Low Febrile Seizure Risk After Acellular Pertussis Vaccine

Troy Brown

February 21, 2012

February 21, 2012 — A combination vaccine that guards against pertussis raises the relative risk for febrile seizures on the day of the first and second vaccinations, but the absolute risk is still small, and vaccination does not increase the risk of epilepsy, according to a new study.

The findings come at a time when concern about possible adverse events related to pertussis vaccine, including epilepsy, has caused many parents to forego these shots for their children. Some public health experts fear that parental refusal of vaccination has contributed to the rise in pertussis among teenagers and babies younger than 6 months of age since the 1980s, a trend identified by the US Centers for Disease Control and Prevention.

Yuelian Sun, PhD, from the Department of Public Health at Aarhus University in Denmark, and colleagues report the results of their study in the February 22 issue of JAMA.

Dr. Sun and coauthors write that public health authorities in most countries have switched from whole-cell pertussis vaccine to an acellular version because the latter has substantially fewer adverse events, including fever. The authors tackled the heretofore unanswered question of whether acellular pertussis vaccine carries the risk for febrile seizures, which is the case with whole-cell pertussis vaccine. To do that, they studied the use of a combination vaccine (diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus-Haemophilus influenza e type B [DTaP-IPV-Hib]) that was introduced in Denmark in 1997.

Dr. Sun and colleagues identified a cohort of 388,817 children from the Danish Civil Registry who were born between January 1, 2003, and December 31, 2008, in Denmark. A total of 9983 children were excluded because they died; emigrated; were diagnosed with febrile seizures or epilepsy in their first 3 months of life; or had a missing value on sex, birth weight, gestational age, and parity of the mother. This left 378,834 children.

The investigators conducted 2 analyses, a cohort analysis and a self-controlled case series (SCCS study), on the same data set.

According to the Danish Civil Registry, approximately 98% of Danish citizens have a general practitioner (GP) who gives them their vaccines. The vaccines are free, and the GP is reimbursed for them. Vaccines are typically given at 3, 5, and 12 months of age, with a booster at 5 years.

The Danish National Hospital Register records information on febrile seizures and epilepsy, based on the Danish version of the International Statistical Classification of Diseases, Tenth Revision.

Of the 378,834 children, 329,521 (87.0%) received the first DTaP-IPV-Hib immunization, 339,288 (90.0%) received the second, and 320,049 (84.5%) received the third during the follow-up period from 3 to 18 months. A total of 6854 children (1.8%) were not given any DTaP-IPV-Hib immunizations. The number of children diagnosed with febrile seizures before 18 months was 7811 (2.1%).

Febrile Seizure Risk in First 7 Days After Vaccination

Of those diagnosed with febrile seizures (7811), 17 were diagnosed between 0 and 7 days after the first vaccination (incidence rate, 0.8/100,000 person-days), 32 were diagnosed between 0 and 7 days after the second vaccination (incidence rate, 1.3/100,000 person-days), and 201 were diagnosed between 0 and 7 days after the third vaccination (incidence rate, 8.5/100,000 person-days).

There were no higher risks for febrile seizures between 0 and 7 days after the 3 immunizations when participants were compared with a reference cohort of children who were not in that period after vaccination.

The study found a higher risk for febrile seizures on the day of the first vaccination (hazard ratio [HR], 6.02; 95% confidence interval [CI], 2.86 - 12.65), as well as on the day of the second vaccination (HR, 3.94; 95% CI, 2.18 - 7.10), but the higher risk was not seen on the day of the third vaccination (HR, 1.07; 95% CI, 0.73 - 1.57) when compared with the reference group.

On the day of immunization, 9 participants were diagnosed with febrile seizures after the first vaccination (incidence rate, 5.5/100,000 person-days), 12 after the second vaccination (incidence rate, 5.7/100,000 person-days), and 27 after the third vaccination (incidence rate, 13.1/100,000 person-days).

The relative incidences from the SCCS design were comparable to the HRs from the cohort study, and the results were unchanged when the researchers restricted their analyses to girls, boys, children who were given the immunization according to the suggested schedule, or children who were immunized after the pneumococcal vaccine was introduced. Children who were given the pneumococcal vaccine with the DTaP-IPV-Hib vaccine had an increased risk for febrile seizures within the first 3 days after the second vaccination and on the day of the third vaccination.

Recurrent Seizure Risk

Of the 250 children who had their first febrile seizure within 0 to 7 days of immunization, 80 (32.0%) had a later episode of febrile seizures, and 8 (3.2%) developed epilepsy at a later date.

Of the 7561 participants whose first febrile seizures occurred outside the 0- to 7-day postvaccination window, 2207 (29.2%) had recurrent febrile seizure episodes and 208 (2.8%) later developed epilepsy.

Children who had the first febrile seizure within 0 to 7 days of vaccination experienced a similar risk for recurrent febrile seizures ((HR, 1.09; 95% CI, 0.86 - 1.38) and epilepsy (HR, 0.61; 95% CI, 0.27 - 1.40) as children whose first febrile seizures occurred outside of that time period.

When compared with the unvaccinated group, vaccinated children were at lower risk of developing epilepsy during the first 15 months of age (HR, 0.63; 95% CI, 0.50 - 0.79), and there was a similar risk of developing epilepsy later (HR, 1.01; 95% CI, 0.66 - 1.56).

Absolute Risk Low

"[W]e found that the relative risks of febrile seizures were increased on the day of the first and the second vaccinations, but the absolute risks were low (<4 per 100 000 vaccinations) and the overall risk of febrile seizures was not increased within 0 to 7 days after DTaP-IPV-Hib vaccinations," write the authors. "The risks of recurrent febrile seizures or subsequent epilepsy were not increased for children whose first febrile seizure occurred within 0 to 7 days of vaccination. The risk of epilepsy was not higher among vaccinated vs unvaccinated children," they note.

Robert Lowes contributed to this article.

The study was supported by a grant from the Lundbeck Foundation. Dr. Sun also received support from the Lennart Grams Memorial Foundation. Grants from the Danish Medical Research Council, NordForsk, and the European Research Council supported data recruitment. The authors have disclosed no relevant financial relationships.

JAMA. 2012;307:823-831.

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