adjusted (a) 5.6 (2.7 to 11.9) (b) 9.1 (3.7 to 22.3) (c) 0.54 (0.08 to 3.6) (d) 8.4 (0.7 to 100.3) (e) 28.7 (1.9 to 443.5) rr (95% CI) unadjusted (f) 20.7 (2.7 to 157.6) (g) not estimable
eb‐Lafaurie 2018 Case cross‐over	Population‐based study in France including all children newly diagnosed for primary ITP between July 2009 and June 2015. n = 2549	Immune thrombocytopenia	MMR vaccine: not described Exposed period 6‐week interval immediately preceding the event (frequency of exposure to vaccines) Control period (1) 6 weeks, 6 months before (2) 6 weeks, 3 months before the case period	Conclusion: in this nationwide study, no significant risk was observed for vaccines against DTP, pneumococcus, meningococcus, and HBV. The increased risk of MMR‐induced ITP is shown in children (previously demonstrated as lower than after the natural infection with measles). Vaccine‐induced ITP remains an exceptional adverse drug reaction, including for MMR vaccines. The numbers of attributable cases per million MMR doses dispensed were 9.8.	n = 492 patients included in analysis	OR (95% CI) 1.62 (1.21 to 2.16)
gb‐Jonville‐Bera 1996 Case‐only ecological study	Pharmacovigilance reports: case observed after vaccine administration between 1984 and 30 June 1992 (n = 60). Estimated number of administered vaccine doses was 9,205,483.	Thrombocytopenic purpura Acute haemorrhagic syndrome associated with platelet count of < 100,000/mm³, all cases within 45 days of vaccination, over 8‐year period	MMR vaccine: (a) ROR, Trimovax (measles Schwarz strain, mumps Urabe AM9 strain, rubella Wistar RA 27/3 M strain) Other measles‐containing vaccines: (b) Rouvax (measles Schwarz strain) (c) Rudi‐Rouvax (measles Schwarz strain, rubella Wistar RA 27/3 M strain) Other vaccine: (d) Rudivax (rubella Wistar RA 27/3 M strain) + DTbis (e) Rudivax (rubella Wistar RA 27/3 M strain, diptheria, tetanus) (e) Imovax Oreillons (mumps Urabe AM9 strain) 2 to 45 days following immunisation	Authors' conclusion: according to the clinical course and biologic findings, vaccine‐associated TP appears to be similar to that occurring after natural measles or rubella infections and is not distinguishable from acute childhood idiopathic thrombocytopenic purpura not associated with vaccination. Such observation, combined with a clear temporal relationship between MMR vaccination and occurrence of TP, make a causal relationship highly plausible. Nevertheless, the incidence of these events remains relatively low with a favourable immediate outcome.	Case/doses (a) 42/4,396,645 ‐‐‐ (b) 2/860,938 (c) 12/1,480,058 ‐‐‐ (d) 4/2,295,307 (e) 0/172,535	*Incidence x 100,000 doses (95% CI)()** (a) 0.96 (0.71 to 1.29) ‐‐‐ (b) 0.23 (0.06 to 0.85) (c) 0.81 (0.46 to 1.42) ‐‐‐ (d) 0.17 (0.07 to 0.45) (e) 0.00 (0.00 to 2.23) (*) confidence intervals were recomputed by Wilson 1927 method.

CI: confidence interval DTP: diphtheria, tetanus, and pertussis GPRD: General Practice Research Database HMO: health maintenance organisation HPV: human papillomavirus ICD: International Classification of Diseases ITP: idiopathic thrombocytopenic purpura MCOs: Managed Care Organizations MMR: measles, mumps, rubella vaccine MMRV: measles, mumps, rubella, and varicella vaccine OR: odds ratio PT: person‐time rr: rate ratio (relative incidence, incidence rate ratio) incidence: cases/PT RR: risk ratio (relative risk) TP: thrombocytopenic purpura WHO: World Health Organization