HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by TENTI, P. Articles by CARNEVALI, L. Search for Related Content PubMed PubMed Citation Articles by TENTI, P. Articles by CARNEVALI, L.

Perinatal Transmission of Human Papillomavirus From Gravidas With Latent Infections

From the Departments of Human and Hereditary Pathology, Pathologic Anatomy Section, and Obstetrics and Gynecology, University of Pavia, Pavia, Italy; and IRCCS Policlinico San Matteo, Pavia, Italy; and Neonatology Service, IRCCS Policlinico San Matteo, Pavia, Italy.

Address reprint requests to: Patrizia Tenti, MD, Department of Human Pathology, University of Pavia, via Forlanini 14, Pavia 27100, Italy, E-mail: tentiap{at}ipv36.unipv.it

	Abstract

Top Abstract Materials and Methods Results Discussion References

 
Objective: To evaluate the risk of perinatal human papillomavirus (HPV) transmission from mothers with latent infections to the oropharyngeal mucosae of their infants.

Methods: Seven hundred eleven mother-newborn pairs were tested. Polymerase chain reaction was done with MY09/MY11 consensus primers to identify HPV DNA in maternal cervicovaginal lavages and newborn nasopharyngeal aspirates. Positive cases were further amplified with type-specific primers for HPVs 6, 11, 16, 18, and 33. All infants born to HPV-positive mothers were observed to 18 months for appearance of HPV in oropharyngeal mucosae.

Results: Human papillomavirus DNA was detected in 11 neonates born vaginally to HPV-positive women, a vertical transmission rate was 30% (95% confidence interval [CI] 15.9, 47). Nasopharyngeal aspirates were HPV-negative in all 11 cases in which rupture of membranes occurred less than 2 hours before delivery. When rupture preceeded delivery by 2–4 hours, and when it occurred after more than 4 hours, the respective rates for HPV positivity were seven of 21 and four of five (² for trend = 10.7, P= .001). At follow-up, virus was cleared from the oropharyngeal samples as early as the 5th week.

Conclusion: Pregnant women with latent HPV infections have low potential of transmitting the virus to the oropharyngeal mucosae of their infants. The time between rupture of the amnion and delivery seems to be a critical factor in predicting transmission. Human papillomavirus–positive infants should be considered contaminated rather than infected since virus is cleared over several months after birth.

There is growing evidence that human papillomavirus (HPV) infections, particularly from high-risk types, are acquired not exclusively through sexual contact, and that one potential route is mother-to-child transmission in the perinatal period.¹Amplified DNA hybridization methods found that more than 15% of asymptomatic, sexually active women harbor HPV DNA in their cervices.²Vertical transmission might affect substantially the epidemiology of HPV infection, because a large number of newborns could be at risk of acquiring oropharyngeal or genital HPV infections from asymptomatic, infected mothers. It is possible that passage through an infected birth canal results in a self-limited colonization and not in true infection capable of persisting and contributing to disease later in life.

This prospective study used polymerase chain reaction (PCR) on a series of HPV-asymptomatic pregnant women at term and on their newborn infants. Human papillomavirus DNA was tested in maternal cervicovaginal lavages and newborn nasopharyngeal aspirates. The risk of perinatal HPV transmission from latently infected mothers to oropharyngeal mucosae of their infants was evaluated.

	Materials and Methods

Top Abstract Materials and Methods Results Discussion References

 
Seven hundred fifty-seven pregnant women at term, all from the same geographic area, were assessed consecutively by collecting cervicovaginal lavages in a single obstetric unit from January 1995 through April 1996. At enrollment, five cases were excluded because of visible genital warts (two cases) or abnormal cervical cytology (three cases). The remaining 752-woman cohort (median age 30.0 ± 4.61 years; range 16–43) tested negative on Papanicolaou smear at first trimester and lacked any history of cervical dysplasia or other genital HPV-related lesions.

Polymerase chain reaction was used to identify HPV DNA in cervicovaginal lavages collected at admission for delivery (weeks 36–39), using phosphate-buffered saline solution. At sampling, 739 subjects had intact amnions. In 13 women, the rupture of membranes was questionable. Reproductive history and selected demographic and behavioral features also were investigated. Reliability of answers was assessed by comparing antenatal records with those at enrollment.

In the newborns, all singleton live births, HPV DNA was identified by PCR on nasopharyngeal aspirates taken with suction devices in the delivery room. The test was repeated, on oropharyngeal swabs, at 5 weeks and at 6, 12, and 18 months after birth in all positive cases and in infants born to HPV-positive mothers.

A total of 711 mother-newborn pairs were eligible for the study, because cases lacking matched samples of maternal cervicovaginal cells and neonatal nasopharyngeal aspirate were not considered. At the time of sampling, amnion was intact in 704 cases; rupture of membranes could not be ruled out in the remaining seven cases.

Polymerase chain reaction amplification and DNA extraction procedures were done as described.³When red blood cells were in maternal samples, the pellet was resuspended in blood lysis buffer (saccarose 0.32 M; Tris-HCl 10 mM, pH 7.4; MgCl₂ 2.5 mM, Triton X-100 1%) and centrifuged at 12,000 rpm two or three times.

Preliminary screening to determine overall prevalence of HPV was done with consensus primers MY09/MY11,⁴and positive cases were amplified further with type-specific primers for HPVs 6, 11, 16, 18, and 33.³Samples from infants born to HPV-positive mothers were transferred to a nylon filter by Southern blotting, hybridized with oligonucleotide probes for MY09/MY11,⁴and autoradiographed. Hybridization with oligonucleotide probes for HPVs 6, 11, 16, 18, and 33³ was done for positive cases.

We used Fisher exact test, odds ratio (ORs), and 95% CIs to compare categoric variables; ² for trend to test for linear trends; and Mann-Whitney Utest to compare continuous variables.

	Results

Top Abstract Materials and Methods Results Discussion References

 
Thirty-seven of 711 (5.2%) mothers were HPV-positive. Human papillomavirus DNA of oncogenic types 16 and 18 were identified in 1.3% (nine) subjects; seven cases were positive for HPV 16, one case for HPV 18, and one for HPVs 16 and 18. One of the seven cases positive for HPV 16 also was positive for HPVs 6 and 11. Six pregnant women were infected with HPVs 6 and 11, 4 with HPV 33, and 18 with HPVs as yet untyped. The seven subjects with questionable rupture of membranes all were HPV-negative.

Reproductive features were similar in HPV-negative and HPV-positive mothers, and there were no differences in gestational age or birth weight of newborns (Table 1). In none of our cases was maternal HPV genital infection associated with congenital or neonatal abnormalities. Selected demographic and behavioral features of HPV-negative and HPV-positive mothers are reported in Table 2. Mothers with HPV infections were younger than HPV-negative mothers and were more frequently unmarried. Smoking during pregnancy was associated with an increased risk of HPV infection (² for trend = 3.5, P = .05).

Obstetric characteristics of infants born to HPV-positive women are reported in Table 3. All HPV-positive infants were born vaginally, and their gestational ages and birth weights were similar to those of HPV-negative cases. The median (range) time from rupture of membranes to delivery was 2 (0.5–18) hours for HPV-positive babies and 1.1 (0–11) hour for HPV-negative babies (P= .006 by Mann-Whitney test). Neonatal nasopharyngeal aspirates were HPV-negative in all 11 cases in which rupture of membranes occurred less than 2 hours before delivery. When rupture preceded delivery by 2–4 hours or occurred after more than 4 hours, the respective rates for HPV positivity were seven of 21 and four of five (² for trend = 10.7, P= .001). The 37 infants born to HPV-positive mothers were treated successfully at programmed visits. Their oropharyngeal swabs tested negative at 5 weeks, and at 6, 12, and 18 months after delivery.

	Discussion

Top Abstract Materials and Methods Results Discussion References

Reported rates of vertical perinatal HPV transmission to the oropharyngeal mucosae varied widely, from as low as 0% to as high as 80.9%. Such differences can derive partly from sensitivity of the method employed to detect HPV DNA. Using PCR, Cason et al¹⁰found vertical transmission rates of up to 70% in a cohort of pregnant women selected deliberately on the basis of a high prevalence of HPV infection (presence of genital warts and history of abnormal Papanicolaou smears). Puranen et al¹¹reported a higher detection rate (up to 80%) using PCR followed by Southern blot hybridization or reamplification. Sedlacek et al⁶used Southern blotting, a less sensitive technique than PCR, and found 60% vertical transmission in a high-risk population of young women from a low socioeconomic group. Using Vira Pap/Vira Type (Life Technologies, Gaithersburg, MD) in a randomly selected cohort of women with high school or college education, Smith et al⁹found a rate of less than 10%, a finding that might be due to sensitivity of their detection method being poor when only a few copies of the virus are present. In a prospective cohort study on a population with a high prevalence of HPV during pregnancy, Watts et al¹²did not find PCR virus-positive nasopharyngeal aspirates at birth. The absence of any positive reaction suggests that transient prenatal contamination of infant nasopharyngeal specimens by maternal HPV, without actual infant infection, did not occur.

It is known that the various populations investigated differ in incidences of several risk factors for HPV infections, such as younger age, history of cervical dysplasia and genital warts, smoking, infections with other sexually transmitted diseases, promiscuity, and low socioeconomic level. The chance of perinatal HPV transmission, and the differences in the transmission rates reported, are probably related more to viral load in infected cells than to the well-established risk factors for infection.

Our study focused on asymptomatic pregnant women with no histories of abnormal Papanicolaou smears or genital warts. Latent HPV infections were recognized only after the advent of PCR, a highly sensitive and specific technique. Most infections are probably transient and of little significance to subsequent disease. Nonetheless, they are to be regarded as possible sources of infections in newborns.

Cervicovaginal lavages were collected from our subjects on admission for delivery because it was ascertained that detectable levels of HPV DNA might vary during pregnancy,^13,14and that early testing in the third trimester might not be sufficiently predictive of HPV status at the critical time of delivery, when perinatal transmission might happen.⁹The overall prevalence of HPV latent infections in our cohort can be considered reliable, on the basis of a previous case-control study on two age-matched sets of women.¹⁵

Vertical transmission was lower than that reported in certain other studies, in which subjects included women carrying florid HPV-related lesions. We did not identify viral DNA in the samples obtained from infants delivered by cesarean. Cesarean delivery is generally thought to protect against perinatal transmission of HPV, provided that the amnion is intact, but detection of HPV DNA in peripheral blood mononuclear cells¹⁶ and amniotic fluid^6,17indicates that the virus can cross the placental barrier and infect the fetus in the uterus.

Our data suggest that the time between rupture of the amnion and delivery might be an important factor in predicting perinatal oropharyngeal HPV transmission. None of the newborns of infected mothers tested positive when born within 2 hours of membrane rupture.

All our HPV-positive newborns carried HPV types identical to those found in their mothers. However, discordant mother-newborn pairs have been reported in several papers, as well as HPV-positive babies from HPV-negative mothers.^7,8Explanations include false negativity of maternal samples, HPV transmission by transplacental route in advance of delivery, and HPV transmission to the newborn by another route.¹⁸

The presence of HPV DNA in newborn nasopharyngeal samples does not necessarily indicate infection; it might just indicate contamination with infected maternal cells. Its presence demonstrates a mechanism by which the virus can be transmitted at birth.⁶Confirmation of infection, rather than contamination, would require other evidence, such as detection of mRNA. Infection might be subclinical and short-lived, thus devoid of any pathologic implications. Knowing if HPV-positive newborns stay positive for a long time might increase our understanding. In most studies, the infants were not studied after sampling at birth. Those studies that did follow-up analysis of HPV-positive neonates found persistence of orally located HPV DNA in 23–66% of infants for at least 6 weeks.^8,10,18,19We were able to study our HPV-positive infants until 18 months after delivery. Five weeks after birth, all the infants tested negative and continued to throughout the 18-month follow-up.

	Footnotes

 
This study was supported by grant no. 030RFM92/02 from the Italian Ministry of Health (to IRCCS Policlinico San Matteo).

The authors gratefully acknowledge Doctor Umberto Maccarini’s help in collecting samples.

PII S0029-7844(98)00459-1

Received June 18, 1998. Received in revised form September 10, 1998. Accepted October 1, 1998.

	References

Top Abstract Materials and Methods Results Discussion References

 
1. Cason J, Kaye JN, Best JM. Non-sexual acquisition of human genital papillomaviruses. Papillomavirus Rep 1995;6:1–7.

2. Franco EL, Villa LL, Richardson H, Rohan TE, Ferenczy A. Epidemiology of cervical human papillomavirus infection. In: Franco EL, Monsonego J, eds. New developments in cervical cancer screening and prevention. Oxford, United Kingdom: Blackwell Science,1997:14–22.

3. Tenti P, Zappatore R, Romagnoli S, Civardi E, Giunta P, Scelsi R, et al. p53 overexpression and human papillomavirus infection in transitional cell carcinoma of the urinary bladder: Correlation with histological parameters. J Pathol 1996;178:65–70.[Medline]

4. Manos MM, Wright DK, Lewis AJ, Broker TR, Wolinsky SM. The use of polimerase chain reaction amplification for the detection of genital papillomavirus. In: Steinberg BM, Brandsma JL, Taichman LB, eds. Cancer cells 7, Molecular diagnostics of human cancer. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press, 1989:209–14

5. Hajek ZF. Contribution to the etiology of laryngeal papilloma in children. J Laryngol Otol 1956;70:166–8.[Medline]

6. Sedlacek TV, Lindheim S, Eder C, Hasty L, Woodland M, Ludomirsky A, et al. Mechanism for human papillomavirus transmission at birth. Am J Obstet Gynecol 1989;161:55–9.[Medline]

7. Smith EM, Johnson SR, Pignatary S, Cripe TC, Turek L. Perinatal vertical transmission of human papillomavirus and subsequent development of respiratory tract papillomatosis. Ann Otol Rhinol Laryngol 1991;100:479–83.[Medline]

8. Pakarian F, Kaye J, Cason J, Kell B, Jewers R, Derias NW, et al. Cancer associated human papillomavirus: Perinatal transmission and persistence. Br J Obstet Gynaecol 1994;101:514–7.[Medline]

9. Smith EM, Johnson SR, Cripe T, Perlman S, McGuinness G, Jiang D, et al. Perinatal transmission and maternal risks of human papillomavirus infection. Cancer Detect Prev 1995;19:196–205.[Medline]

10. Cason J, Kaye JN, Jewers RJ, Kambo PK, Bible JM, Kell B, et al. Perinatal infection and persistence of human papillomavirus types 16 and 18 in infants. J Med Virol 1995;47:209–18.[Medline]

11. Puranen MH, Yliskoski MH, Saarikoski SV, Syrjänen KJ, Syrjänen SM. Exposure of infant to cervical human papillomavirus infection of the mother is common. Am J Obstet Gynecol 1997;176:1039–45.[Medline]

12. Watts DH, Koutsky LA, Holmes KK, Goldman D, Kuypers J, Kiviat NB, et al. Low risk of perinatal transmission of human papilloma-virus: Results from a prospective cohort study. Am J Obstet Gynecol 1998;178:365–73.[Medline]

13. Fife KH, Rogers RE, Zwickl BW. Symptomatic and asymptomatic cervical infections with human papillomavirus during pregnancy. J Infect Dis 1987;156:904–11.[Medline]

14. Rando RF, Lindheim S, Hasty L, Sedlacek TV, Woodland M, Eder C. Increased frequency of detection of human papillomavirus deoxyribonucleic acid in exfoliated cervical cells during pregnancy. Am J Obstet Gynecol 1989;161:50–5.[Medline]

15. Tenti P, Zappatore R, Migliora P, Spinillo A, Maccarini U, De Benedittis M, et al. Latent human papillomavirus infection in pregnant women at term: A case-control study. J Infect Dis 1997;176:277–80.[Medline]

16. Tseng CJ, Lin CY, Wang RL, Chen LJ, Chang YL, Hsieh TT, et al. Possible transplacental transmission of human papillomaviruses. Am J Obstet Gynecol 1992;166:35–40.[Medline]

17. Armbruster Moraes E, Ioshimoto LM, Leão E, Zugaib M. Presence of human papillomavirus DNA in amniotic fluids of pregnant women with cervical lesions. Gynecol Oncol 1994;54:152–8.[Medline]

18. Puranen M, Yliskoski M, Saarikoski S, Syrjänen K, Syrjänen S. Vertical transmission of human papillomavirus from infected mothers to their newborn babies and persistence of the virus in childhood. Am J Obstet Gynecol 1996;174:694–9.[Medline]

19. Fredericks BD, Balkin A, Daniel HW, Schonrock J, Ward B, Frazer IH. Transmission of human papillomaviruses from mother to child. Aust N Z J Obstet Gynaecol 1993;33:30–2.[Medline]

This article has been cited by other articles:

				R A Tasca and R W Clarke Recurrent respiratory papillomatosis. Arch. Dis. Child., August 1, 2006; 91(8): 689 - 691. [Abstract] [Full Text] [PDF]

				M. A. M. Rintala, S. E Grenman, M. H. Puranen, E. Isolauri, U. Ekblad, P. O. Kero, and S. M. Syrjanen Transmission of High-Risk Human Papillomavirus (HPV) between Parents and Infant: a Prospective Study of HPV in Families in Finland J. Clin. Microbiol., January 1, 2005; 43(1): 376 - 381. [Abstract] [Full Text] [PDF]

				H. Minkoff, K. R. Powderly, F. Chervenak, and L. B. McCullough Ethical Dimensions of Elective Primary Cesarean Delivery Obstet. Gynecol., February 1, 2004; 103(2): 387 - 392. [Abstract] [Full Text] [PDF]

				T. C. Wright Jr., S. J. Goldie, J. M. Cain, and M. K. Howett Screening for Cervical Cancer Science, December 1, 2000; 290(5497): 1651a - 1651. [Full Text]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by TENTI, P. Articles by CARNEVALI, L. Search for Related Content PubMed PubMed Citation Articles by TENTI, P. Articles by CARNEVALI, L.