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Gardasil safe for pregnant women, researchers say
Exposure to the Gardasil quadrivalent HPV vaccine during pregnancy appears to be safe, according to a large nationwide cohort study in Denmark.
Nikolai M. Scheller, MD, of the department of epidemiology research at Statens Serum Institut in Copenhagem, and colleagues used national health care databases to identify pregnant women and their exposure to Gardasil (Merck; 4vHPV) and to compare the birth outcomes of those who received the vaccine during pregnancy with those who did not.
They found that inadvertent 4vHPV vaccination during pregnancy was not associated with a significantly higher risk for major birth defects, spontaneous abortion, preterm birth, stillbirth, low birth weight, and small size for gestational age.
“Our results are consistent with other evidence that does not indicate that the vaccination of pregnant women with inactivated virus, bacterial, or toxoid vaccines generally confers a higher risk of adverse pregnancy outcomes than no such vaccination,” Scheller and colleagues wrote in The New England Journal of Medicine.
Five cohorts
Scheller and colleagues used the Medical Birth Register and the National Patient Register to identify all pregnancies between Oct. 1, 2006, and Nov. 30, 2013, that ended in a single birth or abortion. They obtained HPV vaccination information through either the Danish Childhood Vaccination Database or the Danish National Prescription Registry, which covered women who received a prescription for the vaccine. Women were considered exposed to the vaccine on the date they received the first vaccination or filled their prescription.
During the study period, 4vHPV was the only HPV vaccine used in the Danish national vaccination program, according to Scheller and colleagues. A few women who received the bivalent HPV vaccine Cervarix (GlaxoSmithKline) before or during their pregnancy were excluded from the study, as were pregnancies with missing or “implausible” data on gestational age, those with multiple overlapping records, and pregnancies in women who had not continuously lived in Denmark for 2 years before becoming pregnant.
Also, in their analysis of spontaneous abortions, Scheller and colleagues excluded those that occurred in the first 6 weeks of gestation because these cases may be clinically unrecognized, and those in which women had been exposed to vaccination in the first 6 weeks.
They analyzed the five outcomes using different exposure windows: the first trimester for the analysis of major birth defects; week 7 through week 22 of gestation for the analysis of spontaneous abortion; the start of week 7 until birth for the analysis of stillbirth; before 37 completed weeks for the analysis of preterm birth; and at any time during pregnancy for the analyses of low birth weight and small size for gestational age.
In each of the five cohorts, Scheller and colleagues matched vaccinated women with unvaccinated women in a 1:4 ratio according to age, with unexposed pregnancies defined as those occurring in women who were not vaccinated during the specified exposure window for each outcome.
Results expand on earlier studies
Scheller and colleagues noted 65 cases of major birth defects among 1,665 exposed pregnancies compared with 220 cases among 6,660 unexposed pregnancies for a prevalence OR of 1.19 (95% CI, .90-1.58). The other results were as follows:
- 20 cases of spontaneous abortion among 463 exposed pregnancies compared with 131 cases among 1,852 unexposed pregnancies for an HR of 0.71 (95% CI, .45-1.14);
- 116 preterm births among 1,774 exposed pregnancies compared with 407 cases among 7,096 unexposed pregnancies for a prevalence OR of 1.15 (95% CI, .93-1.42);
- 76 cases of low birth weight among 1,768 exposed pregnancies compared with 277 cases among 7,072 unexposed pregnancies for a prevalence OR of 1.10 (95% CI, .85-1.43);
- 171 cases of small size for gestational age among 1,768 exposed pregnancies compared with 783 cases among 7,072 unexposed pregnancies for a prevalence OR of 0.86 (95% CI, .72-1.02); and
- two stillbirths among 501 exposed pregnancies compared with four cases among 2,004 unexposed pregnancies (HR = 2.43; 95% CI, 0.45-13.21).
Scheller and colleagues said it was not possible to draw clinically meaningful conclusions about stillbirths because of the small number of cases. They said their results “confirm and considerably expand” on previous studies about 4vHPV, including a pooled analysis of five phase 3 clinical trials and a study of a pregnancy register that relied on voluntary reporting.
“Our study specifically investigated risks that are associated with vaccination during pregnancy in a large population-based cohort,” Scheller and colleagues wrote. “The use of data from nationwide registers allowed comparison with a control group of women who did not receive vaccination in pregnancy, and the data provided detailed individual-level information on the characteristics of the participants. Furthermore, information on exposure and outcomes were collected in a prospective and independent manner that limited susceptibility to recall and selection bias.”
In a related editorial, Kathryn M. Edwards, MD, pediatrics chair and professor of pediatrics at the Vanderbilt University School of Medicine, said pregnant women were largely excluded from clinical trials until recently because of safety concerns, but that a concerted effort has been made to include them in studies of drugs and vaccines that are used in pregnancy.
Edwards noted a recent update to the Common Rule to remove the “vulnerable population” classification for pregnant women, as well as the 21st Century Cures Act, which advocates for the inclusion of pregnant women in clinical trials.
“This marked change in attitude about clinical trials involving pregnant women comes at an opportune time since the usefulness of immunizing pregnant women to protect both them and their infants from serious infectious diseases has been clearly shown,” she wrote.
“When vaccines are to be used specifically in pregnant women, it is important that they be carefully studied in prelicensure trials and that their safety be ensured,” Edwards added. “In the case of HPV vaccine or other vaccines that are not intended for pregnant women but are inadvertently administered to them, postmarketing safety evaluations assume great importance.” – by Gerard Gallagher
Disclosure: Please see the full study for a list of all authors’ relevant financial disclosures. Edwards reports receiving grants from the CDC, NIH and Novartis outside of her submitted editorial.