Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: Pooled analysis of two randomised controlled trials

Objective: To assess whether vaccination against human papillomavirus (HPV) increases the risk of miscarriage. Design: Pooled analysis of two multicentre, phase three masked randomised controlled trials Setting: Multicentre trials in several continents and in Costa Rica. Participants: 26 130 women aged 15-25 at enrolment; 3599 pregnancies eligible for analysis. Interventions: Participants were randomly assigned to receive three doses of bivalent HPV 16/18 VLP vaccine with AS04 adjuvant (n=13 075) or hepatitis A vaccine as control (n=13 055) over six months. Main outcome measures: Miscarriage and other pregnancy outcomes. Results: The estimated rate of miscarriage was 11.5% in pregnancies in women in the HPV arm and 10.2% in the control arm. The one sided P value for the primary analysis was 0.16; thus, overall, there was no significant increase in miscarriage among women assigned to the HPV vaccine arm. In secondary descriptive analyses, miscarriage rates were 14.7% in the HPV vaccine arm and 9.1% in the control arm in pregnancies that began within three months after nearest vaccination. Conclusion: There is no evidence overall for an association between HPV vaccination and risk of miscarriage. Trial registration: Clinical Trials NCT00128661 and NCT00122681.