Women in a clinical trial who became pregnant after vaccination with a human papillomavirus (HPV) vaccine did not have an increased risk of miscarriage compared with women who were not exposed to the vaccine, according to a new analysis of additional data from a clinical trial conducted in Costa Rica.
The observational study, led by researchers in Costa Rica and from the National Cancer Institute, appeared September 7 in the British Medical Journal.
The trial evaluated the efficacy of a vaccine manufactured by GlaxoSmithKline that is now sold as Cervarix. This vaccine is known as a bivalent HPV vaccine because it protects against infection with two HPV types, 16 and 18. Together, these types cause most (about 70 percent) cervical cancers and some other anogenital and head and neck cancers.
The Food and Drug Administration has approved three vaccines to protect against infection with types of HPV that can cause cancer. Because the vaccines may be given to women of reproductive age, any effect of HPV vaccines on the ability to carry a pregnancy to term would be a concern.
In the new analysis, the researchers assessed the risk of miscarriage among close to 10,000 young adult women who were part of the NCI Costa Rica HPV Vaccine Trial and the trial’s extended follow-up. In the clinical trial, nearly 7,500 women had been randomly assigned to receive the bivalent HPV vaccine or a control vaccine (hepatitis A vaccine). The trial researchers also looked at pregnancy outcomes in a group of more than 2,800 unvaccinated women who were not part of the original randomized trial.
Following Up on an Earlier Finding
The analysis focused on pregnancies conceived within 90 days from vaccination to address a concern raised in 2010 by the trial’s data safety monitoring board based on information from a different trial. A subsequent pooled analysis of data from the two trials found no evidence supporting an increased risk of miscarriage for pregnancies conceived at least 90 days after vaccination using the bivalent HPV vaccine.
However, the investigators observed a possible increase in miscarriage rates for pregnancies conceived within 90 days from HPV vaccination compared with the control arm. Although this finding was not statistically significant, the study authors could not exclude the possibility of a small increase in risk among pregnancies conceived within 3 months of vaccination.
In the new study, statistical analyses of the data showed that the risk that a pregnancy conceived within 90 days from vaccination would end in a miscarriage was not higher than the risk of a miscarriage among women who did not receive the HPV vaccine. Similarly, the miscarriage risk among pregnancies conceived at any time after HPV vaccination was not higher than the risk among unvaccinated women.
In an analysis by subgroup, however, there was an indication of a small (less than 1 percent) increase in the absolute risk of miscarriage in the second trimester for vaccinated women.
“Given the lack of an established pathophysiological mechanism that could explain the subgroup finding, it may be due to the role of chance in statistical analyses,” said the study’s first author, Orestis Panagiotou, M.D., Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics, adding that there are no reports of this association in the scientific literature. Nonetheless, because a genuine association cannot totally be ruled out, the authors suggested that this finding should be explored further in future studies.
The researchers noted that the new findings should not be extrapolated beyond the bivalent vaccine. The HPV vaccines are not recommended for use by pregnant women.
In an interview given a few weeks before his recent death, Dr. Sholom Wacholder, who led the first safety analysis in 2010 as the lead statistician for the NCI trial, said the new results “provide stronger evidence and reassurance” about the lack of a miscarriage risk associated with the bivalent HPV vaccine.
“The findings also support the safe continuation of HPV vaccination programs as recommended by groups such as the Center for Disease Control’s Advisory Committee on Immunization Practices, the World Health Organization, and policy makers in individual countries,” Dr. Wacholder added.