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Critical Reviews http://cro.sagepub.com/
in Oral Biology & Medicine
Human Papillomavirus Infections in Children: the Potential Role of Maternal Transmission
Stina Syrjanen and Mirja Puranen
CROBM 2000 11: 259
DOI: 10.1177/10454411000110020801
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HUMAN PAPILLOMAVIRUS INFECTIONS IN CHILDREN:
THE POTENTIAL ROLE OF MATERNAL TRANSMISSION
Stina Syripinen*
Mira Puronen
Department of Oral Pathology and Radiology, Institute of Dentistry, Lemminkaisenkatu 2, FIN-20520 Turku, Finland; and MediCity Research Laboratory, Facully of Medicine, University of
Turku, Finland; *corresponding author, [email protected]
ABSTRACT: To date, more than 100 types of human papillomavirus (HPV) have been identified. In the past 20 years, there has
been an increasing interest in HPVs because of their potential role in the pathogenesis of malignant tumors. HPV infections
are known to affect predominantly adult, sexually active age groups, whereas skin warts, at various anatomic sites, are usually
associated with younger individuals. The modes of viral transmission in children remain controversial, including perinatal
transmission, auto- and hetero-inoculation, sexual abuse, and, possibly, indirect transmission via fomites. Recent studies on
perinatal infection with HPV have been inconclusive. It is still unclear how frequently perinatal infection progresses to clinical
lesions, whether genital, laryngeal, or oral. Conflicting reports have been published on the prevalence of HPV infections in children. The current consensus is, however, that newborn babies can be exposed to cervical HPV infection of the mother. The
detection rate of HPV DNA in oral swabs of newborn babies varies from 4% to 87%. The concordance of HPV types detected in
newborn babies and their mothers is in the range of 57% to 69%, indicating that the infants might acquire the HPV infection
post-natally from a variety of sources. HPV antibodies have been detected in 10% to 57% of the children, and there is usually
no correlation between seropositivity and the detection of HPV DNA in either the oral or the genital mucosa. There is also evidence that transmission in utero or post-natal acquisition is possible. The mode of in utero transmission remains unknown, but
theoretically the virus could be acquired hematogenously, by semen at fertilization, or as an ascending infection in the mother. The understanding of viral transmission routes is important, particularly because several vaccination programs are being
planned worldwide. The serologic response to HPV detected in different populations of young women or women at risk of cervical cancer might be due to genital infections, but the possibility that HPV infection has been acquired earlier in life through
the oral mucosa or respiratory tract cannot be ruled out.
Key words. Human papillomavirus, HPV transmission, child, infant, mouth, vertical transmission.
(1) Introduction
Human papillomaviruses (HPVs) are DNA viruses that
can induce hyperplastic, papillomatous, and verrucous squamous cell lesions in the skin and at various
mucosal sites. HPV infections are widespread and occur
worldwide. Today, the plurality of HPVs is well-established; more than 100 HPV types have been identified.
HPVs have gained increasing interest because of their
potential role in the pathogenesis of malignant tumors.
Both low-risk and high-risk HPV types exist-the latter
constituting a significant risk for cervical pre-cancerous
lesions and cervical cancer. Recently, HPVs have been
implicated in oral, laryngeal, and esophageal carcinogenesis, though the evidence is as yet less convincing
than that for cervical cancer (Miller and White, 1996;
Snijders et al., 1997; Syrjanen, 1997b,c). The biologic
behavior of HPV infection is unpredictable, and more
data are needed before the synergistic factors involved in
these HPV-associated diseases can be identified.
While genital HPV infections seem to affect predominantly adult, sexually active age groups, skin warts at
various anatomic sites have been characteristically
regarded as a disease affecting children. Apart from
these cutaneous HPV lesions, HPV infections of the oral
mucosa, and particularly those of the larynx, seem to be
typical pediatric diseases as well. More recently, HPV
infections have also been described in the nasal mucosa
and genital tract of children (De long et al., 1982;
Sundararaj et al., 1991; Handley et al., 1993a,b; Obalek et
al., 1993; Alberico et al., 1995).
There is ample evidence that the incidence of anogenital warts in pre-pubertal children is increasing. This
increased incidence cannot be entirely attributed to the
increased awareness of this disease but reflects a true
increase in the incidence of these infections. The modes
of viral transmission in children remain important and
controversial. Several potential modes of transmission
can be theorized for these pediatric HPV infections,
including perinatal transmission, auto- and hetero-inoculation, sexual abuse, and, possibly, indirect transmission via fomites. ln the early days, it was thought that all
genital warts in children were contagious. Subsequently,
childhood sexual abuse was thought to be the most com-
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259
TABLE 1
Modes of HPV Transmission in Children
(1) Non-sexual Transmission
Directly
- from one person to another
- auto-inoculation
Indirectly
- via contaminated objects
- via contaminated surface
(2) Maternal transmission
Directly
- during vaginal delivery from the mother
- at Caesarean section/early rupture of membranes
- from mother when taking care of the baby
- via saliva?
- via breast milk?
Indirectly
- during vaginal delivery via contaminated
objects or surfaces
- when born by Caesarean section via
contaminated objects or surfaces
Transmission, in utero
- through semen
- ascending infection from mother's genital tract
- transplacentally
(3) Sexual abuse
mon mode of viral transmission, and HPV types 6 and 11
were found to be the two most prevalent viral types in
genital warts of children. However, more recent studies
suggest that perinatal infection and auto- or hetero-inoculation may be much more prevalent than previously
thought (Armbruster-Moraes et al., 1994; Cason et al.,
1995; Puranen et al., 1996a, 1997; Bennett and Powell,
1987). It has been repeatedly documented that HPV type
2 is present in a significant proportion of pediatric anogenital lesions, strongly implicating auto- or heteroinoculation as an important mode of disease transmission. Similarly, the origins of HPV infections in oral and
laryngeal mucosa are uncertain, although modes of
transmission similar to those proposed for ano-genital
HPV infections have been suggested.
The present review deals with the different manifestations of HPV infections in children with special
emphasis on their potential routes of transmission
(Table 1). These data are largely based on,our experience of the biologic behavior of genital HPV infections
gained from a long-term (since 1981) cohort study of
HPV-infected women, conducted at the University
Hospital of Kuopio. During this study, the authors
undertook a systematic examination of babies born to
these women. We also had access to a large series of
tissue samples from upper aerodigestive tract lesions
26
260
(in the oral
mucosa,
sinonasal mucosa, larynx, lung,
esophagus), in which HPV involvement was first suspected by our group in the early 1980s and later confirmed by the detection of HPV DNA in these lesions
(Syrjanen and Syrjanen, 1981, 1987; Syrjanen et al.,
1983a,b, 1986b, 1987, 1988; Chang et al., 1990;
Kellokoski et al., 1992a,b; Hippelainen et al., 1993;
Kataja et al., 1993).
(2) Clinical Manifestations of HPV Infection
(2.1) ORAL HPV INFECTIONS
date, major epidemiological studies have been conducted only on genital infections, and thus, the natural
history of oral HPV infection has not been well-established. However, several recent studies on adults suggest
that HPV infection can also exist as a latent, subclinical,
or clinical infection in oral mucosa. In oral mucosa, squamous cell papilloma, condyloma, verruca vulgaris, and
focal epithelial hyperplasia (FEH) are well-established
benign epithelial lesions with an HPV etiology. Fig. 1
shows a typical, HPV type- l I-positive oral papilloma of a
child. Of the over 100 known HPV types, the following 24
types have thus far been detected in oral lesions: 1, 2, 3,
4, 6, 7, 10, 13, 16, 18, 31, 32, 33, 35, 45, 52, 55, 57, 58, 59,
69, 72, and 73. Several comprehensive reviews have
recently been published on HPV infections in oral
mucosa and/or in the upper aerodigestive tract fof adults
To
(Scully et al., 1985; Syrjanen, 1987, 1997a,b; Chang et al.,
1991; Garlick and Taichman, 1991; Yeudall, 1992; Miller
and White, 1996; Praetorius, 1997; Snijders et al., 1997).
Only a few studies on oral HPV infections in children
have been published, and therefore no reliable preva-
lence rates of such infections in children are available.
Squamous cell papilloma has been estimated to
account for about 7-8% of all oral tumors in children. In
a series of 2370 biopsy samples from patients up to 20
years of age, neoplastic lesions accounted for 12% of the
samples, and of all neoplastic lesions, papillomas
accounted for 28% (Das and Das, 1993). No such prevalence data for oral condylomas or verruca vulgaris are
available in children.
Using the most sensitive method, polymerase
chain-reaction (PCR), investigators have found HPV 6b
and HPV 16 DNA in 24% and 19%, respectively, of the
oral scrapings taken from 21 pre-school children
(0enison -et al., 1990). In ancAher study of .healthy..chi4ldren aged 3 to 7 years, HPV 16 DNA was detected by
PCR in 67 of the 142 buccal swabs (47%) (Rice et al.,
1996). In our recent series of 98 children (from 0.3 to
11.6 years of age), born to the mothers included in our
prospective cohort of 530 women (Puranen et al.,
1996a), oral smears were analyzed for the presence of
HPV DNA with PCR, followed by Southern blot
CrtRvOalBo.e
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1 1(2):259-274
(2000)
hybridization (SBH). HPV DNA was present in 31/98
(31.6%) oral scrapings. On clinical examination, normal
oral mucosa was found in 25 and 51 children with and
without oral HPV infections, respectively. Minor hyperplastic growths of the oral mucosa were discovered in
22/98 children (22.4%), eight of whom (36.4%) had
detectable HPV DNA in their oral scrapings One child
had an oral papilloma where HPV 16 was detected. HPV
16 infection was also detected in her mother's genital
mucosa at delivery (Puranen et al., 1996a). Levy et al.
(1998) detected HPV DNA in only 3.7% (6/164) of oral
swabs or mouthrinses taken from children aged less
than 12 years, while the detection rate in adolescents
was 2.1 % (2/96). Positive amplification for HPV was
confirmed by direct DNA sequencing. By PCR targeting
the LI region of the HPV genome, Koch et al. ( 1997) carried out a study testing a random sample of Danish
children, aged 0 to 17 years, for the presence of HPV in
the anal region and the oral cavity. Only four of the 249
anal samples and one of 392 oral samples were HPVpositive. The authors concluded that ano-genital types
of HPV are not transmitted, to any measurable degree,
by non-sexual routes, and that HPV infection occurs
mainly later in life, This view, however, is not supported by studies on newborn babies in whom HPV DNA
has been detected in 37% to 73% of nasopharyngeal
aspirates or buccal swabs (Sedlacek et cil., 1989; Cason
et aii, 1992; Fredericks et al., 1993; Pakarian et a l, 1994,
Puranen et cl., 1997) This issue is discussed in detail
below (see 'MATERNAL, TRANSMISSION ). Similarly, HPV
infections of children seem to be common, as identified by HPV serology (10%-46%), as discussed below
(see "Detection of Serum Antibodies to HPV").
(2.2) JUVENILE-ONSET LARYNGEAL PAPILLOMAS
The most notable characteristic of laryngeal papillomas is their tendency to recur even after a radical surgical excision. The disease is therefore also known as juvenile-onset recurrent respiratory papillomatosis (10-RRP).
Re-operations may be indicated at annual intervals or
even as frequently as every two weeks (Mounts and Shah,
1984; Kashima et al 1993). The number of operations
needed by single JOP patients has been between I and
118. The mean number of operations in 141 patients
from three different studies was 13.7 (Cohen et cil, 1980;
Abramson et ca, 1987; Padayachee and Prescott, 1993)
Another characteristic of laryngeal papillomas is their
tendency to regress spontaneously. Remission can be
temporary or for the lifetime of the patient, and remission periods of as long as 25 or 30 years have been
reported (Abramson et al, 1987; Daya and Gallimore,
1993). Spontaneous remissions have been reported at
puberty, and recurrence or increase in the severity of disease during pregnancy (Hirschfield and Steinberg, 1989).
(2.3) ANOGENITAL HPV
INFECTIONS
(2.3.1) Subclinical infections
Only a few studies are available on subclinical genital
HPV infections in children, In a series of 70 clinically
normal foreskins of newborns undergoing routine circumcision, three foreskins (40/.) were found to contain
HPV DNA, with no correlation to the abnormal PAP
smears of the mothers (Roman and Fife, 1986). HPV
DNA was not examined in the mothers. In a series of 52
neonatal foreskins and 46 neonatal cervical specimens
obtained at necroscopy and analyzed for HPV DNA by
means of PCR and LI consensus primers, no evidence
was found for HPV infection (Chen et 6il., 1993). Recent
cervical cytology was available in 70 of the mothers, of
whom only six had cytologic evidence of HPV infection
Laryngeal papillomas are the most common benign
tumors of the larynx in infants and children. There are two forms of laryngeal
papilloma, one appearing at an early
age (juvenile-onset papilloma; JOP)
and the other in adults (adult-onset
papilloma, AOP). Laryngeal papillomas
are usually located on the vocal cords
and epiglottis or subglottis but can
involve the entire larynx as well as the
tracheo-bronchial tree and even the
lungs (Hirschfield and Steinberg, 1989;
Kashima et al., 1993). The lesions may
be single or multiple. Surgery is generally indicated in children more often
than in adults, and malignant conversion also appears to be more common
in JOP than in the AOP disease
Figure 1. Oral Fpapilloma of a seven-year-old child.
(Mounts and Shah, 1984)
1
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261
TABLE 2
Reported Anogenital Warts in Children Aged
Between Newborn and 12 Years
Mode of Acquisition (N)
C D E F G
References
A
B
1967-1989*Boyd, 1990
1968-1980*Neinstein etal., 1984
Shelton etal., 1986
1986
RocketaL., 1986
1986
5
0
0
0
0
0
10
0
0
2
1
0
10
2
8
0
6
0
0
0
0
0
0
0
6
0
0
1
0
0
15 28
0 8
1 21
0 2
0 9
0 1
5
13
26
0
7
16 69
0
0
0
0
0
0
0
0
0
0
1
0
0
0
0
1
0
6
10
0
0
0
0
5
0
1
0
0
2
0
0
7
2
2
0
0
0
0
1 5
16 5
0 66
2 11
0 1
0 0
0 5
0 10
0
0
0
0
0
1
0
0
3
4
0
0
0
4
8
0
2
0
1
0
0
0
0
0
4
1
1
0
0
0
4
0
0
0
0
0
0
0
6
3
2
0
1
21
32
12
Year
1989
1989
Hanson eta!., 1989
Weitzner etaL., 1989
TOTAL (136)
1990
1990
1990
1990
1990
1991
1991
1992
1992
1992
1993
1993
1993
1993
1993
1994
1994
1995
TOTAL (339)
Padel eta!., 1990
Obalek et aL., 1990
Cohen etaL., 1990
Gibson et aL., 1990
Kumar etal., 1990
Sundararaj etaL., 1991
Nuovo eta/., 1991
Igawa and Nakano, 1992
Derksen, 1992
Matsumura eta., 1992
Handleyetal., 1993b
Yun and Joblin, 1993
Tamsen etaL., 1993
Handley et aL., 1993a
Obalek eta!., 1993
McLachlin etal., 1994
Gutman etal., 1994
deVilliers, 1995
0 0 2
0 0 1
0 3 7
0 0 4
0 0 1
0 12 25
0 5 10
0 0 54
0 0 9
0 0 12
14 41 218
A = Sexually active; B = Suspected sexual abuse; C = Proven sexual abuse; D = Autoinoculation; E = Possible non-sexual transmission from other family members; F =
Possible vertical transmission from the mother; G = Unknown source. Includes cases
where no data from sources other than sexual abuse were recorded. * = Review.
The specimens were obtained after birth, and some
degree of autolysis was present in 30 samples, which
might have adversely affected the detection of HPV
DNA in these samples (Chen et al., 1993).
(2.3.2) Condylomas
Ano-genital warts in children may have serious medical,
social, and legal implications. Issues such as the sexual
abuse of the child, transmission of the virus from the
mother to the child, as well as the potential for the future
development of ano-genital malignancies in children
with ano-genital HPV infections, especially with HPV
262
types 16 and 18, cause a great deal of anxiety
in parents.
Ano-genital warts in girls affect vulvar,
vaginal, urethral, and peri-anal areas. Most
lesions in boys are located in the peri-anal
area. Penile warts are rare, although they have
been described (Copulsky et al., 1975; Kumar et
al., 1990; Oriel, 1992). The vast majority of
ano-genital HPV lesions in children are
condylomatous or papular (Fig. 2). Flat warts,
after application of 5% acetic acid, have also
been described, usually in the presence of
condylomatous and papular lesions (Cohen et
al., 1990; Oriel, 1992).
In the 1990s, the reported incidence of
ano-genital warts has dramatically increased
in children. Until 1990, only 136 cases had
been reported, whereas between 1990 and
1994, at least 326 additional cases were
described (Table 2). This trend is considered
to parallel the increased incidence of anogenital warts in adults (Bennett and Powell,
1987; Koutsky et al., 1988).
(2.3.3) HPV types detected
In anogenital warts of children
In all the studies presented in Table 2, 254 of
457 ano-genital warts in children were analyzed for HPV DNA. HPV DNA was found in
230 (90.5%) of those 254 samples, and the
type distribution was: HPV 6 and 11 in 75.6%,
HPV 2 in 11.3%, HPV 16/18 in 5.6%, and HPV
27 or 57 in 3% of the positive samples.
Detection of the genital types HPV 6, 11, 16,
and 18 was suggested to imply either a sexual
or a vertical transmission, and the presence of
cutaneous type HPV 2 hetero- or auto-inocu-
lation (Obalek et al., 1990; Nuovo et al., 1991).
Figs. 2 and 3 show a HPV type- 1-positive
peri-anal condyloma of a two-year-old boy. No
evidence of sexual abuse was found. Recently,
Handley et al. (1997) studied ano-genital warts
of 31 pre-pubertal children for the presence of HPV DNA.
In these warts, HPV 2 was the most common type of HPV
detected (1 3/3 1), followed by HPV 6 (7/3 1), HPV I 1 (5/3 1),
and HPV 16 (1/31). The results suggest that the mucosal
HPV type in a child's ano-genital warts signifies transmission from mucosal warts, and, conversely, that cutaneous HPV 2 signifies transmission from warts at a cutaneous site. The authors also concluded that the high
prevalence of HPV 2 in children's warts and the low
prevalence of sexual abuse (two of 31 children) suggest
that innocent auto- or hetero-inoculation from cutaneous warts may be a common way for children to
Med
Bid Med
Oral Biol
Rev Oral
Crit Rev
Crit
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11(2):259-274 (2000)
gous with other DNA viruses where
genes are turned on according to a
specific time schedule in the course of
productive infection, The so-called
early genes are expressed shortly after
infection prior to the onset of DNA
replication. Early gene products are
also involved in transformation of the
host cells. The late genes code for
structural proteins of viral particles
and are activated during the final
stages of the viral cycle. In HPVs, there
are eight ORFs: six early genes,
referred to as El, E2, E4, E5, E6, and
E7; and two late genes, LI and L2
3A,
lenison et al. ( 1990) were the first to
study serum IgG antibodies to HPV
6b, 16 and 18 E and L gene products
Figure 2. A peri-anal condyloma of a two-year-old child before (A) and after treatment (B) in hospitalized children (n = 81, age >
with local alpha-interferon compression (courtesy of Dr. Olli Ruuskanen).
12 mos). Antibodies to L gene proacquire ano-genital warts, Auto- or hetero-inoculation
teins were detected more frequently than those to the E
can also explain the presence of mucosal types in chilproteins, Antibodies were detected in 57%'O of the children's ano-genital warts (Handley et al., 1997).
dren, and antibody to LI protein of HPV 6b was the
most frequent (Ienison et al., 1990). Bonnez et cil. ( 1992)
(3) Detection of Serum Antibodies to HPV
analyzed sera from 32 children with a biopsy-confirmed
HPV serology offers another potential means for assesslaryngeal papillomatosis and 31 healthy children for
ment of the prevalence of HPV infection in children.
antibodies to HPV 6b and HPV II LI fusion proteins. In
Currently, the main obstacles of HPV serology are the pluthe diseased group, 47%O (15/32) proved to be seroposirality of HPV types and weak immunogenicity of HPVs.
tive, but 10% of the controls also harbored these antiHowever, interest in serological detection of HPV has subbodies The difference was statistically significant, howstantially increased in the past few years. This does not yet
ever (P = 0.001). lochmus-Kudielka et ali (1989) examapply to children, however, because only six studies are
ined patients with and without HPV infection for the
available in which serum HPV antibodies have been analyzed in children
(lochmus-Kudielka et ci., 1989, lenison et
al., 1990, Bonnez et ci, 1992; Cason et ail.,
'tv
1992, 1995, MOller et al., 1995) The data
seem to be unanimous in that HPV
seropositivity is remarkably more com\
mon in children and adolescents than in
adults. Importantly, these studies clearly
e
indicate that seroreactivity to HPV 6 and
M
,9
HPV 16 infections seems to be common
and develops early in life. The available
data are reviewed below.
For those readers who are not
familiar with HPV, a short overview on
viral genome will be presented, The
size of the genome of human papillomavirus is about 7.9 kb. All putative
protein coding sequences (open read- Figure 3. HPV
11 DNA was detected in the biopsy sample taken from the lesion
ing frames, ORFs) are restricted to one shown in Fig. 2. Fype
The positive signals with in situ hybridization were found in the upper
DNA strand, The individual frames are part of the epithielium in two different regions. The strong signals indicate a productive
classified as early (E) or late (L), analo- HPV infection.
i.
-
'
I2nnnI
74 (2000)
111121
59-2274
1(2):225Q
cr11 R.'e (Thrcl
Crit
Rev Orcit Biol Med
Binl
M'd
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263
263
tivity in younger age groups was seen Serum
antibodies (IgG) to different HPV 16 gene products were measured. Low positivity rates were
found for E6 (5 l'o(, E7 (2.5%), or LI -L2 proteins
(1.5%), but 20.3/,, of the sera reacted with the
E4-specific peptide Interestingly, no correlation
was found to occur between seropositivity and
the detection of HPV DNA (Mund Yt al., 1997)
To conclude, all these studies indicate that
HPV type 6 and/or 16 infections are common
at an early age and may provoke a serological
response. However, the importance of these
HPV antibodies acquired during childhood is
not understood Do they neutralize the virus
or do they help the virus escape the immunological defense system? These are some of the
key questions for the future studies in this
field of HPV research
Figure 4. A plantar wart of a six-year-old boy. The wart was HPV 1 -DNA -positive,
as detected by in situ hybridization.
presence of HPV antibodies to HPV 16 E4 and E7
Antibodies to E4 and E7 were detected in 18% and 3 7% of
the 336 control subjects, respectively. The age range of the
control group was from 3 months to 90 years. The highest
detection rate (40.7%) of E4 antibody positivity was found
in the II -to-20-year age group. Muller et al. ( 1995) reported
HPV 16 E4 antibodies in 1.14% of their adult population,
but the prevalence was much higher (20%) in children and
adolescents. In another recent study, investigators used
HPV 16 LI and L2 proteins to examine sera from 229 children to determine the age at which IgM antibodies to HPV
were acquired (Cason et al., 1995). A bimodal distribution of
IgM seropositivity was found peaking between 2 and 5 as
well as between 13 and 16 years of age, suggesting that two
distinct modes of transmission may occur (Cason et a).,
1995). Marais et al. (1997) tested sera from 155 children
(aged between I and 12 years) by an enzyme-linked
immunosorbent assay (ELISA) for serum IgG antibodies to
3 HPV peptides (HPV-16 E2 1E2-161, HPV-18 E2 )E2-181,
HPV-16 LI ILI-16)), as well as HPV 16 virus-like particles
(VLP-16) and BPV type I virus-like particles (BPV-VLPs).
Antibodies were detected to E2-16 (44.5%), E2-18 (18.7%),
LI-16 (20%), VLP-16 (4.5%), and BPV-VLP (5.1%). Between
the ages of 3 and 12 years, the prevalence of antibodies to
E2- 16 decreased with age.
Only one report has been published where an attempt
was made to correlate the detection of HPV DNA in buccal
or genital swabs of children with HPV antibody response
(Mund et al, 1997). Samples obtained from 79 children were
tested, and low-level positivity was found in 34 samples,
twice as often in oral swabs than in genital swabs. No sexspecific difference was found. A trend toward higher posi-
264
(4) Modes of HPV Transmission
HPVs are transmitted directly by skin or
mucosal contacts, or indirectly through
contaminated objects, or sexually or perinatally. Table
I summarizes the modes of HPV transmission in children. According to the best available estimates, the
incubation period for condyloma acuminata varies
from three weeks to eight months and that of skin
warts from two weeks to more than a year (Bunney et
cik 1987).
(4.1) NON-SEXUAL TRANSMISSION
Infections with HPV types causing skin warts are usually
acquired through micro-injuries. Transmission occurs
either directly from one person to another, or indirectly
via contaminated objects or surfaces. In children, indirect
HPV transmission to fingers and hands from shared glue
pots has been reported (Bunney ct Il., 1987). Auto-inoculation (by scratching) from one site of the body to another is also possible HPV 2 is frequently detected in
lesions of the oral mucosa, and it might be acquired by
the chewing of common warts present on hands. The
increased incidence of cutaneous warts in children more
than 5 years of age is believed to be due to exposure to
common showers during the first years of school
(Schiffman, 1994, lohnson, 1995). Fig. 4 shows a typical
plantar wart of a child. The lesion was HPV type-1-positive. We were interested in determining whether HPV
DNA can be detected in the floor and seat surfaces of
humid dwellings-e .g, showers, saunas, and dressing
rooms. The survey included three bathing resorts, one
indoor swimming pool, two schools, and two private
homes. The samples were collected with a toothbrush.
Beta-globin (human single-cell gene) could be amplified
only from one of the 36 samples collected. No HPV DNA-
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positive sample was found. Our
results indicate that transmission
of genital HPV infection via floor
or seat surfaces on the above
premises is highly unlikely
(Puranen et al., 1996b).
(4.2) SEXUAL ABUSE
TABLE 3
Maternal Genital Condylomata as a Source
of HPV-induced Lesion in the Child
Time of Maternal HPV
Infection and HPV Type Birth
Reference
Age at Onset, Location
Hajek, 1956
In contrast to the unequivocal
Pregnancy, delivery
No data 3 mos, laryngeal
Patel and Groff, 1972
Pregnancy, delivery
No data 13 mos, vulva
data on sexual transmission of
Cook
et
1973
al.,
Delivery
No
data 1 mo, laryngeal
genital warts in adults and sexuDelivery
No
data
6 mos, laryngeal
ally active adolescents, reports
Delivery
data
No
4
mos, laryngeal (3 children)
on the primary mode of transmiset al., 1978
Eftaiha
Pregnancy,
delivery
No
data
3
mos, peri-anal
sion of genital warts in children
Tang et al., 1978
Pregnancy, delivery
Vaginal
0
mo,
peri-anal
have been more contradictory
De Jong et al., 1982
After pregnancy
No data 14 mos, peri-anal
(Gutman et al., 1992). In children,
Pregnancy, delivery
No data 7 mos, peri-anal
the issue of genital warts origiZamora et al., 1983
Pregnancy
No data 2 yrs 6 mos, genital
nating from sexual abuse was
Rogo and Nyansera, 1989 Pregnancy
Section 0 mo, neck, ear
raised in the 1980s, when vulvar
Williams et al., 1990
Pregnancy
No data 3 yrs 6 mos, gingiva
Sundararaj et al., 1991 Pregnancy, delivery
condylomata in young children,
Vaginal 8 mos, peri-anal, laryngeal
Igawa and Nakano, 1992 After delivery
No data 3 yrs, perineal skin
previously considered extremely
Obalek et al., 1993
Pregnancy
No data 1 wk, anal
rare, were reported with increasPregnancy
No data 2 yrs 8 mos, anal
ing frequency (Stumpf, 1980). The
Pregnancy
No
data 6 mos, anal
full extent of the complex probPregnancy
No
data 10 yrs 9 mos, anal
lems posed by genital warts in
Pregnancy
No
data
6 yrs 11 mos, genital
small children was fully appreciMenton et al., 1993
Pregnancy, delivery
Vaginal 2 yrs, scrotum
ated only in the early 1990s. Table
(HPV6/11)
(HPV6/11)
2 summarizes the studies on
Handley et al., 1993b
Unknown
Vaginal ? 3 yrs, peri-anal
anogenital warts in children aged
(HPV6/11)
(HPV6/11)
between newborn and 12 years.
Unknown
Vaginal ? 2 yrs, clitoris
Unknown
Sexual abuse was proved in only
Vaginal ? 10 mos, vulva
Unknown
Vaginal ? 2 yrs, peri-anal
32 of the 339 children with
Handley et al., 1993a
Pregnancy
Vaginal 0-1 mo, anogenital
anogenital warts.
(5 children)
Rose and Thompson (1989)
Delivery
Vaginal
1-3 yrs, anogenital (7 children)
reported a series of 15 children
Alberico et al., 1995
Unknown
10
Vaginal
mos, laryngeal
with ano-genital warts. Of these
(HPV
6/16)
(HPV
6)
15 children, 12 were referred for
an assessment of sexual abuse,
which could be confirmed in six cases, strongly suspectsuggested, including auto-inoculation. Nevertheless, sexed in one, and excluded in three. In two additional cases,
ual abuse was suspected or evident in only half of the
the source of infection remained unclear. Seven biopsy
children, suggesting that other routes of transmission
samples were positive for HPV 6 or 11, one for 6/11 and
(e.g., perinatal) might be involved. The authors concluded
16/18. Two samples were positive for HPV 2, and further,
that although the likely mode of transmission was inditwo hybridized with both HPV 18 and HPV 2. The authors
cated, to a certain extent, by the type of HPV, it can be
emphasized that the diagnosis of sexual abuse was made
confirmed only in conjunction with all available clinical
on the basis of history rather than by clinical examinaand social information (Padel et al., 1990).
tion, and that only two children showed physical signs of
Undoubtedly, the assessment of pediatric ano-genital
sexual abuse (Rose and Thompson, 1989). HPV typing
condyloma as a result of possible sexual abuse is one of
the most difficult issues in the entire field of HPV epiplays an important role in the determination of whether
the source of infection might be mucosal transmission or
demiology. Recently, techniques for interviewing and evalauto-inoculation from the skin. Accordingly, of the 17
uating children for suspected sexual abuse have been
defined. Such an evaluation should always include (1)
biopsy samples reported by Padel et al. (1990), 10 were
positive for HPV 6 or 11, while 6 contained skin types HPV
behavioral indication of abuse, (2) medical examination
2 or 3. In the latter case, non-sexual transmission was
to identify physical indications of abuse, (3) microbiolog11(2)259-274
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265
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ic assessment of other sexually transmitted diseases
(STDs), and (4) age-adjusted interviews of the child and
caretakers by skilled personnel (Gutman et al., 1992, 1994).
The detailed discussion of these issues falls outside the
scope of this review. The latest guidelines from the
Center for Disease Control and Prevention (1998) for the
treatment of sexually transmitted diseases include an
expanded section on *STDs, including HPV among
infants, children, and pregnant women, and the management of patients with genital warts.
(4.3) MATERNAL TRANSMISSION
As early as 1956, Hajek suspected transmission of a viral
wart from a mother to her child at birth. Since then, several studies have been published that provide more
insight into the maternal transmission of HPV. Table 3
summarizes the cases where maternal genital condylomata have been proven as a source of HPV-induced
lesions in the child. Because of its major impact on our
understanding of the basic pathobiology of HPV infections, current evidence on maternal transmission of HPV
and factors predisposing to this mode of viral spread are
discussed below.
(4.3.1) Laryngeal papillomas
In 1956, Hajek wrote: "Multiple laryngeal papillomata
are found in small children and adolescents. They are
not hereditary, but in 20% of cases they can be found at
birth." Following this early notion, a large number of
studies have reported a relationship between JOP and
maternal genital condylomata (Cook et al., 1973; Strong
et al., 1976; Quick et al., 1980; Hallden and Majmudar,
1986; Abramson et al., 1987). Recently, a case of laryngeal papilloma was reported in a one-year-old child
delivered vaginally (Alberico et al., 1995). The papilloma
of the child was positive for HPV 6, and the cervical
smear from the area of the condyloma of the mother
was positive for HPV 6 and 16, as determined by PCR
and DNA sequencing. Interestingly, the mother had
been previously treated for cervical intra-epithelial neoplasia (CIN), a finding that suggests a residual infection
by oncogenic HPV 16.
The incidence of JO-RRP was found to be 0.6/100,000
and prevalence 0.8/100,000 in a Danish population at
risk (Bomholt, 1988; Lindeberg and Elbr0nd, 1990). The
incidence of JO-RRP seems to be considerably higher in
the US, up to 4.3/100,000 (Derkay, 1995). Assuming that
25% of child-bearing women have genital HPV infections, of which 2-5% are clinically overt, it has been estimated that the number of births at risk for HPV infections in USA is 72,000 to 180,000 (Shah et al., 1986).
However, the prevalence of genital condylomata in
women of child-bearing age far exceeds the reported
number of new cases of JOP. Thus, the risk of a newborn
266
contracting a laryngeal lesion as a result of viral transmission from an HPV-infected mother must be relatively low-according to the best estimates, on the order of
1:80 to 1:1500 (Shah et al., 1986).
Children infected at birth may develop laryngeal
papillomatosis during the first 5 years of life. In some
cases, papillomas may spread extensively and cause
aphonia or severe respiratory obstruction. Kashima et al.
(1992) evaluated the risk factors of JOP and AOP.
Compared with juvenile controls, lOP patients were more
often first-born, delivered vaginally, and born to a
teenage mother. AOP patients reported more lifetime
sexual partners and a higher frequency of oral sex than
adult controls. A maternal history of genital condyloma
at the time of delivery or during pregnancy among RRP
patients has been reported to vary from 54% to 67%
(Cook et al., 1973; Quick et al., 1980; Hallden and
Majmudar, 1986). In a series of 109 JOP patients, only one
child was delivered by Caesarean section (Shah et al.,
1986). These patients are also at risk, albeit low, of a
malignant transformation of the laryngeal lesions during
adulthood. JOPs are nearly always associated with HPV
type 6 or 11 infection. The necessity of a Caesarean section in mothers with genital HPV infection has been
debated. Evidently, more information on risk factors linking maternal condyloma with lOP is needed before
Caesarean section can be advocated as a means of eliminating or reducing the risk of JOP in the newborn
(Derkay, 1995). Recently, Shah et al. (1998) reported a
relationship between observed and expected number of
JO-RRP cases as follows: Caesarean births, 4.6-fold less;
first-order births, 1.6-fold greater; and maternal age < 20
years old, 2.6-fold greater. Based on these results, the
authors stressed that the option of Caesarean delivery
should be discussed with a mother who has condyloma
at the time of delivery.
(4.3.2) Oral mucosa
Sedlacek et al. (1989) were the first to demonstrate HPV
DNA in 11/23 (48%) nasopharyngeal aspirates of infants
born by vaginal delivery to mothers with genital HPV
infection. Amniotic fluid samples after rupture of the
membranes were obtained from 13 patients, and two of
them were positive for HPV DNA. Fredericks et al. (1993),
using PCR, analyzed exfoliated cervical epithelial cells,
from women 6 wks post partum, for HPV DNA, and the
results were compared with those from buccal mucosal
smears of their babies. Eleven mothers had genital HPV
types in their cervical smears, and eight children of these
mothers had an identical HPV genotype in their buccal
mucosal samples. Nineteen mothers had no HPV DNA
detected in their cervical smears. Only one child had a
buccal mucosal sample positive for HPV DNA (p <
0.0001). The authors concluded that a contamination of
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a child's mouth with genital HPV from the mother's cervix
appears to occur commonly at birth or during the perinatal period. Such acquired HPV DNA or infection may
persist for at least 6 weeks (Fredericks et al., 1993).
St. Louis et al. (1993) assessed the frequency of HPV
in HIV-infected women and the detection rate of the
viruses in their children. They collected cervico-vaginal
lavage specimens from 80 mothers living in Kinshasa,
Zaire (52 HIV-seropositive and 28 HIV-seronegative at
the time of delivery), and oropharyngeal and perineal
specimens from 81 of their three-year-old children (21
HIV-seropositive and 60 HIV-seronegative). Detection of
HPV in the mothers was highly associated with HIVseropositivity; HPV DNA was detected in 20 HIVseropositive and one seronegative mother. Ten children
were found to be HPV-DNA-positive. However, detection
of HPV in children was not associated with the mothers'
HPV or HIV status or with the child's HIV status. Thus,
these results do not specifically support the hypothesis
of a mother-to-child transmission of genital HPV types
(St. Louis et al., 1993).
We recently obtained similar data in a series of 98
children (0.3 to 11.6 years of age) born to mothers included in our prospective cohort of 530 women (Puranen et
al., 1996b). Our evaluations included medical history,
clinical examination of the oral cavity and hand warts, as
well as cytological samples from the oral mucosa for HPV
detection by PCR and subsequent Southern blot
hybridization (SBH). Altogether, HPV was found in 31/98
(31.6%) oral scrapings. Nineteen of the positive samples
become positive only when hybridized, indicating a low
viral load. At delivery, five mothers had a genital HPV
infection with the same virus type as that found in their
children. In an additional 11 mothers, genital infection
with the same HPV type as in the child was diagnosed a
few months before or after delivery. One child had an oral
papilloma where HPV 16 was detected, a type that was
also found in her mother's genital mucosa (Puranen et al.,
1996b). These results support the concept that an infected mother can transmit HPV to her child, and that this
infection can persist for years.
Alberico et al. (1996) assessed the prevalence of HPV
infection in pregnant women and the prevalence of
maternal-to-fetal transmission in a prospective longitudinal cohort of 11 months' duration. They collected
endocervical biopsy samples from 170 pregnant women
during the 1st and/or 2nd trimester of pregnancy and/or
at the onset of labor, and oropharyngeal secretions from
their neonates. Of these subjects, 23 mother-baby pairs
provided all biopsy and other samples. HPV DNA was
detected by PCR in at least one of the three samples collected during the various periods of pregnancy in 31.2%
of the mothers and in 30.4% of those completing the
whole sampling protocol. HPV DNA positivity in the
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oropharyngeal secretions from the neonates was 21.7%.
The concordance of HPV DNA positivity between the
mothers at the time of labor and their neonates was
57.1%. Analysis of these data indicates that the possibility of HPV DNA transmission from an infected mother to the child is high, particularly when the maternal
PCR test is positive at the time of delivery, or in the presence of a high viral load (Alberico et al., 1996). Similar
data were reported from another recent study (Tseng et
al., 1998), where 301 pregnant women and their neonates, born by vaginal delivery (n = 160) or Caesarean
delivery (n = 141), were assessed by PCR for the presence
of HPV 16 and 18 DNA sequences in buccal and genital
swabs. The overall frequency of HPV 16/18 infection
among the pregnant women was 22.6% (68/301). At
delivery, the frequency of HPV transmission from HPV
16/18-positive mothers to their newborn babies was
39.7% (27/68). A significantly higher rate of HPV 16/18
infection was found at birth in infants delivered vaginally compared with those delivered by Caesarean section
(18/35 or 51.4% vs. 9/33 or 27.3%, p = 0.042). These findings suggest that neonates are at higher risk for exposure to HPV after vaginal delivery than after Caesarean
delivery (Tseng et al., 1998).
These high rates of vertical HPV transmission were
not confirmed by Smith et al. (1995), who found only one
of the 25 baby-mother pairs to be positive for the same
HPV type. An additional baby was HPV-positive, but the
mother appeared to be negative. The samples were collected during the third trimester and prior to delivery
from the cervix of the mothers and one to three days after
birth from the oral cavity of the babies. The transmission
rate was low (4% or 8%) compared with those reported in
the other studies, but the method used for HPV detection was also less sensitive than PCR. A similar detection
rate was reported recently (Watts et al., 1998). HPV-positive oral scrapings were obtained from three of 80 infants
born to women with cervical HPV DNA detected at 34
weeks' pregnancy and from five (8%) of 63 born to women
without HPV DNA (Watts et al., 1998). No clinical manifestations were found in the newborn babies. The
authors concluded that the upper 95% confidence interval for detection of perinatal transmission from a woman
with evidence of genital HPV was only 2.8%. Recently,
Favre et al. (1998) found HPV genotypes (HPV types 5, 8,
and 24) associated with epidermodysplasia verruciformis
(EV) in the amniotic fluid and placenta specimens and
cervical scrapes of a mother suffering from EV-induced
skin lesions. The child was born by Caesarean section,
and the amniotic fluid specimen was taken prior to rupture of membranes. No viral sequences were detected in
peripheral blood mononuclear cells collected two years
and six months before Caesarean section, rendering a
hematogenous transmission unlikely (Favre et al. 1998).
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(5) HPV in the Neonates-A Passenger
or True Infection?
weeks, HPV DNA persisted in 8/31 (26%) infants, HPV 16
in six, and HPV 18 in two infants.
Currently, HPV infection can be diagnosed only by the
detection of virus-induced epithelial changes or by the
presence of HPV DNA/RNA in the tissue. HPV infection
is regarded as a latent one, if there are no clinical or histological signs of HPV infection detectable but viral DNA
is found with PCR. Repeated detection of HPV DNA in
tissue and/or cell samples taken from the same anatomical region at different time points indicates that the
virus has infected the tissue and is not detected on the
basis of the contamination of the mucosal surfaces. So
far, only a few studies have analyzed the persistence of
viral DNA in newborn babies. Cason et al. (1995) reported persistent HPV DNA in 3 of 4 oral smears of babies
who had HPV-DNA-positive nasopharyngeal aspirates at
birth. The babies were born to mothers with HPV-DNApositive cervical swabs. The nasopharyngeal aspirate of
one baby born to an HPV-DNA-negative mother was also
positive. HPV DNA persisted for at least 6 weeks in
79.5% of the babies and for six months in 65%.
Fredericks et al. (1993) sampled cervical cells from
women 6 wks post partum and buccal smears of their
babies for analysis of HPV DNA by PCR. In 73% (8/1 1) of
the mother-baby pairs, an identical HPV type was
detected in both the buccal mucosa of the newborn and
the uterine cervix of the mother. This study also confirmed that HPV infection transmitted from the mother
at birth can persist for at least 6 weeks.
Cason et al. (1995) assessed whether HPV 16 and 18
DNA in infants contaminated at delivery persists until
the infants are 6 months of age. Of the 61 pregnant
women recruited, 42 (68.8%) were HPV 16- and 13
(21.3%) were HPV-18-DNA-positive. At 24 hrs following
delivery, the transmission rates from HPV-DNA-positive
mothers to their infants was 73% (HPV 16, 69%; HPV 18,
76.9%). Ten mothers who were HPV 16- and 18 DNA-positive delivered six (60%) infants who were also dual-positive at 24 hrs (Cason et al., 1995). HPV DNA persisted for
up to 6 weeks in 79.5% (HPV16, 84%; HPV 18, 75%) of
those infants who were positive at birth. At 6 months,
persistent HPV 16 DNA was still detected in 83.3% of the
infants, but HPV 18 DNA had dropped to 20% by this
time. Similar data have been recently provided by other
workers as well. Pakarian et al. (1994) used PCR and
detected HPV DNA in the cervical swabs of pregnant
women between the 20th and 38th weeks of pregnancy
as well as in the buccal and genital swabs of their infants
at 24 hrs and 6 wks after delivery. Twenty of the 31 (65%)
women were positive for HPV DNA. A total of 12/32
(38%) infants were HPV-DNA-positive at 24 hrs. Five
mother-infant pairs showed HPV 16, two had HPV 18,
and three had an HPV 16 and 18 double-infection. At six
The above results are fully consistent with our own
results (Puranen et al., 1997). In a study on the potential
oropharyngeal exposure of infants to cervical HPV infection in the mother, 106 infants born by vaginal delivery or
Caesarean section and their 105 mothers were analyzed
by PCR and subsequent confirmation with direct
sequencing and single-strand confirmation polymorphism (SSCP). HPV DNA was detected in the cervical
scrapings of the mother and nasopharyngeal aspirate
fluid (NPAF) of her infant. Both the mother and her child
were positive for the same HPV type in 29 mother-infant
pairs. Interestingly, five infants born by Caesarean section were also HPV-DNA-positive for the same HPV type
as their mothers. The concordance between the HPV
types of the mothers and their newborns was 69%
(29/42). Regardless of a perfect match in the HPV types
between the mothers and their infants, the overall HPV
DNA positivity in NPAF of infants was 37% (39/106
infants) (Puranen et al., 1997). The most frequent HPV
type occurring in both infant and mother was HPV 16 (10
pairs), followed by HPV 33 (3 pairs). HPV 6, 11, 31, or 53
was found in two pairs and HPV 18 or LVX160L1 in one
pair. Unknown types were found in eight pairs and multiple types in two pairs. Analysis of the follow-up data
showed that vertically transmitted HPV DNA of the same
type was detectable from 2 days up to 3 years in 16 of the
36 (44%) babies. In 15 cases, HPV DNA was no longer
detectable at the age of 2-4 days. HPV DNA was detected
in another five babies during follow-up, but the HPV type
was different from that detected in NPAF samples
268
Crit Rev
(Puranen
et
al., personal communication). Interestingly,
baby born by Caesarean section had HPV 16 and 33
detectable in the NPAF sample at birth. Oral smear after
3 years was also HPV-positive. The HPV type detected in
the mother of this baby at delivery was HPV 33. Analysis
of these data clearly suggests that great individual variation occurs in babies in the persistence of neonatally
acquired oral HPV infections (Puranen et al., 1997). In
addition to our study, there is only one other study confirming the maternal origin of infant infections by determination of the nucleotide sequence of HPV. By sequencing the amplified LI region, we found 12 identical samples in mothers and their newborn babies. The detected
HPV types were HPV 6b, 11, 16, 33, 53, and a new type,
LVX16OL1. Another 14 mother-baby pairs exhibited identical HPV types, as shown by the similar patterns of SSCP.
Kaye et al. (I1996) determined the nucleotide sequence of
the upstream regulatory region (URR) of HPV 16 in cervical smears from 13 HPV-DNA-positive mothers and oral
and genital swabs from their infants at 6 wks and 2 yrs of
age. Concordant variants or prototypic sequences were
detected in nine of 13 mother/infant sample pairs, indione
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cating that up to 69.2% of HPV-16-positive infants
acquired the virus from their mothers.
(5.1) VIRAL LOAD AND VERTICAL TRANSMISSION
So far, only two studies have evaluated the impact of the
viral load as a determinant of HPV transmission. Kaye et
al. (1994) analyzed the viral load in cervical/vaginal cells
of 15 pregnant HPV-16-infected women. Eight of these
women had infants who were positive for HPV 16 DNA at
genital and/or buccal sites. The viral load was estimated
by laser densitometry of the PCR products. The eight
mothers (four with a history of abnormal smears and two
with previous genital warts) who transmitted the infection to their infants had significantly higher viral loads (p
< 0.05) than those who did not. The authors concluded
that the viral load is an important although not the sole
determinant of the transmission of HPV 16 from the
mother to her infant (Kaye et al., 1994). Thus, other factors such as immunological status and genetic constitution may contribute to the transmission and subsequent
persistence of the virus. Similarly, Alberico et al. (1996)
undertook a study of 23 mother-baby pairs and concluded that the frequency of transmission of HPV from an
infected mother to the fetus is high in the presence of
high viral load.
(5.2) Is THE TRANSMISSION OF HPV
in utero POSSIBLE?
Theoretically, in utero transmission of HPV can occur
hematogenously, by semen at fertilization, or as an
ascendant infection of the mother. It is known that HBV,
CMV, HSV, parvo, and rubella virus infections can be
transmitted from the mother to the child in utero
(Mounts and Shah, 1984; Matero and Sever, 1990;
Whitley, 1993; Treadwell, 1994). So far, hematogenous
HPV transmission has been considered unlikely,
because HPV is known to multiply locally at the site of
entry on the skin or mucous membranes, and there has
been no proof of disseminated HPV viremia (Mounts
and Shah, 1984).
Nevertheless, there are reports on congenital
condyloma lesions (Tang et al., 1978), even after
Caesarean section, without premature rupture of the
membranes (Rogo and Nyansera, 1989). More importantly, in these mothers, amniotic fluid also contained
HPV DNA. Armbruster-Moraes et al. (1994) used PCR to
analyze the amniotic fluids from 37 pregnant women
with cervical HPV lesions. They found HPV DNA in 65%
(24/37) samples: HPV 16 in 13, HPV 18 in 5, and 6 samples remained untyped. In contrast, a recent study
could not find HPV DNA in amniotic fluid (Maxwell et
al., 1998). However, these investigators used only visualization of amplified HPV DNA fragments on the gel,
and DNA samples below 10 ng are not easily detectable
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by this technique. As described above, Favre et al.
(1998) also found HPV DNAs in amniotic fluid and placenta specimens by a nested PCR method. Because the
same HPV types were also detected in cervical smears
of the mother, an ascending infection of the placenta
was suggested.
In the early 1990s, four studies were published providing evidence of HPV detection in blood cells.
However, the results of these studies have never been
confirmed by other groups. Tseng et al. (1992) assessed
cervico-vaginal cells and peripheral blood mononuclear
cells (PBMC) from 52 pregnant women in the third
trimester of pregnancy as well as cord blood specimens
from neonates born to these mothers (Tseng et al.,
1992). HPV 16 DNA was found in 6 (11.5%) cervico-vaginal smears and in 9 (17.3%) samples of peripheral blood
mononuclear cells. Seven cord blood specimens of
neonates born to nine mothers with HPV 16 DNA in
their PBMCs were found to contain HPV 16 DNA. One
cervico-vaginal and two PBMC specimens contained
HPV 18 DNA, but this type was not found in the cord
blood specimens.
HPV DNA has been detected in circulating blood
leukocytes (Kedzia et al., 1992; Pao et al., 1991). HPV 16
DNA has been detected in granulocytes and on lymphocytic cell membranes in the blood of cervical cancer
patients (Kedzia et al., 1992). Pao et al. found HPV DNA,
of various types, in PBMCs of 13/24 (52%) patients with
urogenital HPV infections, but in none of 19 individuals
without urogenital HPV infections (Pao et al., 1991).
Similarly, Jalal et al. (1992) found HPV 16 DNA in blood
mononuclear cells of 2/8 (25%) individuals who had
latent oral HPV 16 infection. In two of them, peripheral
blood lymphocytes also exhibited positive amplification
with HPV 16 primers (Jalal et al., 1992). Honig et al. (1995)
studied HPV DNA with in situ hybridization (ISH) from
leukocytes of 40 patients with HPV-positive oral squamous cell carcinomas. In 92.8% of these cases, HPV
DNA of an identical type could be detected in leukocytes taken from pre-operative blood samples and oral
carcinomas. Despite these reports, the true hematogenous transmission of HPV must still be regarded as an
unconfirmed concept.
Recently, HPV DNA has been found in hydatidiform
moles and choriocarcinomas of the placenta (Pao et al.,
1995). Importantly, in one study, HPV DNA was demonstrated in syncytiotrophoblasts of the placenta in 5/6
cases of spontaneous abortion by ISH PCR (Hermonat et
al., 1997). It was speculated that, while trophoblastic
cells maintain the placental contact with maternal tissues, it might well be that HPV-infected trophoblasts
may have been a predisposing factor in the compromised pregnancy in these cases (Hermonat et al., 1998).
These observations could also explain the transplacen-
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tal transmission of HPV from an infected mother to the
fetus. At the mo ment, our laboratory is currently
attempting to assess the role of the placenta as the
source of such persistent HPV infections.
implications in the design of any vaccination programs
against HPV infection aimed at eliminating its worst outcome: cancer of the uterine cervix.
(6) Implications of Maternal HPV Transmission
REFERENCES
The current consensus is that, not infrequently, the
newborn baby is exposed to the cervical HPV infection
of the mother, although no reliable exposure rates can
be calculated. In reported studies, HPV DNA detection
rates in mother-baby pairs have ranged from 4% to 87%.
Several obvious reasons for this variability can be listed: (1) The study groups have been small (11-98 children and mothers); (2) the modes of sample collection
have varied; (3) the children have not been of the same
age in the different studies; (4) different HPV DNA
detection methods have been used; (5) technical
aspects have to be kept in mind, including contamination of samples either in hospitals or in laboratories,
and inappropriate sample collection; and (6) false-positive results in PCR amplification. Recent follow-up
studies have confirmed, however, that maternally transmitted HPV can cause a true infection of the upper
aerodigestive tract or genital region of the child, and
that the virus is not just a passenger.
Although HPV infection can probably be acquired
during the baby's passage through an infected birth
canal, transmission in utero or post-natal acquisition
seems to be possible as well. Several studies (Cason et
al., 1995; Puranen et al., 1997) have reported cases of HPVpositive newborn babies having HPV-negative mothers.
This might be because HPV DNA was not detected in the
genital tract of the mothers, i.e., a false-negative result,
which does occur. The other possibility is that the virus
resides in the placenta, a tissue which has not thus far
been systematically examined. Further, the concordance
of HPV types detected in the newborn babies and their
mothers is only in the range of 57% to 69%. This might
signify that the infants may have acquired HPV infection
post-natally from a variety of sources, including breast
milk, from siblings via kissing, or even through exposure
to contaminated fomites, or that semen has been the
vector of virus transmission.
A proper understanding of viral transmission routes
is of crucial importance, particularly because several vaccination programs are ongoing worldwide. The serological response to HPV detected in various populations of
young women might be due to genital infection, but
there is currently no way to rule out the possibility that
the HPV infection may be acquired earlier through the
oral mucosa. Theoretically, HPV infection already
acquired in utero or post-natally may even induce
immunological tolerance to HPV infection. It should be
evident that these considerations would have important
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(2000)
11(2):259-274 (2000)