Worldwide, cervical cancer is the second most common cause of death from cancer among women.1 In addition to cervical cancer, infection with high–oncogenic risk types of human papillomavirus (HPV), such as HPV16 and HPV18, may lead to cancer of the vulva, vagina, anus, penis, and oropharynx. Infections with low–oncogenic risk HPV such as HPV6 and HPV11 can cause genital warts and recurrent respiratory papillomatosis.1 Multinational phase III trials of a quadrivalent HPV vaccine (HPV6/11/16/18 vaccine) have shown that women who are DNA negative to one or more of the four vaccine HPV types before vaccination obtain up to 100% protection from HPV6/11/16/18-related cervical, vulvar, or vaginal intraepithelial neoplasia, cervical adenocarcinoma in situ, and genital warts.2–4 In June 2006, the HPV6/11/16/18 vaccine was licensed in the United States, Australia, and subsequently in the European Union. It has since been approved in more than 100 countries and more than 50 million doses have been distributed globally as of June 2009. The vaccine is made up of non-DNA containing, noninfectious virus-like particles that are not capable of causing HPV-related disease.
The target population for the HPV6/11/16/18 vaccine includes women in their childbearing years. To minimize the risk of exposure during pregnancy, all clinical trial participants were asked during the informed consent process to agree to use effective birth control during the vaccination phase, and each had a pregnancy test before each vaccination. Those with a positive pregnancy test were not vaccinated, and those who became pregnant were not to return for subsequent visits until after resolution of the pregnancy. All pregnancies (those that occurred inadvertently during the vaccination phase and those that occurred after the receipt of all three doses) were followed for outcome and were reviewed by the U.S. Food and Drug Administration (FDA). Human data, supported by extensive toxicology studies in animals resulted in the FDA classification of the vaccine as a pregnancy category B medication, which is given to medicines that have not been studied in pregnant humans but do not appear to cause harm to the fetus in animal studies. Here we provide an updated, combined analysis of the pregnancy outcomes for the women enrolled in the five phase III clinical studies of the HPV vaccine. As it is not known whether vaccine antigens or antibodies induced by the HPV6/11/16/18 vaccine are excreted in human milk, we also report adverse events in infants who were potentially exposed to HPV vaccine during lactation.
MATERIALS AND METHODS
We combined the raw data from five phase III clinical trials of the HPV6/11/16/18 vaccine (Table 1). All clinical trials of the vaccine in which women became pregnant are included. The study populations, inclusion/exclusion criteria, and results from the primary hypotheses have been described previously, following the Consolidated Standards of Reporting Trials.2,3,5–7 For each study, the range of follow-up, with 25th to 75th percentiles is provided in Table 1. All were in accordance with established practices for conducting vaccine clinical studies and followed existing Good Clinical Practice guidelines. An Institutional Review Board at each site approved the protocol. Written informed consent was obtained from each participant or legal guardian.
The HPV6/11/16/18 vaccine (Gardasil/Silgard; Merck and Co., Inc., Whitehouse Station, NJ) is composed of the L1 major capsid proteins of HPV6 (20 micrograms), HPV11 (40 micrograms), HPV16 (40 micrograms), and HPV18 (20 micrograms), synthesized in Saccharomyces cerevisiae.8 The vaccine contains a proprietary amorphous aluminum hydroxyphosphate sulfate adjuvant that is currently used in other vaccines manufactured by Merck and Co., Inc, for which more than 300 million doses have been distributed globally.
All women were required to use birth control during the vaccination phase (day 1 through month 7). All participants were evaluated for pregnancy before the administration of each dose of HPV6/11/16/18 vaccine or placebo using β-hCG assays sensitive to 25 international units before any vaccination at the investigative site: test results must have been available before vaccine administration. Any woman with a positive pregnancy test was not vaccinated. If a woman were to inadvertently become pregnant before receiving all three doses, she was not to return for subsequent visits until the resolution of the pregnancy (term or preterm delivery, spontaneous pregnancy loss, elective termination, etc.). The investigator maintained regular contact with the woman for the purpose of pregnancy assessment. Irrespective of pregnancy outcome, at the resolution of pregnancy, the woman resumed the study visits starting with the visit that was pending before pregnancy. The woman was eligible to complete the vaccination series, starting at a minimum of 2 weeks after resolution of pregnancy and normalization of β-hCG levels. If pregnancy was detected after completion of the vaccine series, the woman completed the study visits and procedures per protocol and at the investigator’s discretion.
Breastfeeding was not a contraindication to enrollment or vaccination. Administration of HPV6/11/16/18 vaccine or placebo to nursing mothers was reported and followed for outcome. All serious adverse experiences were collected for both the mother and her infant(s) from the time of the infant’s possible vaccine exposure via breast milk, until the infant was weaned, or until breast milk made up less than 50% of the infant’s diet.
Adverse pregnancy outcomes were defined as pregnancies resulting in a fetal loss, including spontaneous abortion, elective abortion, late fetal death, ectopic pregnancy, or unknown. Available information on aborted fetuses with regard to whether the fetus was normal or abnormal (congenital or other anomaly, or other medical conditions) was also collected.
If a woman’s fetus experienced death in utero, stillbirth, a congenital or other anomaly, or neonatal death, the sponsor was granted access to the woman’s and fetus’s or neonate’s medical records for review, after a release of medical information form was signed by the woman. We considered all congenital anomalies as reported by investigators, including but not limited to malformations, deformations in which uterine constraint or other mechanical force alters otherwise normal fetal tissue (eg, some congenital hip dysplasia and talipes), chromosomal abnormalities (eg, trisomy 21), and anomalies that have been associated with teratogens. Detailed reports for pregnancies that resulted in an anomaly at any time during the studies were reviewed by up to five independent experts in teratology. Each of the 70 cases was assessed using a form that included questions regarding 1) pathogenesis of the anomaly (known or unknown, and description of pathogenesis); 2) whether the anomaly is viewed as a major or minor malformation, is typically seen with environmental insults, could be characterized as a single-gene, chromosomal defect, or as having a diverse etiology; 3) gestational age at which a particular abnormality would usually occur; and 4) likelihood of relationship to study vaccination. The experts provided written opinion reports summarizing their findings. After review of the cases while blinded to treatment group, the experts were provided the same data in an unblinded fashion (with knowledge of treatment assignment) and again provided expert opinion reports. The experts independently reviewed the first 25 cases that had occurred before the FDA’s approval of the vaccine in 2006. A similar adjudication was performed for the 45 subsequent cases.
All trials evaluated safety by observing participants for at least 30 minutes after each injection. Vaccination report card aided surveillance was used in all studies, with the exception of protocol 015, where it was used in only a subset (n=916) of women.3 The vaccination report card was used to collect adverse experiences, serious and nonserious, and any use of concomitant vaccines or medications on days 1–15 after vaccination. Those women in protocol 015 who did not use a vaccination report card were evaluated using a general surveillance method in which questions were asked at each visit to determine if any serious adverse experiences had occurred. The investigator was responsible for determining seriousness, action taken, and relationship of the adverse experience to study vaccine. Serious adverse experiences were to be recorded at any time during the studies if the event resulted in death or was considered by the investigator to be related to vaccine/placebo or a study procedure. Mandatory worksheets were completed to ensure that none went unreported.
Two populations were considered for evaluations of safety: 1) the overall safety population (ie, all enrolled women, regardless of method of surveillance) and 2) the enrolled women who were followed using the vaccination report card–aided surveillance method. Adverse experiences that occurred among women who became pregnant during the trials were summarized as frequencies and percentages according to study group (using the number of participants with follow-up as the denominator) and the type of adverse experience reported, considering all visits for the administration of a dose of vaccine or placebo. In this article, safety evaluations focus on all women who became pregnant at any time during the study (systemic and serious adverse experiences) and those women who became pregnant and who were followed using vaccination report card–aided surveillance (injection-site adverse experiences and fever).
The studies were powered to address the prespecified primary hypotheses regarding efficacy, safety, and immunogenicity. They were neither designed nor powered to investigate the association between vaccination and infant outcome. Formal hypothesis testing was not prespecified, and no adjustments for multiplicity were made. Risk differences and nominal P values were calculated using the methods of Meittinen and Nurimen.9 Kaplan Meier curves were generated for both vaccine groups, plotting the time from last vaccine exposure to conception for pregnancies resulting in anomalies.10
Across the phase III trials, 1,796 women in the HPV6/11/16/18 group and 1,824 women in the placebo group became pregnant. The majority of the pregnancies occurred in FUTURE I, II, and III and were in women aged 16–45 (10,126 vaccine, 10,425 placebo) (Table 1). Pregnancy outcomes for the individual studies can be found in supplementary Tables 1–5, available in the Appendix online at http://links.lww.com/AOG/A136.
Baseline demographic characteristics of the women who became pregnant during the trials were well balanced between the vaccine and placebo group (Table 2).
Of the 3,620 women who became pregnant, 521 (251 in the vaccine group, in the 270 placebo group) reported more than one pregnancy during the studies. The total number of fetuses and/or neonates with known outcomes among all pregnancies at the time of this report was 2,008 of 2,085 (96.3%) and 2,029 of 2,121 (95.6%) in the HPV6/11/16/18 vaccine and placebo groups, respectively. Approximately 30% of pregnancies with unknown outcomes were ongoing pregnancies in FUTURE III. The remainder of the unknown outcomes was in women who were lost to follow-up.
Table 3 describes the outcomes among live births through the neonatal period (ie, the first 6 weeks of life). No significant differences were seen for the outcomes reported in Table 3, with the exception of failure to progress for reasons for cesarean delivery (P=.015, data not shown). The majority of the live births were vaginal deliveries (72.1% in the vaccine group, 73.3% in the placebo group). The most common reasons for a cesarean delivery in both groups were repeat or elective cesarean delivery and failure to progress or dystocia.
A total of 8.7% (175 of 2,008) and 9.4% (191 of 2,029) of pregnancies with known outcomes among HPV6/11/16/18 vaccine and the placebo recipients, respectively, were electively terminated (Table 3). There were no significant differences in the rates of spontaneous abortions between the vaccination groups (18.2% in the vaccine group, 19.5% in the placebo group; P=.96). Late fetal deaths occurred with a frequency of less than 1% in both groups (P=.57).
We considered all congenital anomalies as reported by the study investigators. Table 3 presents those cases that were detected at the time of pregnancy resolution; however, some anomalies may be detected in utero or after discharge from the hospital. Figure 1 presents an accounting of all anomalies. There were 70 infants/fetuses with one or more anomalies (40 infants [2.0%] in the vaccine group, 30 infants [1.5%] in the placebo group; P=.20). In Figure 1, each anomaly is counted once, and the total number of anomalies is greater than the number of infants, as 10 infants (five from vaccine recipients and five from placebo recipients) had more than one anomaly. The conclusions drawn from a review by specialists blinded to treatment group were that the types of anomalies observed were diverse and consistent with those generally observed in pregnancy outcomes among young women and that none were vaccine-related.
As shown in Figure 2A and B, the pregnancies that resulted in an anomaly were distributed across the entire study period in both the vaccine and placebo arms, with no apparent clustering with respect to the timing of vaccine exposure relative to the estimated date of conception. Kaplan Meier curves were generated for both vaccine groups, plotting the time from last vaccine exposure to conception for pregnancies resulting in anomalies (Fig. 3). As shown in Figure 3, the pattern of timing of the anomalies was similar between the vaccine and placebo groups.
As women were asked to use effective birth control only during the vaccination phase, the majority of the estimated dates of conceptions occurred at least 6 months after receiving a vaccination (1,589 of 2,085 [76%] in the vaccine group, 1,632 of 2,121 [77%] in the placebo group). In a previous report, Koutsky et al3 considered pregnancies with estimated dates of conception within 30 days of any vaccination3 to assess whether there is an underlying high-risk period after conception (supplementary Table 6, available in the Appendix online at http://links.lww.com/AOG/A136). Since the Koutsky report, there have been no additional participants with an estimated date of conception within 30 days of vaccination in protocol 013, 015, 016, and 018. However, in protocol 019, there were 38 women (14 in the vaccine group, 24 in the placebo group) with estimated dates of conception within 30 days of vaccination (supplementary Table 6, available in the Appendix online at http://links.lww.com/AOG/A136); thus, of the total number of pregnancies, those with an estimated date of conception within 30 days of any vaccination comprise only 6.3% (266 of 4,206). Among these 266 pregnancies, there were six neonates born with a congenital anomaly (five in the vaccine group compared with one in the placebo group; risk difference 3.2%, 95% confidence interval −0.5% to 6.9%). The congenital anomalies observed in these six neonates were relatively common and pathogenetically unrelated, suggesting a variety of causes. The rate of spontaneous abortion among pregnancies with an estimated date of conception with 30 days of any vaccination was 18.2% (vaccine group) and 21% (placebo group).
The most common “other medical conditions” among infants born to mothers who received HPV6/11/16/18 vaccine or placebo were prematurity (21 cases in the vaccine group compared with 18 cases in the placebo group), respiratory distress (seven compared with 10), jaundice (six compared with seven), small gestational age (five compared with four), and neonatal infections (seven compared with four).
The vaccine was generally well tolerated among women who became pregnant. Among women who became pregnant at any time during the study and who were followed using vaccination report card–aided surveillance (775 in the vaccine group, 770 in the placebo group), vaccine recipients had a higher incidence of injection-site adverse experiences than placebo recipients (82.7% in the vaccine group, 74.0% in the placebo group). The most common injection-site adverse experiences were bruising, erythema, pain, pruritis, and swelling. Vaccine recipients also had a higher incidence of fever (37.8°C [100°F] or higher) compared with placebo recipients (18.1% in the vaccine group, 14.3% in the placebo group). Systemic adverse experiences (all women who became pregnant, regardless of surveillance) were comparable (31.7% in the vaccine group, 31.3% in the placebo group). The most common systemic clinical adverse experiences reported were headache, pyrexia, and nausea. It should be noted however, that the majority of the women became pregnant more than 6 months after receiving the three doses of vaccine or placebo. Women who received the HPV6/11/16/18 vaccine during pregnancy or within 30 days before conception (range 30 days before to 48 days after the estimated date of conception) had similar incidences of injection-site (74.7%) and systemic adverse experiences (33.6%).
Overall, 117 participants (54 women who received HPV6/11/16/18 vaccine and 63 women who received placebo) who became pregnant at any time during the study reported 1 or more serious adverse experiences. Two women reported serious adverse experiences that were determined by the investigator to be related to study therapy; however, these serious adverse experiences occurred before pregnancy: headache and hypertension which occurred 18 days before the estimated date of conception (HPV6/11/16/18 vaccine arm), and chills, headache, and pyrexia, which occurred approximately 1 year before the estimated date of conception (placebo arm). The three most common serious adverse experiences reported among women who became pregnant during the study were premature labor, threatened abortion, and cephalopelvic disproportion.
Two women who became pregnant died during the study. These two deaths (as were all deaths that occurred during the trials) were classified by the investigator as not related to study treatment or procedures. The cause of death in the vaccine arm was interstitial myocarditis, septic shock, pelvic/mesenteric thrombophlebitis, disseminated intravascular coagulation (363 days after dose 3), and the cause of death in the placebo arm was sudden death postpartum from asphyxia of undetermined pathology (255 days after dose 2).
Twenty neonates who were born before day 1 and who were breastfed when the mother received the first dose of vaccine or placebo experienced a serious adverse experience (12 in the vaccine group, eight in the placebo group). The most common infant serious adverse experience in both groups was pneumonia.
One hundred twenty-eight and 97 neonates from women who received HPV6/11/16/18 vaccine and placebo, respectively, experienced a serious adverse experience between birth and the first 6 weeks. The three most common for both vaccination groups were prematurity (36 vaccine, 20 placebo), neonatal jaundice (26 in the vaccine group, 18 in the placebo group), and neonatal respiratory distress syndrome (10 in the vaccine group, 12 in the placebo group). Three serious adverse experiences among neonates born to vaccine recipients were deemed by the study investigator as possibly vaccine-related: congenital Hirschsprung’s disease, congenital hydronephrosis, and meningitis and sepsis (same neonate).
Sixteen neonates born to study participants who received HPV6/11/16/18 vaccine experienced a serious adverse experience during the lactation period. The two most common were pneumonia/bronchopneumonia (five) and bronchiolitis (five). Four neonates born to study participants who received placebo experienced a serious adverse experience during the nursing period: hematemesis, bronchiolitis, pyrexia, and hyperbilirubinaemia.
Fifty-eight neonates born to HPV6/11/16/18 vaccine recipients and 51 neonates born to placebo recipients experienced a serious adverse experience that did not occur between birth through 6 weeks or during nursing. The two most common in both groups were pneumonia/bronchopneumonia (nine in the vaccine group, 19 in the placebo group) and bronchiolitis (seven in the vaccine group, nine in the placebo group).
In the phase III clinical trials, the HPV6/11/16/18 did not appear to negatively affect pregnancy outcomes. There were no significant differences between the vaccine and placebo arms with respect to the number of live births or adverse outcomes. The majority of the observed anomalies were relatively common, and their prevalence rates within the study population were consistent with the prevalence rates described in surveillance registries and the literature.11,12 Rates of spontaneous abortions were similar to those reported in women who are actively followed for pregnancy.13 Vaccination was also generally well tolerated.
According to the Centers for Disease Control and Prevention, the risk to a developing fetus from vaccination of the mother during pregnancy is primarily theoretical.14 In general, the administration of live attenuated virus vaccines are contraindicated during pregnancy; this includes vaccines against measles, mumps, poliomyelitis, rubella, yellow fever, and varicella. Based on the current evidence, there is no excess risk from vaccinating pregnant women with inactivated virus or bacterial vaccines or toxoids.15–20 The HPV6/11/16/18 vaccine is produced by recombinantly expressing the major HPV capsid protein (L1) for each of the four HPV types in S. cerevisiae (yeast). It contains no viral DNA and is therefore noninfectious. The vaccine is adjuvanted with a well-studied proprietary adjuvant used in other vaccines. For example, hepatitis B vaccines, which are also manufactured in yeast and adjuvanted with aluminum salts, have been administered to millions of girls and women without evidence of teratogenicity, and pregnancy is not a contraindication to vaccination.14 Furthermore, neither the L1 major coat proteins of HPV nor antibodies against these proteins are believed to be chemically or pharmacologically related to known teratogens. Preclinical testing data further support the safety of HPV vaccine in pregnancy. Pregnant rats were administered HPV6/11/16/18 vaccine in doses 300-fold greater (on a mg/kg basis) than are given to humans, with no observed adverse effects on mating, fertility, pregnancy, parturition, lactation, embryonic–fetal, or preweaning and postweaning development.21 There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in the reproductive studies.
The present study had several strengths. These large multinational trials were unique in that they were run in women of childbearing age. All pregnancies were followed for outcome. All serious adverse experiences were recorded, including those in pregnant women, nursing mothers, and neonates. In addition, up to five independent teratology experts reviewed each of the congenital anomaly cases in a blinded and unblinded fashion.
Although there are some advantages to the use of data from phase III trials to investigate the association between vaccination and adverse outcomes, the analyses presented here are accompanied by some limitations. They were neither designed nor powered to study pregnancy outcomes with HPV vaccination. This is especially true for the detection of a specific malformation or group of malformations. Furthermore, formal hypothesis testing was not prespecified, and no adjustments for multiplicity were made. Nominal P values should be interpreted cautiously, as 1 of every 20 comparisons would be expected to be significant (P<.05) by chance.
The number and type of serious adverse experiences that occurred among neonates were similar between the vaccine and placebo groups. Administration of HPV6/11/16/18 vaccine did not appear to affect the health of breastfeeding neonates of vaccinated mothers. It is not known whether vaccine antigens or antibodies induced by the HPV6/11/16/18 vaccine are excreted in human milk.
The vaccine was well tolerated in women who became pregnant at any time during the studies and had a similar safety profile to that observed in the overall clinical trial population. For example, the overall rate of injection site adverse experiences among vaccine recipients in FUTURE I and II was 84.4%2 and 86.8%,3 respectively, compared with 82.6% for the subpopulation of women who became pregnant at any time during the studies.
The numbers of infants/fetuses with congenital anomalies were numerically higher in the group that received HPV6/11/16/18 vaccine compared with placebo, but the difference was not significant (P=.20). The independent experts determined that it was unlikely that any of the congenital anomaly cases was causally related to study vaccination. Additionally, as early embryologic insult often results in spontaneous loss due to multiorgan involvement, our findings suggest that administration of HPV6/11/16/18 vaccine does not result in early embryologic damage of sufficient severity as to cause spontaneous loss. However, as the study had limited power to detect differences, these findings should be considered preliminary. Given the inherent limitations of the clinical trials to detect rare adverse events during pregnancy, the vaccine’s manufacturer and marketers (Merck and Co., Inc., and Sanofi Pasteur MSD), in cooperation with relevant national authorities, have established a pregnancy registry for the HPV6/11/16/18 vaccine, which is conducted in the United States, Canada, and France. The source of the registry data are postmarketing reports of pregnancy exposures that are spontaneously reported to the company. A summary of the pregnancy outcomes which have been reported to this registry since the vaccine’s approval in June 2006 through May 2008 can be found in the accompanying manuscript by Dana et al.22
In conclusion, HPV6/11/16/18 vaccine did not appear to negatively affect pregnancy outcomes. Hence, should a woman inadvertently be vaccinated during pregnancy, these data may serve to inform clinical practice and improve patient counseling. Longer-term data are forthcoming in the postmarketing setting. Although the vaccine is a pregnancy category B medication, vaccination is not recommended during pregnancy, as there are still limited data on vaccination and pregnancy to date.
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