Research

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

BMJ 2010; 340 doi: 10.1136/bmj.c712 (Published 2 March 2010)
Cite this as: BMJ 2010;340:c712
  1. Sholom Wacholder, study statistician and principal investigator1,
  2. Bingshu Eric Chen, assistant professor2,
  3. Allen Wilcox, senior investigator3,
  4. George Macones, professor of obstetrics and gynaecology4,
  5. Paula Gonzalez, study co-investigator5,
  6. Brian Befano, senior programmer6,
  7. Allan Hildesheim, study investigator, principal investigator1,
  8. Ana Cecilia Rodríguez, study co-investigator5,
  9. Diane Solomon, study co-investigator7,
  10. Rolando Herrero, study principal investigator5,
  11. Mark Schiffman, study co-investigator, senior investigator1
  12. for the CVT group
  1. 1Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, Rockville, MD 20852, USA
  2. 2NCIC Clinical Trials Group, Queen’s University, 10 Stuart Street, Kingston, Ontario, Canada K7L 3N6
  3. 3National Institute of Environmental Health Sciences, Division of Intramural Research, PO Box 12233, Research Triangle Park, NC 27709, USA
  4. 4Department of Obstetrics and Gynecology, Washington University, Campus Box 8064, St Louis, MO 63130 USA
  5. 5Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, Torre La Sabana, Piso 7, Sabana Norte, San José, Costa Rica
  6. 6Information Management Services, 12501 Prosperity Dr, Suite 200, Silver Spring, MD 20904, USA
  7. 7Division of Cancer Prevention, National Cancer Institute, Rockville, MD 20852, USA
  1. Correspondence to: S Wacholder WacholdS{at}mail.nih.gov
  • Accepted 26 October 2009

Abstract

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.

Footnotes

  • Affiliations of the Costa Rica Vaccine Trial (CVT) group

  • Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, San José, Costa Rica: Mario Alfaro (cytologist), Manuel Barrantes (field supervisor), M Concepcion Bratti (co-investigator), Fernando Cárdenas (general field supervisor), Bernal Cortés (specimen and repository manager), Albert Espinoza (head, coding and data entry), Yenory Estrada (pharmacist), Paula Gonzalez (co-investigator), Diego Guillén (pathologist), Rolando Herrero (co-principal investigator), Silvia E Jimenez (trial coordinator), Jorge Morales (colposcopist), Lidia Ana Morera (head study nurse), Elmer Pérez (field supervisor), Carolina Porras (co-investigator), Ana Cecilia Rodriguez (co-investigator), Maricela Villegas (clinic MD).

  • University of Costa Rica, San José, Costa Rica: Enrique Freer (director, HPV diagnostics laboratory), Jose Bonilla (head, HPV immunology laboratory), Sandra Silva (head technician, HPV diagnostics laboratory), Ivannia Atmella (immunology technician), Margarita Ramírez (immunology technician).

  • US National Cancer Institute, Bethesda, MD, USA: Allan Hildesheim (co-principal investigator), Douglas R Lowy (HPV virologist), Nora Macklin (trial coordinator), Mark Schiffman (co-project officer and medical monitor), John T Schiller (HPV virologist), Mark Sherman (QC pathologist), Diane Solomon (medical monitor and QC pathologist), Sholom Wacholder (statistician).

  • SAIC, NCI-Frederick, Frederick, MD, USA: Ligia Pinto (head, HPV immunology laboratory), Alfonso Garcia-Pineres (scientist, HPV immunology laboratory):

  • Women’s and Infants’ Hospital, Providence, RI, USA: Claire Eklund (QC cytology), Martha Hutchinson (QC cytology).

  • DDL Diagnostic Laboratory, Voorburg, Netherlands: Wim Quint (HPV DNA testing), Leen-Jan van Doorn (HPV DNA testing).

  • Contributors: SW, AW, and GM designed the pooled analysis. SW, PG, ACR, RH, AH, and BB were responsible for data collection. SW, BEC, AW, GM, and BB analysed the data. SW wrote the paper. SW, BEC, AW, GM, PG, BB, AH, ACR, DS, RH, and MS interpreted the data. SW, BEC, AW, GM, PG, AH, ACR, DS, RH, and MS critically reviewed all material. SW is guarantor.

  • Funding: The CVT trial is sponsored and funded by the National Cancer Institute (N01-CP-11005) with support from the NIH Office for Research on Women’s Health and conducted in agreement with the Ministry of Health of Costa Rica. PATRICIA is funded by GSK Biologicals. GSK Biologicals contributed data from PATRICIA to the analysis, and commented on aspects of the trial at the design stage and after the results were shared with investigators of both trials, with the permission of the Data Safety Monitoring Board of CVT. GSK Biologicals had no role in study design and the collection, analysis, and interpretation of data from CVT in this paper, or in the writing of the article. GSK Biologicals took no part in the decision to submit an article for publication. The pooled analysis reported here was supported by the Intramural Research Programs of the National Cancer Institute (NCI) and the National Institute of Environmental Health Sciences, both parts of the National Institutes of Health.

  • Competing interests: Vaccine was provided for CVT by GSK Biologicals, under a clinical trials agreement with NCI. GSK also provided support for aspects of the trial associated with regulatory submission needs of the company under FDA BB-IND 7920. Douglas Lowy and John Schiller from NCI are named inventors on US government owned HPV vaccine patents that are licensed to GSK and Merck, and so are entitled to limited royalties as specified by federal law. None of the other NCI and Costa Rica co-authors have any potential conflicts of interest to report. The researchers are completely independent from the non-government funders and sponsors. After a planned interim analysis, including safety review, of PATRICIA in December 2006,3 the data and safety monitoring board (DSMB) of CVT requested an assessment of possible effects of the vaccine on miscarriages by performing a pooled post hoc analysis of data from the two parallel trials. GSK provided data on pregnancy for this miscarriage analysis from PATRICIA3 to the statistician for CVT (SW). Two outside consultants (GM and AW), who are experts in reproductive epidemiology, helped in the preparation of the analysis and report. Both the data and safety monitoring board and the independent data monitoring committee (IDMC), which oversees CVT and PATRICIA trials, respectively, recommended that NCI statistician prepare a manuscript describing the results for publication in the scientific literature. GSK scientists provided background information and data from PATRICIA, and provided suggestions on the methods, analysis and interpretation. CVT investigators from NCI and Costa Rica prepared this manuscript with input from the expert and consultants. GSK scientists commented on draft manuscripts, but the named authors made the final decisions about its content.

  • Ethical approval: The NIH Office of Human Subjects Research granted an exemption from institutional review board review to NCI investigators to use data from PATRICIA for this pooled analysis. The study protocol, amendments, informed consent, and other information regarding PATRICIA that required pre-approval were reviewed by a national, regional or investigational centre independent ethics committee or institutional review board.

  • Data sharing: No additional data available.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

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