A Case for Immunization of Human Papillomavirus (HPV) 6/11–Infected Pregnant Women With the Quadrivalent HPV Vaccine to Prevent Juvenile-Onset Laryngeal Papilloma
A Case for Immunization of Human Papillomavirus (HPV) 6/11-Infected Pregnant Women With the Quadrivalent HPV Vaccine to Prevent Juvenile-Onset Laryngeal Papilloma
Keerti V. Shah () 0
0 Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland
Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a rare disease caused by intrapartum or perinatal transmission of human papillomavirus (HPV) types 6 and 11 from an infected mother to the newborn. Immunization of a pregnant woman who has condyloma or HPV-6/11 infection with the quadrivalent HPV vaccine will result in a high neutralizing antibody response to HPV 6 and HPV 11 in her serum, and these antibodies transferred to the newborn will likely protect the child against the development of JORRP. Because of the low incidence of disease in at-risk children, it may be difficult to test the effectiveness of maternal immunization for prevention of JORRP.
Juvenile-onset recurrent respiratory
papillomatosis (JORRP) is a rare disease of
young children caused by infection with
nononcogenic human papillomavirus
(HPV) types 6 and 11. The reservoir of
HPV-6 and HPV-11 is the genital tract
where the infection may be subclinical or
is manifest as genital warts (condyloma).
The child who develops JORRP acquires
the infection at birth, or perinatally, from
the infected maternal genital tract. Few
cases of JORRP occur in the first 6 months
of life, and most occur at 2–5 years of age.
The number of cases decreases after that
age, but those with onset until the age of
14 are classified as JORRP. The same
disease with onset at older ages is also
caused by infection with HPV-6 or
HPV11, but is probably acquired by sexual
contact and is classified as adult-onset
recurrent respiratory papillomatosis.
CHARACTERISTICS OF JORRP
JORRP is rare, with an estimated
incidence of about 820 cases annually and an
estimated annual medical cost of $123
million in the United States . Although
the papillomas are benign, they may
grow rapidly and need repeated surgery
to keep the airway open; in some cases as
many as 100 surgeries may be required
by the age of 10 years (Figure 1). In
addition to respiratory blocking, extension
of the disease to trachea and lungs
and transformation to malignancy may
threaten life . The disease is more
severe if it is associated with HPV-11 or
has an onset by the age of 3 years .
None of the recommended nonsurgical
treatments for JORRP (interferon,
cidofovir, celecoxib, photodynamic therapy,
and others) have been successful enough
to avoid frequent surgical intervention.
That infection is transmitted from
mother to child at birth was first
suggested by Hajek, who reported laryngeal
papilloma in a child born to a mother who
had extensive condylomas late in
pregnancy . Subsequently, several
investigators have reported additional clinical cases,
and mothers of children with JORRP
frequently give a history of genital warts. In
the early 1980s, HPV-6 and HPV-11,
viruses that are responsible for >90% of
genital warts, were also shown to be
responsible for nearly all cases of JORRP
[5, 6]. Maternal HPV infection appeared
likely to have been transmitted
intrapartum by contact of the fetus to the infected
maternal genital tract. However, cesarean
delivery does not fully protect against
JORRP , suggesting that infection may
also be transmitted in the perinatal
period. The antibody response to HPV-6/11
in women who have condyloma  and
in children who have JORRP  is low or
CONDYLOMA IN PREGNANCY
This association was examined in a
population-based study in Denmark . Over
a period of 20 years, between 1974 and
1993, 1 206 213 births were recorded. Of
these, 3033 (0.25%) were born to women
who had condyloma recorded during
pregnancy. Fifty-seven cases of JORRP
were identified to have occurred between
January 1974 and December 1999, thus
ensuring at least a 5-year period of
observation for children born in 1993.
Condyloma during pregnancy was strongly
predictive of JORRP in the child; it
conferred a >200-fold risk of JORRP in these
children (6.9 cases per 1000 women),
compared to children born to mothers
who did not have condyloma recorded
during pregnancy (0.03 cases per 1000
women) (Table 1). Nevertheless, a
majority of children with JORRP were born to
mothers who did not have condyloma
recorded during pregnancy; these mothers
probably had subclinical HPV-6 or
HPV11 infection of the genital tract.
Although condyloma during
pregnancy was an overwhelming risk factor for
JORRP in the child, the incidence of
JORRP in the at-risk child was low, and
only 1 case of JORRP occurred per 144
women with condyloma. It is probable
that all children considered to be
“exposed” were not infected and that some
infants may have been protected by the
low-level antibodies to HPV-6/11
transferred from the mothers.
GARDASIL HPV VACCINE
ADMINISTERED TO INFECTED
PREGNANT WOMEN WILL
PROTECT THE NEWBORN
The quadrivalent Gardasil HPV vaccine
is a prophylactic vaccine that contains
virus-like particles (VLPs) of the major
capsid (L1) proteins of HPV-6 and
HPV11 in addition to the VLPs of the
oncogenic HPV types 16 and 18. In clinical
trials, immunization with 3 doses of
Gardasil has markedly reduced the incidence
of HPV-6 and HPV-11 infections and of
genital warts . The vaccine induces a
high and uniform level of antibody
response, much higher than that by natural
infection with HPV-6 and HPV-11 .
The vaccine has been administered to
millions of women all over the world and has
been found to be safe. With respect to the
immunization of pregnant women, the
vaccine does not contain live virus,
so there is no risk of inadvertently
infecting the fetus. It has not been
purposefully tested in pregnant women, but in
1796 women who inadvertently became
pregnant during phase 3 clinical trials
of the vaccine, there were no negative
pregnancy-related outcomes attributable
to the vaccine . Its use in pregnancy is
not prohibited, and the Gardasil package
insert states that it “should be used in
pregnancy only if clearly needed.”
It is most likely that there will be a very
much lower risk of JORRP in children
whose mothers have been prophylactically
immunized with Gardasil, but these data
are not yet available. However, Gardasil
With genital warts
Without genital warts
Relative Risk (95% CI)
Abbreviations: CI, confidence interval; JORRP, juvenile-onset recurrent respiratory papillomatosis.
a Modified from Silverberg et al .
vaccine uptake has been variable. In the
Immunization of pregnant women has
been effective in preventing infectious
dis17 years in 2010 had received all 3 doses of
eases in the women, in their newborn
chilHPV vaccine . Therefore, despite the
dren, or in both. Maternal immunization
availability of the Gardasil vaccine, there
with tetanus toxoid
will be many pregnant women, mostly
unreduced the risks of both maternal as well
vaccinated, who are infected with HPV-6
as neonatal tetanus in communities where
or HPV-11 subclinically or have
condyloma. Administration of the Gardasil HPV
this disease is common . Inactivated
influenza vaccines protect pregnant women
vaccine to these women holds promise to
as well as their infants against the disease
markedly reduce, or even eliminate, the
. Acellular pertussis vaccine is
recomrisk of JORRP in their children. Although
mended for pregnant women to protect
the vaccine will not alter the course of
the newborn against pertussis .
AlHPV-6 and HPV-11 genital tract
infecthough JORRP is rare, the disease is an
tions in the infected women, it will
enormous challenge for the young patients
produce high levels of neutralizing
antiand their families. A vaccine found to be
body in their sera, and these antibodies
safe and effective for women is already
will be transferred transplacentally to the
available. Screening for HPV-6 and
HPVnewborn at birth. In Gardasil-vaccinated
11 infection of the genital tract or
diagnosas well as in unvaccinated women, the
ing condyloma in pregnant women is
HPV-6 and -11 antibody titers in the
simple, and it may identify about 3% of the
newborn match maternal antibody titers
pregnant women who are infected. The
. The presence of these antibodies may
Centers for Disease Control and
Prevenbe expected to protect the newborn
tion and the learned societies in obstetrics,
against the establishment of HPV-6 or
pediatrics, and otolaryngology should
conHPV-11 infection in much the same way
sider endorsing and providing guidelines
as they protect the prophylactically
immufor the use of this vaccine in
HPV-6/11–innized adult against these infections. While
fected women and help set up studies to
this is a reasonable expectation, it will be
difficult to test it in a randomized
controlled trial because of the rarity of the
test its effectiveness for prevention of
JORRP in the children of infected mothers.
disease even in the high-risk group. In the
the effectiveness of an immunization
Danish study, only about 7 of 1000
children born to mothers who had condyloma
during pregnancy developed JORRP. The
risk of JORRP might be even lower in
children born to women who are subclinically
infected with HPV-6 or HPV-11. To test
egy, large numbers of HPV-6/11–infected
pregnant women would have to be
recruited for each arm of a randomized
controlled trial, and the children born to these
women would have to be observed for
3–5 years to identify the cases of JORRP.
In noninstitutionalized US women aged
14–59 years, the prevalence of HPV-6
or HPV-11 infection is estimated to be
3.1% , so a large number of pregnant
women will have to be screened for
HPV6/11 infection to identify and recruit
infected women eligible for such a trial.
Potential conflicts of interest. Author
certifies no potential conflicts of interest.
The author has submitted the ICMJE Form
for Disclosure of Potential Conflicts of Interest.
Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
Figure 1. A, Papilloma on the vocal cord . B, Papilloma obstructing the respiratory tract .
United States , only 32 % of girls aged 13 -
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