Final report on exposure during pregnancy from a pregnancy registry for quadrivalent human papillomavirus vaccine

doi:10.1016/j.vaccine.2015.04.014

Vaccine

Volume 33, Issue 29, 26 June 2015, Pages 3422-3428

https://doi.org/10.1016/j.vaccine.2015.04.014 Get rights and content

Abstract

Objective

To better describe the safety profile of pregnancy exposures to the qHPV vaccine by acquiring and analyzing post-marketing data on pregnancy outcomes.

Methods

This is a voluntary, post-marketing prenatal vaccine exposure registry. Enrollment criteria included an identifiable patient and health care provider from the United States, France, or Canada and exposure within 1 month before the date of onset of the last menstrual period or at any time during pregnancy. Outcomes of interest were pregnancy outcomes and birth defects. Prospectively reported cases were used for rate calculations.

Results

For the 1752 prospective reports with known outcome, 1518 (86.6%) were live births, including ten twin pregnancies. Of 1527 neonates, 1444 (94.6%) had no congenital anomalies. The overall rate of spontaneous abortion was 6.7 per 100 outcomes (95% confidence interval [CI] 5.5–8.2). The prevalence of major birth defects was 2.4 per 100 live-born neonates (95% CI 1.7–3.3). There were 12 fetal deaths (0.8 per 100 outcomes, 95% CI 0.4–1.4).

Conclusion

Rates of spontaneous abortions and major birth defects were not greater than the general population rates. Although no adverse signals have been identified to date, the qHPV vaccine is not recommended for use in pregnant women.

Introduction

Human papillomavirus (HPV) causes premalignant and malignant lesions of the cervix [1], [2], vagina [3], [4], vulva [4], [5], anus [4], [6], penis [7] and oropharynx [8], as well as genital warts [9], [10]. The quadrivalent HPV vaccine (GARDASIL^®/SILGARD^®, Merck and Co., Inc.) was licensed in the United States in June 2006, and subsequently in many countries around the world.

The quadrivalent HPV vaccine (qHPV vaccine) is not recommended for use in pregnancy. However, as this vaccine is recommended to women of child-bearing age, it is likely that inadvertent exposure during pregnancy could occur in the general population. To collect further data regarding the safety profile of the qHPV vaccine, Merck and Co., Inc. established the “Pregnancy Registry for GARDASIL”, one of the largest registries of its kind. The goal of the registry was to acquire and analyze information on pregnancy outcomes (i.e., live births, abortions, fetal deaths, and congenital anomalies) to better describe the safety profile of pregnancy exposures.

Previous analysis and publication of registry data which covered the first 2 years after U.S. licensure (from June 1, 2006, through May 31, 2008) indicated that the rates of spontaneous abortions and major birth defects for qHPV vaccine-exposed pregnant women were not greater than the unexposed population rates [11]. Here, we provide an update of these data encompassing data from qHPV vaccine approval (June 1, 2006) through December 31, 2012.

Section snippets

Pregnancy registry

The pregnancy registry was a company-run registry whose purpose was to collect data regarding the safety profile of qHPV vaccine in pregnancy. Because the vaccine is not indicated in pregnancy, all pregnancy exposures are either inadvertent or due to off-label use. The registry was, therefore, based on voluntary post-marketing reports. The pregnancy registry was conducted in the United States, Canada, and France. However, regardless of the country of origin, all reports of exposure during

Results

Four thousand nine hundred and nineteen (4919) reports of exposure to qHPV vaccine during pregnancy were recorded from June 1, 2006 through December 31, 2012. One thousand nine hundred and seventy seven (1977) cases were not eligible for enrollment in the pregnancy registry due to failure to meet 1 or more of the enrollment criteria. Overall, 2942 patients with reports of exposure to qHPV vaccine during pregnancy were enrolled in the registry and are included in this analysis (Fig. 1). Of the

Discussion

The pregnancy registry for the qHPV vaccine was established at the time of licensure as part of a multifaceted approach to monitoring exposures to the vaccine during pregnancy. Potential limitations of such pregnancy registries should be recognized. Limitations of registry methodology include that there is no comparator group because the source of cases is spontaneous reporting. Other limitations include underreporting, differential reporting, underascertainment/differential ascertainment of

Acknowledgements

Registry personnel wish to convey their gratitude to the women and health care providers who have reported cases of use during pregnancy and have completed the registry questionnaires. Writing support was provided by Scott C Vuocolo, PhD.

Précis: Data collected in the pregnancy registry for the HPV6/11/16/18 vaccine do not support a relationship between vaccine exposure and adverse pregnancy or fetal outcomes.

Author contributions and disclosures: The authors are responsible for the work

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Cited by (47)

Adverse events following HPV vaccination: 11 years of surveillance in Australia
2020, Vaccine
Australia was the first country to implement a fully funded vaccination program with quadrivalent human papillomavirus vaccine (4vHPV) in 2007, including males from 2013. We examined adverse events (AE) following vaccination with 4vHPV from 11 years of post-marketing data, focusing on a period of enhanced surveillance and adverse events of special interest (AESI).
AE following 4vHPV doses administered between April 2007 and December 2017 reported to Australia’s national regulator, the Therapeutic Goods Administration, were examined; reports collected during enhanced surveillance in 2013 and 2014 were analyzed separately. Age and sex-specific rates, using denominator data from the national HPV vaccination register, were determined. Pre-specified AESI were identified using Medical Dictionary for Regulatory Activities (MedDRA®) Preferred Terms and examined in detail.
Following nine million doses of 4vHPV vaccine administered in Australia, 4551 AE reports were identified. The crude reporting rate was 39.8 per 100 000 doses in the funded cohorts, excluding the enhanced surveillance period. The reported rate of syncope in 12 to 13-year-old males and females was 29.6 per 100 000 doses during enhanced surveillance and 7.1 per 100 000 doses during the remaining study period; rates of syncope were higher in younger compared to older adolescents. The rate of anaphylaxis (0.32 per 100 000 doses) was consistent with published rates. Other AESI including autoimmune disease, postural orthostatic tachycardia syndrome, primary ovarian insufficiency, Guillain-Barré syndrome, complex regional pain syndrome and venous thromboembolism, were reported at low rates and analysis did not reveal unexpected patterns that would suggest causal association.
AESI, apart from syncope, were reported rarely. The higher rate of syncope among younger adolescents highlights the need for management protocols to prevent syncope-related injury. Analysis of this large, longitudinal dataset in a country with high vaccine uptake, including a period of enhanced surveillance, affirms the safety profile of 4vHPV.
Maternal and infant outcomes following exposure to quadrivalent human papillomavirus vaccine during pregnancy
2020, Vaccine
The Department of Defense encourages service members ≤26 years of age to receive the human papillomavirus (HPV) vaccine. Although this vaccine is not recommended in pregnancy, inadvertent vaccination may occur. The objective of this study was to assess whether active duty US military women who received the quadrivalent HPV vaccine (4vHPV) during pregnancy were at increased risk for adverse maternal or infant outcomes.
The study population included active duty US military women aged 17–28 years with at least one pregnancy between 2007 and 2014, and the infants resulting from those pregnancies. Pregnancies, live births, and outcomes were identified using medical codes in administrative medical records. Exposure to 4vHPV during pregnancy was ascertained from personnel immunization records. Multivariable regression models were used to calculate risk estimates and 95% confidence intervals for the maternal outcomes of spontaneous abortion, preeclampsia/eclampsia and preterm labor, and the infant outcomes of preterm birth, birth defects, growth problems in infancy or in utero, and infant sex.
Overall, 90,600 pregnancies and 75,670 singleton infants were identified. Approximately 2% of pregnancies and infants were exposed to 4vHPV during pregnancy. After adjustments, no positive associations were detected between inadvertent exposure to 4vHPV during pregnancy and any adverse pregnancy or infant outcomes.
Our findings add to an established body of literature demonstrating the safety of 4vHPV when inadvertently administered during pregnancy. Although 4vHPV is no longer administered in the US, its use continues overseas; therefore, safety studies remain important. Furthermore, such studies can provide reassurance to women inadvertently exposed to nonavalent HPV vaccine (9vHPV) in pregnancy, which protects against four of the same antigens as 4vHPV, since safety of 9vHPV has not yet been established in pregnant women.
Safety of MenACWY-CRM vaccine exposure during pregnancy
2020, Vaccine
Although the meningococcal conjugate MenACWY-CRM vaccine is not approved for use in pregnant women, unintentional exposure during pregnancy can occur, especially during early pregnancy among women of child-bearing age. This study provides safety information about inadvertent MenACWY-CRM vaccination during pregnancy.
The evaluated population consisted of pregnant female members of Kaiser Permanente Southern California who inadvertently received MenACWY-CRM at 11–21 years of age during 09/30/2011-06/30/2013 within 28 days prior to conception or during pregnancy. Chart abstraction was conducted to identify pregnancy and birth outcomes, including spontaneous and induced abortions, preterm births, low weight births, and major congenital malformations (MCMs).
There were 92 women who received MenACWY-CRM during the pregnancy exposure period, mainly during the first trimester (76.1%). Hispanics represented the largest race/ethnicity category (68.5%). Among the known pregnancy outcomes (n = 66; excluding induced abortions and unknown pregnancy outcomes), the prevalence of spontaneous abortions was 18.2% (n = 12). Among live born infants (n = 55; from 54 pregnancies), 14.5% (n = 8) were born preterm (<37 weeks gestation) and 9.1% (n = 5) had a low birthweight (<2500 g). The prevalence rate of MCMs among live born infants (n = 55) was 1.8% (n = 1).
This study provides baseline prevalence estimates of spontaneous abortions, preterm births, low weight births, and MCMs among women inadvertently exposed to MenACWY-CRM during the pregnancy period. These estimates appear to be comparable with U.S. background prevalence estimates.
Safety of 9-valent human papillomavirus vaccine administration among pregnant women: Adverse event reports in the Vaccine Adverse Event Reporting System (VAERS), 2014–2017
2019, Vaccine
Citation Excerpt :
The findings for 9vHPV are in line with prior studies assessing AEs following 4vHPV administration during pregnancy that have not revealed any concerning patterns of pregnancy-specific or infant/neonatal outcomes following vaccine administration [9–13]. An analysis of prospective reports of vaccine exposure during pregnancy from the United States, Canada, and France submitted to the vaccine manufacturer (Merck & Co., Inc.) registry did not find any concerning patterns of spontaneous abortions, fetal deaths, or birth defects following 4vHPV administration [10]. An analysis of data from the Danish Childhood Vaccine Database, Danish National Prescription Registry, and other Danish health and demographic registries did not indicate a statistically significant difference in risk of spontaneous abortion, preterm birth, major birth defects, small size for gestational age, or low birth weight between women who did and did not receive 4vHPV during pregnancy [11].
9-valent human papillomavirus vaccine (9vHPV) was approved by the Food and Drug Administration (FDA) in December 2014. 9vHPV is not recommended during pregnancy, but some women of childbearing age may be inadvertently exposed. This study aims to evaluate reports submitted to the Vaccine Adverse Event Reporting System (VAERS) of pregnant women exposed to 9vHPV.
We searched the VAERS database, a national post-licensure vaccine safety surveillance system, for reports of pregnant women vaccinated with 9vHPV in the United States between December 10, 2014 and December 31, 2017. Disproportionate reporting of adverse events (AEs) was assessed using proportional reporting ratios (PRRs).
A total of 82 pregnancy reports were identified. Sixty reports (73.2%) did not describe an AE and were submitted only to report the vaccine exposure during pregnancy. The most frequently reported pregnancy-specific AE was spontaneous abortion (n = 3; 3.7%), followed by vaginal bleeding (n = 2; 2.4%). Among non-pregnancy-specific AEs, injection site reaction (n = 3; 3.7%) was most common. No disproportionate reporting of any AE was found.
No unexpected AEs were observed among these pregnancy reports.
Safety of a quadrivalent human papillomavirus vaccine in a Phase 3, randomized, double-blind, placebo-controlled clinical trial among Chinese women during 90 months of follow-up
2019, Vaccine
A quadrivalent human papillomavirus (qHPV) vaccine (HPV6/11/16/18) has demonstrated efficacy and acceptable safety in international studies. However, these studies did not include participants from mainland China, which has a substantial burden of HPV-related disease. This is the first safety report with a follow-up period of up to 90 months from a randomized, double-blind, placebo-controlled trial of qHPV vaccine in Chinese women 20–45 years of age.
Participants were randomized 1:1 to receive three doses of qHPV vaccine or placebo (Day 1, Month 2, and Month 6). Efficacy outcomes are reported elsewhere. Injection-site and systemic adverse events (AEs) were collected using vaccination report cards (VRCs) for 15 days following each vaccination. Serious AEs (SAEs), pregnancy outcomes, new medical conditions, and fetal/infant SAEs were collected during the entire study.
Of 3006 participants randomized, AEs were reported by 926 (61.8%) qHPV vaccine recipients and 856 (57.1%) placebo recipients over the entire study. Four participants (two in each group) discontinued the study vaccination due to AEs that were considered vaccination-related. Within 15 days following any vaccination, injection-site AEs prompted for on the VRC were more frequent among qHPV vaccine recipients (37.6% vs 27.8%), and systemic AEs prompted for on the VRC were similar in frequency between qHPV vaccine and placebo groups (46.8% vs 45.1%). Thirty-eight and 43 participants reported SAEs in qHPV vaccine and placebo groups, respectively. No SAE was considered qHPV vaccine-related. Pregnancy outcomes, fetal/infant SAEs, and new medical conditions were generally similar in frequency between the qHPV vaccine and placebo groups, and within normal ranges.
The qHPV vaccine was well tolerated and demonstrated a favorable safety profile in Chinese women 20–45 years of age, consistent with findings from global trials and safety surveillance studies.
Trial registration: clinicaltrials.gov; NCT00834106.
Adverse pregnancy outcomes and infant mortality after quadrivalent HPV vaccination during pregnancy
2019, Vaccine
Citation Excerpt :
In addition, the risk of spontaneous abortion was virtually identical among women vaccinated four weeks before conception and women vaccinated after conception, and there was no apparent effect of the number of vaccine doses administered during pregnancy. Our study is in line with the findings in the two previous studies that investigated risk of spontaneous abortion following vaccination with the quadrivalent HPV vaccine during pregnancy [2,3]. In addition, we analyzed the effect of number of HPV vaccine doses for the risk of spontaneous abortion and thereby add valuable information to the existing knowledge.
Few studies have studied the association between unintended human papillomavirus (HPV) vaccination and adverse pregnancy outcomes. This study set out to determine the association between HPV vaccination during pregnancy and subsequent risk of spontaneous abortion, stillbirth, and one-year infant mortality.
Population-based study including all pregnancies in Denmark (October 2006–December 2014) among women born 1975–1992. From nationwide health registries using the personal identification numbers, we obtained information on HPV vaccination, pregnancy outcomes, and infant mortality. The exposure window went from four weeks before conception date until 22 weeks of gestation for the outcome spontaneous abortion, and until birth for stillbirth and infant mortality outcomes. In the analyses of spontaneous abortion, we used time to event models, for stillbirth logistic regression models, and for infant mortality Cox regression was applied.
We included 522,705 pregnancies for the outcome spontaneous abortion (7487 exposed to at least one dose during pregnancy); 351,878 births (5262 exposed to at least one dose during pregnancy) for the stillbirth; and 350,739 live births (5245 exposed to at least one dose during pregnancy) for infant mortality. No significantly increased rate of spontaneous abortion among women vaccinated during pregnancy compared with unvaccinated women was found. In addition, we found no association between HPV vaccination during pregnancy and stillbirth (adjusted odds ratio = 0.96 [95% CI: 0.57–1.61]), or infant mortality (adjusted hazard ratio = 0.94 [95% CI: 0.53–1.67]). A secondary analysis showed no association between number of doses and timing of administration (i.e. vaccination before or during pregnancy) and an increased risk of spontaneous abortion.
We found no increased risk of spontaneous abortion, stillbirth, or infant mortality following unintended HPV vaccination during pregnancy.

View all citing articles on Scopus

¹: Current address: Genentech/Roche, San Francisco, CA, USA.

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Final report on exposure during pregnancy from a pregnancy registry for quadrivalent human papillomavirus vaccine

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Pregnancy registry

Results

Discussion

Acknowledgements

Lancet Oncol

Eur J Cancer

Int J Gynecol Obstet

J Adolesc Health

Am J Obstet Gynecol

Human papillomavirus is a necessary cause of invasive cervical cancer worldwide

J Pathol

The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VaIN)

Am J Surg Pathol

Anal squamous intraepithelial lesions: relation to HIV and human papillomavirus infection

JAIDS

Human papillomavirus (HPV) DNA in penile carcinomas in Argentina: analysis of primary tumors and lymph nodes

J Med Virol

The burden of genital warts: a study of nearly 70,000 women from the general female population in the 4 Nordic countries

J Infect Dis

Natural history of genital warts: analysis of the placebo arm of 2 randomized phase III trials of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine

J Infect Dis

Pregnancy outcomes from the pregnancy registry of a human papillomavirus type 6/11/16/18 vaccine

Obstet Gynecol

A five-year evaluation of reports of overdose with indinavir sulfate

Pharmacoepidemiol Drug Saf

Metropolitan Atlanta Congenital Defects Program. Surveillance procedure manual and guide to computerized anomaly record