Risk of Seizures following Measles Containing Vaccination in Children Born Preterm or Full-term

Transcription

1 Risk of Seizures following Measles Containing Vaccination in Children Born Preterm or Full-term David L. McClure HSCRN 2018 Annual Meeting 1

2 Acknowledgements Co-authors Huong McLean Steven Jacobsen Nicola Klein Allison Naleway Elyse Kharbanda Jason Glanz Lisa Jackson Eric Weintraub Marshfield Clinic Research Institute, Marshfield WI Kaiser Permanente Department of Research and Evaluation, Pasadena CA Kaiser Permanente Vaccine Study Center, Oakland CA Kaiser Permanente Center for Health Research, Portland OR HealthPartners Institute, Minneapolis, MN Kaiser Permanente Institute for Health Research, Denver CO Kaiser Permanente Washington Health Research Institute, Seattle WA Centers for Disease Control and Prevention, Immunization Safety Office, Atlanta GA VSD study site project and data management staff 2

3 Disclosure Statement AN receives research support from Pfizer, Merck, and MedImmune (now AstraZeneca) for unrelated studies NK receives research support from GlaxoSmithKline, Sanofi Pasteur, Protein Science, Pfizer, Merck, and MedImmune (now AstraZeneca) for unrelated studies The remaining authors reported no disclosures This work was supported by the Centers for Disease Control and Prevention [contract number ] The findings and conclusions in this presentation are those of the authors and do not necessarily represent the official position of the CDC 3

4 Background Seizures are associated with measles vaccinations (i.e. receipt of MMR or MMRV) with clustering of seizures in the 7 10 days postvaccination 1 The relative risk of seizures is also increased in children who received their 1 st dose at age months vs months National Academy of Medicine report acknowledges a lack of data concerning the safety of vaccination in children born preterm 3 1. Klein NP, et al. Pediatrics. 2010;126:e Rowhani-Rahbar A, et al. JAMA Pediatr ;167: Institute of Medicine. The Childhood Immunization Schedule and Safety

5 Aims Primary: Does the relative risk of seizures following measles vaccination differ between children born preterm and children born full-term? Secondary: Is there a difference between children born preterm and children born full-term, by Vaccine type received (MMR or MMRV) Age at vaccination (12 15 or months) 5

6 Vaccine Safety Datalink (VSD) Established in 1990 Collaboration CDC s Immunization Safety Office 8 integrated healthcare systems (11.3 million current members) Purpose: monitor vaccine safety Prospective surveillance Observational studies 6

7 Study Population Inclusions Children from 7 VSD data sites 1 st dose of measles vaccine at age months January 2003 September 2015 Non-missing gestational age estimate Exclusions Seizure at age <12 months Pre-existing conditions strongly associated with seizures Birth status classification Full-term ( 37 weeks gestational age) Preterm (<37 weeks gestational age) 7

8 Study Design, Outcome, Vaccination person-times Study Design Risk-interval (vaccinated only) cohort Outcome Seizures were identified by ICD-9 diagnostic code from inpatient or emergency department settings Post-vaccination person-time intervals Risk (exposed) : 7-10 days Control (unexposed) : days Excluded outcomes and person-times following vaccination for: 0-6 days to avoid possible short-term effects with concomitant vaccines days as washout period between the risk and control intervals. 4. Duffy J, et al. Pediatrics ; Jul;138(1). pii: e

9 Risk-Interval Analysis Risk and control incidence rates and 95% confidence intervals by direct calculation Relative Risk (incident rate ratios, IRR) by Poisson regression Time stable variables implicitly controlled: e.g. child gender, site Time varying vaccine exposure status and outcome occurrence as model terms product term: gestational age group X vaccine exposure status Separate models for: vaccine received ( MMR and MMRV) child s age at vaccination (12-15 and months). 9

10 Risk-Interval Analysis Preterm child Vaccination date Seizure X IRR = Preterm Risk Inc Rate, preterm Control Inc Rate, preterm Full-term child days post-vac Seizure excluded Risk Interval washout Control interval X IRR = Full-term Risk Inc Rate, full-term Control Inc Rate, full-term 10

11 Risk-Interval Analysis Preterm child Vaccination date Seizure X IRR = Preterm Risk Inc Rate, preterm Control Inc Rate, preterm test for difference in IRR s with gestational age group X vaccine exposure status product-term Full-term child days post-vac Seizure excluded Risk Interval washout Control interval X IRR = Full-term Risk Inc Rate, full-term Control Inc Rate, full-term 11

12 Characteristics of Study Population by Gestational Age Gestational Age Category (weeks) Preterm (< 37) Full-term ( 37) Number of children 45, ,032 Vaccine received, n (%) MMR 37,262 (82) 403,238 (82) MMRV 8,081 (18) 83,794 (17) Sex, n (%) Female 20,779 (46) 239,775 (49) Male 24,564 (54) 247,257 (51) Mean age in months at vaccination (SD) (1.98) (2.01) Mean birth weight grams (SD) 2,417 (649) 3,449 (474) Mean maternal age in years (SD) 31.9 (5.7) 31.1 (5.3) MMR, measles-mumps-rubella; MMRV, measles-mumps-rubella-varicella; SD, standard deviation 12

13 Incidence rates and incidence rate ratios (IRR) of seizures following any measles vaccination children Risk period a seizures Incidence rate (95% CI) c Control Period b seizures Incidence rate (95% CI) c IRR (95% CI) d p e Preterm 45, (42-89) (12-21) 3.9 ( ) 0.41 Full-term 487, (38-49) (12-15) 3.2 ( ) a 7 10 days after vaccination, b days after vaccination, c Incidence rate and 95% conf. interval per 1000 person-years, d Incidence rate ratios from Poisson regression e Interaction p-value testing the difference between IRR in children born preterm vs full-term 13

14 Incidence rates and incidence rate ratios (IRR) of seizures by vaccine type Risk period a Control Period b children seizures Incidence rate (95% CI) c seizures Incidence rate (95% CI) c IRR (95% CI) d p e MMR Preterm 37, (34-82) (12-22) 3.2 ( ) 0.51 Full-term 403, (31-43) (12-15) 2.7 ( ) MMRV Preterm 8, (47-190) 8 13 (5.6-25) 7.9 (3.0-20) 0.52 Full-term 83, (59-95) (11-16) 5.7 ( ) a 7 10 days after vaccination, b days after vaccination, c Incidence rate and 95% conf. interval per 1000 person-years, d Incidence rate ratios from Poisson regression e Interaction p-value testing the difference between IRR in children born preterm vs full-term 14

15 Incidence rates and incidence rate ratios (IRR) of seizures by age at vaccination children Months seizures Risk period a Incidence rate (95% CI) c Control Period b seizures Incidence rate (95% CI) c IRR (95% CI) d p e Preterm 41, (39-87) (12-21) 3.7 ( ) 0.36 Full-term 442, (36-47) (13-15) 2.9 ( ) Months Preterm 3, (25-237) 5 17 (5.4-39) 5.6 (1.5-21) 0.79 Full-term 44, (45-94) (4.2-11) 6.8 (4.2-11) a 7 10 days after vaccination, b days after vaccination, c Incidence rate and 95% conf. interval per 1000 person-years, d Incidence rate ratios from Poisson regression e Interaction p-value testing the difference between IRR in children born preterm vs full-term 15

16 Limitations Did not distinguish febrile vs afebrile seizures Relatively few seizure cases among children born preterm, particularly among those who were vaccinated after age 15 months and those who received MMRV vaccine Excluded children with a previous history of seizure or risk factors related to seizure so our results may not apply to this population 16

17 Conclusions There was no detectible difference between children born preterm or full-term in the relative risk of seizures following measles-containing vaccine Estimates of seizure risk were consistent with previous VSD studies Increased risk among vs recommended months and MMRV vs MMR (preterm children included but not analyzed separately) Our results support recommendations to administer the first dose of measles-containing vaccine at age months for all otherwise healthy children, including those born preterm. 17