Risk Factors for Juvenile-Onset Recurrent Respiratory Papillomatosis

(Pediatr Infect Dis J, 1998;17:372-6)

Keerti V. Shah, MD, DrPH,1 William F. Stern, MS,2 Farida K. Shah, MS,3
David Bishai, MD, MPH, PhD3 and Haskins K. Kashima, MD4

 

1Dept. of Molecular Microbiology and Immunology, Johns Hopkins University, School of Hygiene and Public Health, 615 N. Wolfe Street, Baltimore, MD 21205. Phone: 410-955-3189; fax: 410-955-0105;email: kvshah@jhsph.edu

2Recurrent Respiratory Papillomatosis Foundation, Lawrenceville, NJ

3Dept. of Population Dynamics, Johns Hopkins University, School of Hygiene and Public Health, Baltimore, MD

4Dept. of Otolaryngology--Head and Neck Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD

Abbreviated title: Risk factors for JORRP

Key words: respiratory papilloma; human papillomavirus; cesarean birth

 

Abstract

Background: Children born to condylomatous mothers are at risk for developing juvenile-onset recurrent respiratory papillomatosis (JORRP). We inquired if the triad of vaginal delivery, being first-born, and maternal age of less than 20 years are also risk factors for JORRP.

Methods: Data for JORRP and adult-onset (AO) RRP cases were obtained from questionnaires answered by patients or their parents for the Recurrent Respiratory Papillomatosis Foundation. The observed numbers of cesarean births, first order births, and births to mothers less than 20 years old were compared with expected numbers for the same variables, which were computed by distributing the cases by year of birth and then applying to them national annual statistics for the year of birth. In addition, observed and expected numbers of first order births to mothers less than 20 years old were compared with corresponding numbers in mothers 20 years old or older.

Results: In JORRP cases, the relationships between observed and expected numbers of cases were as follows: cesarean births, 4.6 fold less; first order births, 1.6 fold greater; maternal age less than 20 years old, 2.6 fold greater. All these differences were statistically highly significant. The observed parity effect was mediated to a large extent by maternal age. In contrast, there were no significant differences between observed and expected numbers of AORRP cases with respect to any of the above variables.

Conclusions: Young, primiparous mothers with condylomas are at a high risk for transmission of JORRP to their infants. The option of cesarean delivery should be discussed with a mother who has condyloma at the time of delivery.

 

 

Introduction

JORRP is a rare disease, with a recent estimate of about 2,300 cases, annually, in the USA.1 The papillomas are histologically benign neoplasms, which often recur after surgical removal and can produce sudden respiratory obstruction and become life-threatening. In the most severe cases, swift regrowth necessitates surgical operations as often as every 2-4 weeks. The disease may fluctuate in severity and may enter remission after several years, or persist into adulthood. The disease is most common on the vocal folds but may extend to other sites (trachea, lung) in the respiratory tract. In rare instances, the papilloma may undergo malignant transformation.

The etiologic link between maternal condyloma at delivery and JORRP in the infant was first recognized by Hajek2 in a case report in 1956. This observation was supported by additional case reports3 and by the finding that more than 50% of mothers of JORRP cases gave a history of having condylomas during pregnancy and/or at delivery.4,5 Subsequent virologic studies fully substantiated the link between genital condylomas and JORRP. HPV types 6 and 11 which are responsible for 80-90% of the condylomas are documented in nearly 100% of JORRP.6-8 Transmission of the virus from mother to infant is believed to occur predominantly intrapartum, as the fetus passes through an infected birth canal.2 Cases of JORRP rarely give a history of cesarean birth, an indication that cesarean delivery decreases the risk of acquiring JORRP.9 Adult-onset RRP (AORRP) is also caused by infection with HPV-6 and HPV-11 but very probably, the infection is not acquired at birth.10

Genital tract infection with HPV-6 and HPV-11 is common, but JORRP is rare. Data are not available to make a reliable estimate of the risk of transmission from an infected mother to a child but this risk is perceived to be low.9-11 It has been suggested that a finer definition of a high-risk birth would be helpful in considering cesarean delivery for the prevention of JORRP.1,9,12,13

Epidemiologic investigations of JORRP and AORRP have been difficult because of the rarity of the disease. In a recent case control study of 26 JORRP and 33 AORRP cases at Johns Hopkins Hospital, it was found that the triad of vaginal delivery, being first-born and having a teenage mother were risk factors for JORRP but not for AORRP.10 A larger data base became available when in 1992, RRP patients and their families, in collaboration with otolaryngologists and other interested investigators nationwide, created the Recurrent Respiratory Papillomatosis Foundation (RRPF) to provide support to patients and their families, to serve as a resource for information about RRP, and to aid in efforts for the prevention and treatment of RRP.14 In this report, we compare JORRP and AORRP cases in the RRPF data base with national statistics with respect to the triad of probable risk factors for JORRP, viz., (1) manner of delivery (vaginal or cesarean), (2) being first-born, and (3) maternal age less than 20 years.

 

Methods

RRP Cases: The RRP Newsletter, a twice a year publication of the RRPF (RRP Foundation, PO Box 6643, Lawrenceville, NJ 08648-0643), provides a detailed and continuing account of recruitment of patients and the status of the RRPF database. The patient information used in this study was collected from answers to questionnaires designed by the RRPF and completed by the patients and parents of underage patients. The RRPF has located and surveyed RRP patients in the USA primarily through their attending otolaryngologists. The RRPF questionnaires were sent to otolaryngologists who distributed them to their RRP patients, with a request to complete and return them to the RRPF. The respondents have given written informed consent to allow the use of the information in the questionnaire for research.

For this study, the following information was extracted from the RRPF database: age at RRP diagnosis; year of birth; manner of delivery (vaginal or cesarean); age of mother at the time of the patient's birth; and birth order. Patients were classified as JORRP if their age at diagnosis (approximation for age of onset of disease) was 14 years or less and as AORRP if their age at diagnosis was greater than 14 years.1 There were no cases diagnosed at 15, 16 and 17 years of age. The proportion of JORRP cases diagnosed by the ages of 1 year, 2 years, 3 years and 5 years were 29%, 58%, 71% and 88%, respectively. Questions regarding maternal age and birth order were added later to the questionnaire, so information about these variables was available from fewer patients than information about age at diagnosis and type of delivery. Only one JORRP and five AORRP cases from Johns Hopkins Hospital who could have possibly participated in the case-control study reported previously10 were registered with RRPF, so there was little overlap between the two studies.

National statistics: Annual cesarean rates from 1965 to 1994 were obtained from publications based on National Center for Health Statistics (NCHS) Surveys.15-18 Annual data for the same years, on proportion of all births that were first order births, that were born to mothers younger than 20 years, and that were first order births born to mothers stratified by age (less than 20 and equal to or greater than 20) were obtained from vital statistics publications from NCHS.19

Statistics: For each of the variables (cesarean birth, first birth order, maternal age less than 20 years, and first order birth in mothers stratified by age), the expected number of JORRP and AORRP cases were computed by first distributing the cases by year of birth and then applying national annual statistics to cases born in that year. All cases born before 1970 were grouped in a single category and the national statistics for 1965 were applied to these births. The expected numbers of cases were compared with the actual numbers of cases using the Z test for proportions.

 

Results

Cesarean births: The national cesarean birth rate increased rapidly from 5.5% in 1970 to greater than 20% in 1983, peaked at 24.7% in 1988 and has since declined gradually to 23.0% in 1994. Among the patients surveyed, a large majority of the JORRP patients (77%) were born after 1980, whereas most of AORRP cases (94%) were born before 1970 (Table 1). The observed number of cesarean births in JORRP cases (6 births) was about 4.6 fold less than the expected number (27.4 births); this difference was statistically highly significant (p < 0.0001) (Table 1). In contrast, the difference between observed and expected numbers of cesarean births in AORRP cases was not statistically significant (Table 1).

We were able to make telephone contact with the mothers of three of the six JORRP cases who were born by cesarean delivery in 1987 and 1988. According to their recollection, in all three instances, cesarean delivery was performed after the labor pains had started and after the rupture of the amniotic membranes.

Maternal age and birth order: The national data on percentage of children who are (1) first-born, (2) born to mothers less than 20 years, and (3) first-born to mothers younger than 20 years were examined. The percentage of children who are first-born increased from 30.8% in 1965 to 38.8% in 1970 and has remained steady around 40% since then, whereas children born to mothers under the age of 20 years has declined from 19.7% in 1973 to 13.1% in 1994. Approximately 10.2% of children born in 1994 were first-births to mothers under the age of 20.

The observed number of JORRP cases who were first-born (85 cases) was 1.6 times greater than the expected number (51.4), a difference which was statistically highly significant (p < 0.001) (Table 2). The number of JORRP cases born to mothers younger than 20 years was 2.6 times greater than the expected number (33 vs. 13.6); this difference was also statistically highly significant (p < 0.002) (Table 2). Because of the known high correlation between maternal age and parity, we compared the observed and expected numbers of first births for mothers <20 years old and mothers > 20 years old (Table 2). The observed births were 2.7 times higher for mothers <20 years old (p < 0.002), but only 1.3 times higher for women >20 years old (p = 0.29) (Table 2). In contrast, the observed and expected numbers of AORRP cases were not significantly different for any of these variables.

 

Discussion

The study revealed a sharp contrast between JORRP and AORRP with respect to risk factors. For each of the variables examined, AORRP cases were not significantly different from national statistics whereas JORRP cases were markedly different from national statistics. These results confirm the findings of an earlier case-control study10 and indicate that JORRP and AORRP, while they are caused by the same HPV types, are very likely acquired under different circumstances.

The rarity of cesarean delivery in JORRP cases is indirect evidence that the cases may be preventable by cesarean delivery. We have previously reported one case of cesarean birth when 10 would have been expected.9 In the present communication, we confirmed the rarity of cesarean births in JORRP cases; there were six cases delivered by cesarean, when 27 would have been expected. In at least three instances, the cesarean section was performed after onset of labor and after rupture of membranes, raising the possibility that in these cases, the fetus could have been exposed to virus after membrane rupture. More direct and objective evidence for the protective effect of timely cesarean delivery could be obtained from a randomized clinical trial in women who have condylomas at delivery. However, given the rarity of the disease, the many years of necessary follow-up and, most important, the ethical dilemma of having a control group which would not have the option of having a cesarean delivery, it is questionable that such a trial can or should be conducted. For similar reasons, it will not be possible to compare directly the importance of clinical condylomas relative to subclinical HPV-6/11 infections of the genital tract for the occurrence of JORRP.

The data presented in our study identify being first-born, and birth to a teenage mother as additional risk factors for JORRP. Ten percent of U.S. births,21 but 28% of JORRP cases, are first-born children to teenage mothers. Our finding that primiparous women older than 20 years were not at significantly increased risk of having a child with JORRP suggests that the observed parity effects are to a large extent mediated by maternal age. One limitation of the study is that these results are based on information provided by families who registered with the RRPF. Therefore, the findings of this study need to be evaluated for their generalizability by investigation of cases in population-based RRP registries, which are being set up in some regions in the USA (Armstrong et al., abstract presented at the 16th International Papillomavirus Conference, September, 1997, Siena, Italy). The conclusions are biologically plausible. The prevalence of condylomas may be higher in young mothers, and young women may be undergoing primary infection when the viral burden, and therefore the risk of transmission, is the highest. The risk of intrapartum transmission of herpes simplex virus, type 2, is very high (1 in 3) when the infection is primary, but is reduced 10-fold or more, when it is recurrent.22 The longer labor in first order birth could potentially increase the time of contact between the fetus and infected maternal secretions.

Cesarean birth is generally not offered to a mother who has condylomas because the risk of JORRP to a child born to a condylomatous mother is perceived to be very low.9,13,20 The guideline on perinatal care of the American College of Obstetricians and Gynecologists states that "cesarean delivery is not recommended solely to protect the neonate from HPV infection".11 We have estimated that the risk of transmission of JORRP from a condylomatous mother to an infant may be 1-3%,12 and could be as high as 8% for first-born children of teenage mothers (Bishai et al., unpublished data). The assumptions on which these estimates are made, as well as other considerations (e.g., maternal morbidity due to cesarean delivery, cost-benefit analysis of cesarean delivery), need to be debated before a population-wide policy regarding the prevention of JORRP by cesarean deliveries is instituted, but personal choice is a different matter. It is highly probable that some women at risk would be willing to personally incur the extra expense and operative risk of cesarean delivery to eliminate a 1%-8% chance of JORRP in their child. The principle of autonomy would suggest that information regarding a possible benefit be disclosed to patients who are at risk.23 The need for cesarean delivery would be lessened if an effective treatment for condylomas, suitable for pregnant women, were available. Several new approaches toward prevention and treatment of condylomas are promising.24,25 Any treatment that would reduce the HPV viral burden in the genital tract during labor, or diminish fetal contact with maternal virus, would likely decrease the incidence of JORRP.

 

 

 

 

Acknowledgements

This study was supported in part by Public Health Service grant U19 AI38533 (KVS) and the Recurrent Respiratory Papillomatosis Foundation (WFS).

References

  • 1. Derkay CS. Task force on recurrent respiratory papillomas. A preliminary report. Arch Otolaryngol Head Neck Surg 1995;121:1386-91.

    2. Hajek E. Contribution to the etiology of laryngeal papilloma in children. J Laryngol 1956;70:166-168.

    3. Kaufman RS, Balogh K. Verrucas and juvenile laryngeal papilloma. Arch Otolaryngol Otol 1969;89:748-49.

    4. Cook TA, Brunschwig JP, Butel JS, Cohn AM, Goepfert H, Rawls WE. Laryngeal papilloma: Etiologic and therapeutic considerations. Ann Otol Rhinol Laryngol 1973;82:649-55.

    5. Quick CA, Watts SL, Krzyzek RA, Faras J. Relationship between condylomata and laryngeal papillomata. Clinical and molecular virological evidence. Ann Otol Rhinol Laryngol 1980;89:467-71.

    6. Gissmann L, Diehl V, Schultz-Loulon HJ, zur Hausen H. Molecular cloning and characterization of human papillomavirus DNA derived from a laryngeal papilloma. J Virol 1982;44:393-400.

    7. Mounts P, Shah KV, Kashima H. Viral etiology of juvenile- and adult-onset squamous papilloma of the larynx. Proc Natl Acad Sci USA 1982;79:5425-9.

    8. Abramson AL, Steinberg BM, Winkler B. Laryngeal Papillomatosis: Clinical, histopathologic and molecular studies. Laryngoscope 1987;97:678-85.

    9. Shah K, Kashima H, Polk BF, Abbey H, Shah F, Abramson A. Rarity of cesarean delivery in cases of juvenile-onset respiratory papillomatosis. Obstet Gynecol 1986;68:795-9.

    10. Kashima H, Shah F, Lyles A, et al. A comparison of risk factors in juvenile-onset and adult-onset recurrent respiratory papillomatosis. Laryngoscope 1992; 102:9-13.

    11. American Academy of Pediatrics and American College of Obstetrics and Gynecology. Guidelines for Perinatal Care, 3rd ed. 1992.

    12. Shah KV, Kashima H. Prevention of juvenile-onset recurrent respiratory papillomas. Curr Opinion Otolaryngol Head Neck Surg 1997;5:107-11.

    13. Kosko JR, Derkay CS. Role of cesarean section in prevention of recurrent respiratory papillomatosis -- Is there one? Intl J Pediatr Oto Rhino Laryngol 1996;35:31-8.

    14. Announcement. Recurrent Respiratory Papillomatosis Foundation. Intl J Pediatr Otorhinolaryngol 1997; (in press).

    15. Placek PJ, Taffel SM. Trends in cesarean section rates for the United States, 1970-78. Public Health Rpt 1980;95:540-8.

    16. Placek PJ, Taffel SM. Recent patterns in cesarean delivery in the United States. Obstet Gynecol Clin NA 1988;15:607-27.

    17. Clarke SC, Taffel S. Changes in cesarean delivery in the United States, 1988 and 1993. Birth 1995;22:63-7.

    18. Guyer B, Strobino DM, Ventura SJ, MacDorman M, Martin JA. Annual summary of vital statistics--1995. Pediatrics 1996;98:1007-19.

    19. National Center for Health Statistics. Vital Statistics of the United States. Annual Reports, 1970-1990, Monthly Vital Statistics Reports 1993-1995. Hyattsville, MD.

    20. Bennett RS, Powell KR. Human papillomaviruses: Associations between laryngeal papillomas and genital warts. Pediatr Infect Dis J 1987;6:229-32.

    21. National Center for Health Statistics. Monthly Vital Statistics Report, 1997. Vol. 46 No. 1, Supplement 2, page 10.

    22. Brown ZA, Benedetti J, Ashley R, et al. Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N Engl J Med 1991; 324:1247-52.

    23. Council on Ethical and Judicial Affairs of the American Medical Association. Code of Medical Ethics, 1977, p. xli.

    24. Buetner KR, Ferenczy A. Therapeutic approaches to genital warts. Am J Med 1997;102:28-37.

    25. Baker GE, Tyring SK. Therapeutic approaches to papillomavirus infections. Dermatol Clin 1997;15:331-40.

     

  • Table 1

    Observed and expected numbers of cesarean births in JO-RRP and AO-RRP cases

     

     

    JO-RRP

     

     

    AO-RRP

     

     

     

     

    Cesarean births

     

     

     

     

    Cesarean births

     

    Years of birth

     

    # cases

     

    observed

     

    expected*

     

     

    # cases

     

    observed

     

    expected*

     

    < 1970

     

    16

     

    0

     

    0.8

     

     

    65

     

    6

     

    3.3

     

    1970-79

     

    16

     

    1

     

    2.1

     

     

    4

     

    1

     

    0.3

     

    1980-89

     

    46

     

    5

     

    10.5

     

     

     

     

     

    1990-94

     

    60

     

    0

     

    14.0

     

     

     

     

     

    Total

     

    138

     

    6 (4.3%)

     

    27.4 (19.9%)

     

     

    69

     

    7 (10.1%)

     

    3.6 (5.2%)

     

    p value < 0.0001

     

     

     

    NS

     

     

  • *estimated by application of annual cesarean birth rate to cases born in that year.
  • Table 2

    Observed and expected numbers of JO-RRP and AO-RRP cases who are first-born, or are born to mothers

    less than 20 years old and are first-born to younger (<20 years) or older (>20 years) mothers

     

     

     

    JO-RRP

     

     

    AO-RRP

     

     

     

     

    All cases

     

    No. of

    cases

     

     

    observed

     

     

    expected*

     

    p

    value

     

     

    No. of

    cases

     

     

    observed

     

     

    expected*

     

    p value

     

    First-born

     

    128

     

    85 (66.4%)

     

    51.4 (40.2%)

     

    <0.001

     

     

    60

     

    22 (36.7%)

     

    18.8 (32.5%)

     

    NS

     

     

    Maternal age <20 years

     

     

    100

     

     

    33 (33.0%)

     

     

    13.6 (13.6%)

     

     

    <0.002

     

     

     

    53

     

     

    4 (7.6%)

     

     

    8.5 (16.0%)

     

     

    NS

     

     

     

    First-born cases

    Maternal age <20 years

     

     

     

    97

     

     

     

    27 (27.8%)

     

     

     

    10.1 (10.4%)

     

     

     

    <0.002

     

     

     

     

    52

     

     

     

    4 (7.7%)

     

     

     

    6.2 (11.9%)

     

     

     

    NS

     

    Maternal age

     

    >20 years

     

     

    97

     

     

    36 (37.1%)

     

     

    28.5 (29.4%)

     

     

    NS

     

     

     

    52

     

     

    14 (26.9%)

     

     

    10.2 (19.6)

     

     

    NS

    *estimated by application of annual national rates.