Drugs in Pregnancy and Lactation: Tenth Edition

VACCINE, HUMAN PAPILLOMAVIRUS QUADRIVALENT, RECOMBINANT

Vaccine

PREGNANCY RECOMMENDATION: Limited Human Data—Probably Compatible

BREASTFEEDING RECOMMENDATION: Compatible

PREGNANCY SUMMARY

Animal studies in one species found no evidence of reproductive or developmental toxicity at doses, based on body weight, that were much higher than those used in humans. The human pregnancy experience supports the lack of toxicity for the embryo and/or fetus. Moreover, the vaccine is noninfectious and preservative- and antibiotic-free. If the vaccine is given in pregnancy, health care professionals are encouraged to call the toll-free number 877-311-8972 for information about patient enrollment in the Organization of Teratology Information Specialists (OTIS) study.

FETAL RISK SUMMARY

Human papillomavirus (HPV) quadrivalent vaccine is prepared by recombinant technology to contain virus-like particles of the major capsid protein of HPV types 6, 11, 16, and 18. It is administered as an IM injection. The vaccine is not infectious and does not contain preservatives or antibiotics. HPV vaccine is indicated in girls and women 9–26 years of age for prevention of the following diseases caused by HPV: cervical cancer, genital warts (condyloma acuminata), cervical adenocarcinoma in situ, and intraepithelial neoplasia of the cervix (grades 1, 2 and 3), vulva (grades 2 and 3), and vagina (grades 2 and 3) (1).

Reproduction studies have been conducted in rats. In pregnant rats, doses up to 300 times the human dose revealed no effects on fertility, pregnancy, parturition, lactation, or embryo or fetal pre- or postweaning development. No vaccine-related structural malformations were observed. In addition, there were no effects on the development, behavior, reproductive performance, or fertility of the offspring (1).

In the third annual report from the Merck Pregnancy Registry covering the period June 2006–May 2009, there were 1636 prospective reported pregnancies, but 396 were lost to follow-up and 132 outcomes were pending. Of the remaining 1108 pregnancies, there were 968 live births (974 newborns includes 1 surviving twin), 64 spontaneous abortions (SABs), 65 elective abortions (EABs), 10 fetal deaths (1 of twins), and 2 ectopic pregnancies (2). The reasons for the EABs were usually unknown, but one termination involved a fetus with anencephaly and a hypoplastic heart defect. Of the 974 newborns, 926 (95%) were normal, 21 had major defects, 26 had minor defects, and there was 1 early neonatal death of an infant born at about 30 weeks with intrauterine growth restriction (mother had antiphospholipid syndrome and was homozygous for methylene-tetra-hydro-folate reductase mutation). The prevalence of major structural anomalies recognized at birth was 2.4 cases per 100 live births. Among 261 retrospective (reported after the outcome was known) cases, there were 12 major defects. The Registry stated that the limited number of reports with known outcomes prevented any definite conclusions about the potential effects of exposure to the vaccine in pregnancy. However, the rates of SABs and major defects, and the fact that the anomalies were varied, suggested that the outcomes were related to the background risk rather than to the vaccine (2).

A 2009 study reported the pregnancy and infant outcomes during phase III clinical trials with quadrivalent HPV vaccine (Note: The Registry data presented above updates the number of exposures) (3). Women aged 15–45 years received the vaccine or placebo on day 1 and months 2 and 6. If a pregnancy test immediately before a dose was positive they were excluded from further doses. During the study, the number of pregnancies with known outcomes in the vaccinated and placebo groups was 1796 and 1824, respectively. There were no significant differences in the proportion of pregnancies resulting in live births, fetal loss, or spontaneous abortion. Congenital anomalies were noted in 40 and 30 neonates, respectively (ns). The anomalies were diverse and consistent with those commonly seen in the general population (3). Two comments on this study were published in 2009 and 2010 (4,5). Because the vaccine and placebo groups did not represent comparable randomized populations, and because some pregnancies were still ongoing, the author recommended that avoiding the vaccine in pregnancy or near the time of conception was still warranted (5).

The American College of Obstetricians and Gynecologists recommends avoiding HPV vaccine in pregnancy. If a woman becomes pregnant before completion of the three-dose schedule, completion of the series should be delayed until the pregnancy is completed (6). As of 2010, the CDC also recommends avoiding the vaccine in pregnant women (7).

BREASTFEEDING SUMMARY

It is not known if the HPV antigens or the antibodies induced by the vaccine are excreted into human breast milk. Five hundred nursing mothers were given the vaccine during clinical trials, compared with 495 women who received a placebo vaccine. The number of nursing infants experiencing a serious adverse experience was higher in the mothers receiving the vaccine than in those receiving a placebo, 4.2% (N = 21) vs. 2.0% (N = 10), respectively. However, none of the adverse experiences were judged to be related to the vaccine. In clinical studies, more nursing infants with acute respiratory illnesses were found in the group of mothers who had received the vaccine within 30 days (N = 6), than in the control group (N = 2) (1,2).

The American College of Obstetricians and Gynecologists states that the vaccine can be given to lactating women because it is safe for the mother and the nursing infant (6). Until further studies demonstrate otherwise, the use of HPV vaccine can be classified as compatible with breastfeeding.

References

1.Product information. Gardasil. Merck and Company, 2006.

2.Third Annual Report on Exposure during Pregnancy from the Merck Pregnancy Registry for Quadrivalent Human Papillomavirus (types 6, 11, 16, 18) Recombinant Vaccine (Gardasil/Silgard). Covering the period from first approval (June 1, 2006) through May 31, 2009.

3.Garland SM, Ault KA, Gall SA, Paavonen J, Sings HL, Ciprero KL, Saah A, Marino D, Ryan D, Radley D, Zhou H, Haupt RM, Garner SM, on behalf of the Quadrivalent Human Papillomavirus Vaccine Phase III Investigators. Pregnancy and infant outcomes in the clinical trials of a human papillomavirus type 6/11/16/18 vaccine—a combined analysis of five randomized controlled trials. Obstet Gynecol 2009;114:1179–88.

4.Smith-McCune K, Sawaya GF. Update on quadrivalent human papillomavirus vaccination and pregnancy outcomes. Obstet Gynecol 2009;114:1168–9.

5.Smith-McCune K. Quadrivalent HPV vaccine administered to women who became pregnant during trials did not appear to adversely affect pregnancy outcome; however, use during pregnancy is not recommended. Evid Based Med 2010;15:80–1.

6.American College of Obstetricians and Gynecology. Human papillomavirus vaccination. Committee Opinion. No. 467, September 2010. Obstet Gynecol 2010;116:800–3.

7.CDC. Guidelines for Vaccinating Pregnant Women. Available at http://www.cdc.gov/vaccines/pubs/preg-guide.htm. Accessed May 16, 2010.