High-risk human papillomavirus associated with incident cervical intraepithelial neoplasia developing in mothers in the Finnish Family HPV Study cohort.

BACKGROUND: Cofactors of high-risk (HR) human papillomavirus (HPV) in the progression of cervical intraepithelial neoplasia (CIN) are incompletely characterized. In this study these cofactors were investigated in a longitudinal setting. METHODS: A cohort of 329 women (mean age 25.5 y) were enrolled in the Finnish Family HPV Study, and followed-up for 6 y with serial cervical samples for HPV genotyping, virus integration status, and HPV serology. Hospital records were reviewed until March 2010 and linked with HPV detection data. All incident CIN lesions were subjected to HPV genotyping. HPV covariates were studied in an age- and HPV-matched nested case-control (1:4) setting. RESULTS: Twelve of the 329 women developed an incident CIN: 2 CIN1, 3 CIN2, and 7 CIN3. HPV16 was detected most frequently (7/12), followed by HPV58 (2/12), HPV18, HPV31, and HPV42. HPV integration was present in 4/12 cases. Long-lasting persistence of HPV31 and HPV16 preceded incident CIN2 and CIN3. In multivariate conditional logistic regression, the risk for incident CIN increased up to 4-fold with increasing number of deliveries (p = 0.024) and decreased with history of genital warts (p = 0.036). CONCLUSION: Baseline HR-HPV infections and their persistence precede incident CIN by several years. The 2 independent covariates of HR-HPV were (1) number of deliveries (increasing the risk), and (2) history of genital warts (protective effect).

Incident cervical infections with high- and low-risk human papillomavirus (HPV) infections among mothers in the prospective Finnish Family HPV Study.

BACKGROUND: The knowledge on type specificity and factors that increase or decrease the risk of incident HPV-infections is important to better understand the dynamics of HPV-infections. METHODS: A series of 329 pregnant women were enrolled in Finnish Family HPV Study at 3rd trimester of pregnancy and followed-up for 6 years, during which 203 baseline HPV-negative women acquired incident HPV infection. Incidence times and incidence rates (IR) were calculated for 24 low-and high-risk HPV-types detected by Multiplex-HPV-genotyping at each visit. Poison regression was used to estimate predictors of incident HPV infections of species 7 and 9 HPV-genotypes. RESULTS: HPV16 was the most frequent (47.8%) incident genotype followed by multiple-type infections (25.1%), and single infection with HPV18, 70, 6 and 45. Actuarial mean times to incident event were longest for HPV31 (34.5 months) and HPV45 (32.8 months), while crude mean times were longest for HPV56 (42.4 months) and HPV16 (23.1 months). Actuarial IR was highest for HPV16 and multiple-type infections. Independent protective factors against incident infections were 1) > 2 life-time sexual partners (p = 0.014), 2) later initiation of oral contraceptives (age > 20 years) (p = 0.017) and 3) pregnancy at FU visit (p = 0.0001). CONCLUSIONS: Among newly delivered mothers, higher number of life-time sexual partners, initiation of OC use after age 20 and becoming pregnant during FU decreased the risk for incident species 7/9 HPV infections.

Human papillomavirus and predictors of cervical intraepithelial neoplasia among young mothers in a prospective follow-up study.

OBJECTIVE: To study the incidence times and rates for cervical intraepithelial neoplasia (CIN) and its predictors. MATERIAL AND METHODS: This is a prospective follow-up study at Turku University Hospital, Finland. The Finnish Family human papillomavirus (HPV) study comprised 329 pregnant women followed up for 3 years. In an extension of the follow-up period, 171 women participated in an additional 3 years follow-up. Cervical scrapings for HPV testing and cervical smears were collected at each follow-up visit (2, 12, 24 and 36 months and 6 years). Following two abnormal cervical smears, colposcopy with biopsies was done. The main outcome measures were actuarial and crude incidence times, incidence rates and predictors of incident CIN. RESULTS: During the follow-up period, 10 women (3.2%) developed biopsy-confirmed CIN, and four presented with incident atypical squamous cells suggesting high-grade squamous intraepithelial lesion cytology. The CIN/squamous intraepithelial lesion developed in 74.5 and 66.3 months, with crude incidence rates of 13.4/1,000 and 15.1/1,000 women months at risk, respectively. In multivariate Poisson regression, independent predictors of incident CIN were as follows: high-risk HPV positive at baseline (incidence rate ratio = 5.54; 95% confidence interval 1.02-30.14, p= 0.048); type-specific high-risk HPV persistence during follow-up (incidence rate ratio = 5.84; 95% confidence interval 2.28-17.93, p= 0.0001); cervical smear cytologically diagnosed for atypical squamous cells of undetermined significance or worse at any follow-up visit (incidence rate ratio = 4.56; 95% confidence interval 2.37-8.78, p= 0.0001); and new sexual partner during follow-up (incidence rate ratio = 9.45; 95% confidence interval 1.90-46.97, p= 0.006). CONCLUSION: The results indicate that combined use of cervical smear and HPV testing, with prompt referral to colposcopy, enables accurate detection of incident CIN well before progression to invasive cancer. In addition to baseline and persistent high-risk HPV, abnormal cervical smear and new sexual partner are key predictors of incident CIN.

Genotype-specific clearance of genital human papillomavirus (HPV) infections among mothers in the Finnish family HPV study.

The majority of cervical human papillomavirus (HPV) infections in young women are transient, but whether the clearance differs among different HPV genotypes and the different factors predicting genotype-specific clearance are partly unknown. In the Finnish Family HPV Study, 131 of 252 women (mean age, 25.5 years) cleared their infection during the prospective follow-up of 6 years (median, 62.4 months; range, 1.6 to 94.5 months). Cervical scrapings collected at each visit were tested for 24 low-risk and high-risk (HR) HPV types with multiplex HPV genotyping. Poison regression (panel data) was used to estimate predictors for the clearance of species 7 and 9 HPV genotypes. Of all HPV genotypes detected in these women, multiple-type and HPV type 16 (HPV16) infections showed clearance least frequently (46.1% and 50.5%, respectively). The actuarial and crude mean times to first clearance were variable among different genotypes. The actuarial clearance rate (events/person-time at risk) was highest for HPV16 and multiple-type infections, while HPV66 and -82 had the highest crude clearance rate. Independent predictors increasing type-specific clearance of species 7/9 HPV genotypes were older age (incidence rate ratio [IRR] = 1.1; 95% confidence interval [95% CI], 1.03 to 1.18; P = 0.002) and baseline oral HR HPV DNA-negative status (IRR = 2.94; 95% CI, 1.03 to 8.36; P = 0.042), while a higher number of sexual partners during the follow-up decreased the probability of clearance (IIR = 0.35; 95% CI, 0.15 to 0.83; P = 0.018). To conclude, HPV16 and multiple-type infections showed the lowest clearance among young mothers. Increasing age and negative oral HR HPV DNA status at baseline were associated with increased clearance, whereas a higher number of current sexual partners decreased the probability of species 7/9 HPV genotype clearance.

Effect of second pregnancy on maternal carriage and outcome of high-risk human papillomavirus (HPV). Experience from the prospective finnish family HPV study.

OBJECTIVES: The effect of second pregnancy on human papillomavirus (HPV) carriage and outcome is modelled in longitudinal setting covering two subsequent pregnancies. STUDY DESIGN: Among 329 (baseline pregnant) women prospectively followed up in the Finnish Family HPV Study, two subcohorts were compiled: (i) 78 women (Group B) who became pregnant for the second time during the follow-up, and (ii) 100 women (Group A) who did not develop 2nd pregnancy. The effect of pregnancy on high-risk HPV (HR-HPV) carriage and outcome was analysed using Kaplan-Meier and Cox survival analyses and generalized estimating equation (GEE) modelling of the longitudinal data. RESULTS: Women in the two groups were similar in their baseline HR-HPV status but significantly different in several known risk factors of HR-HPV infection. Group A women showed higher point prevalence of cervical and oral HR-HPV at the 36-month (p = 0.015) and 6-month (p = 0.024) follow-up visit, respectively. Among Group B women, prevalence of both cervical and oral HR-HPV significantly decreased during 2nd pregnancy (p = 0.005 and p = 0.002) as compared with inter-pregnancy period, but increased again after 2nd pregnancy. There was no difference in acquisition or clearance of cervical or oral HR-HPV between the two groups in univariate (Kaplan-Meier) or multivariate (Cox) survival analysis. In the GEE approach, 2nd pregnancy was not significantly associated with cervical or oral HR-HPV carriage or persistence when adjusted for all other covariates. CONCLUSIONS: Second pregnancy is of little impact on carriage and persistence of oral and cervical HR-HPV infections in a longitudinal setting over time.

Human papillomavirus in the placenta and umbilical cord blood.

OBJECTIVE: To analyze human papillomavirus (HPV) DNA in umbilical cord blood and in placenta, including its cellular localization. DESIGN: Longitudinal prospective study. SETTING: Maternity Unit of Turku University Hospital, and MediCity, University of Turku. SAMPLES: Placental and cord blood samples obtained at delivery from 315 mothers and 311 neonates included in the Finnish HPV Family Study. METHODS: HPV testing by nested PCR and sequencing. Tyramide amplified in situ hybridization (ISH) for viral DNA localization in placenta. Correlation to mother's and neonate's oral and genital HPV status and maternal demographic data. MAIN OUTCOME MEASURES: Detection and cellular localization of HPV DNA. RESULTS: HPV DNA was detected in 4.2 and 3.5% of placenta and cord blood samples, respectively, including HPV types 16, 6, 83 and 39. In placenta, HPV6 and 16 DNA was localized in syncytiotrophoblasts. Abnormal cytology increased the risk of HPV+ placenta and cord blood. History of genital warts was the only independent predictor of cord blood HPV in multivariate analysis (adjusted OR=4.0, 95% CI: 1.09-14.54, p=0.036). HPV DNA in cord blood increased the risk of genital (OR=4.0, 95% CI: 1.08-14.83, p=0.048) and oral (OR=4.4, 95% CI: 1.17-16.14, p=0.039) HPV DNA carriage of the neonate. HPV+ placenta increased the risk of oral HPV of the neonate (OR=8.6, 95% CI: 2.73-27.13, p=0.0001). Delivery mode did not predict HPV status of the neonate. CONCLUSIONS: HPV DNA is detected in placental trophoblasts and umbilical cord blood. The presence of HPV DNA at these sites increases the risk of a neonate testing HPV-positive at birth.

High-risk types of human papillomavirus (HPV) DNA in oral and genital mucosa of infants during their first 3 years of life: experience from the Finnish HPV Family Study.

BACKGROUND: This study is aimed to clarify data on the acquisition, persistence, and clearance of high-risk types of human papillomavirus (HPV) DNA from the mucosa and the determinants of persistent mucosal HPV infection in infants. METHODS: Oral and genital scrapings from 324 infants were collected at birth, 3 days after delivery, and 1, 2, 6, 12, 24, and 36 months after delivery and tested for the presence of HPV DNA by nested polymerase chain reaction and hybridization with 12 high-risk HPV oligoprobes. HPV status and demographic data for parents were analyzed. RESULTS: During the follow-up period (median duration, 26.2 months), HPV DNA was found to be present in 12%-21% of oral scrape samples and in 4%-15% of genital scrape samples obtained from the infants. Oral HPV infection was acquired by 42% of children, cleared by 11%, and persisted in 10% of the infants, whereas 37% were never infected. The corresponding figures for genital HPV infection were 36%, 14%, 1.5%, and 47%. Kaplan-Meier analysis revealed that both the cumulative incidence of infection and clearance of HPV were parallel in oral and genital sites. Persistent oral HPV infection in the child was significantly associated with persistent oral HPV infection in the mother at month 36 of follow-up, hand warts in the mother, young age at onset of sexual activity for the mother, and the mother's use of oral contraception, as well as with the father's oral HPV status at 24 months. Persistent genital HPV infection in the infant was predicted by if the mother had started smoking at 18-21 years of age and by a history of genital warts. CONCLUSIONS: Persistent carriage of high-risk HPV types was detected in oral and genital mucosa specimens obtained from 10% and 1.5% of the infants during their first 26 months of life. The rates of acquisition and clearance of HPV were similar in oral and genital mucosa.

Transmission of high-risk human papillomavirus (HPV) between parents and infant: a prospective study of HPV in families in Finland.

The Finnish HPV Family Study is a prospective cohort study assessing the dynamics of human papillomavirus (HPV) transmission between parents and infant. Serial genital and oral scrapings from 76 families, including mother, father, and infant, and semen samples were collected over 2 years of follow-up, analyzed by nested PCR, and confirmed by hybridization with 12 high-risk (HR) HPV types. The most common HPV profile was HR HPV in all family members (29%), followed by HPV-positive mother-infant pairs (26%). HPV-positive father-infant pairs were less frequent (11%), and in six (8%) families, only the infant was HR HPV positive. The prevalence of genital HR HPV in the parents ranged from 13 to 25%, and that of oral HPV ranged from 8 to 34%. In the infants, HPV DNA was detected in 15% of the genital and 10% of the oral samples at birth, reaching peaks of 18 and 21%, respectively, at 6 months, and declining to 10% at 24 months. Persistent HPV in the mother was a risk factor for oral HPV in the infant (odds ratio [OR], 5.69; 95% confidence interval [95% CI], 1.5 to 21.3), while oral HPV in the mother at 6 months was a risk factor for genital HR HPV (OR, 6.38; 95% CI, 1.15 to 35.32). No such independent risk could be attributed to subclinical HPV in the father. Persistent maternal cervical HPV and subclinical oral HPV affect the risk of infant HPV. The age of 6 months is a critical point for the infant to acquire or be free of HR HPV DNA.

Human papillomavirus DNA is found in the vas deferens.

The role of the male reproductive tract as a reservoir for human papillomavirus (HPV) infection is poorly understood. To analyze the presence of HPV DNA, 27 samples, comprising postvasectomy semen samples and pre- and postejaculation urine samples, were obtained from 18 men recalled for follow-up. HPV DNA was analyzed by nested polymerase chain reaction, confirmed with Southern blot hybridization, cloned, and sequenced. Multiple HPV types were found in different DNA samples of the same men. Five (18.5%) of 27 vas deferens samples contained HPV type 6, 11, or 16. Five (27.8%) of 18 seminal plasma samples (secretions without semen cells) were HPV DNA positive. None of the men had both vas deferens and semen plasma samples HPV positive. Several HPV types can be detected in the male reproductive tract at the same time. This is the first report to show HPV DNA in the vas deferens.