Risk factors for placental human papillomavirus infection.

OBJECTIVE: Human papillomavirus (HPV) has been associated with adverse pregnancy outcomes but placental HPV infection has been rarely studied. The objective was to determine the proportion of HPV-positive placentas and the associated risk factors among HPV-positive women during pregnancy. METHODS: We analysed data from pregnant women enrolled in HERITAGE cohort study between 2010 and 2016 with positive vaginal HPV infection during the first trimester of pregnancy (n=354). Placental swabs and biopsies were collected. HPV genotyping was performed using Linear Array. The predictors of placental HPV detection were identified by generalised estimating equations models. RESULTS: HPV was detected in 78 placentas (22.0%) (one among 96 caesarean sections and 77 among 258 vaginal deliveries). Overall, 91% of HPV-positive placentas were positive for a genotype that was detected in vaginal samples during pregnancy. Among women who delivered vaginally, abnormal cytology (adjusted OR (aOR) 1.78 (95% CI 1.02 to 3.10)), other genitourinary infection (aOR 2.41 (95% CI 1.31 to 4.44)), presence of multiple HPV genotypes in the first trimester (aOR 2.69 (95% CI 1.76 to 4.12)) and persistence of high-risk HPV infections during pregnancy (HPV-16/18: aOR 3.94 (95% CI 2.06 to 7.55) and other than HPV-16/18: aOR 2.06 (95% CI 1.05 to 4.02)) were independently associated with placental HPV. CONCLUSIONS: HPV was frequently detected in the placenta of women who delivered vaginally and may be associated with host immune response characteristics.

Association Between Maternal Human Papillomavirus Infection and Adverse Pregnancy Outcomes: Systematic Review and Meta-Analysis.

BACKGROUND: Experimental studies provide evidence of the harmful effect of human papillomavirus (HPV) infection on pregnancy, but observational studies are inconclusive. We systematically assessed the association between HPV and adverse pregnancy outcomes. METHODS: We searched electronic databases up to December 1, 2019. We included observational studies on the association between HPV and adverse pregnancy outcomes. We conducted a random-effect meta-analysis for each outcome and assessed heterogeneity between studies. RESULTS: From 3034 citations, we included 38 studies and quantitatively synthesized 36 studies. Human papillomavirus was significantly associated with preterm birth (age-adjusted odds ratio [aOR], 1.50; 95% confidence interval [CI], 1.19-1.88), preterm premature rupture of membranes (aOR, 1.96; 95% CI, 1.11-3.45), premature rupture of membranes (aOR, 1.42; 95% CI, 1.08-1.86), intrauterine growth restriction (aOR, 1.17; 95% CI, 1.01-1.37), low birth weight (aOR, 1.91; 95% CI, 1.33-2.76), and fetal death (aOR, 2.23; 95% CI, 1.14-4.37). No significant association was found for spontaneous abortion (aOR, 1.14; 95% CI, 0.40-3.22) and pregnancy-induced hypertensive disorders (aOR, 1.24; 95% CI, 0.80-1.92). Most of the studies were of moderate or low quality, and substantial between-studies heterogeneity remained unexplained. CONCLUSIONS: We found a consistent and significant association between HPV and preterm birth and preterm premature rupture of membranes. Human papillomavirus may also be associated with intrauterine growth restriction, low birth weight, and fetal death, but findings are limited by suboptimal control of biases.

Association between Human Papillomavirus 16 Viral Load in Pregnancy and Preterm Birth.

Recent evidence shows increased preterm birth risk with human papillomavirus-16 (HPV16) infection during pregnancy. This study aimed to measure the association between HPV16 viral load during pregnancy and preterm birth. We used data from participants in the HERITAGE study. The Linear Array assay was used for HPV DNA testing on vaginal samples collected during the first and third trimesters of pregnancy. The HPV16 viral load was measured with a real-time polymerase chain reaction. We used logistic regression to measure the associations between HPV16 viral load during pregnancy and preterm birth (defined as birth before 37 weeks of gestation). The adjusted odd ratios (aORs) and the 95% confidence intervals [CIs] were estimated with inverse probability treatment weighting of the propensity score. This study included 48 participants who tested positive for HPV16 during the first trimester of pregnancy. The aOR for the association between first-trimester HPV16 viral load (higher viral load categorized with a cutoff of 0.5 copy/cell) was 13.04 [95% CI: 1.58-107.57]). Similar associations were found using different cutoffs for the categorization of viral load during the first and third trimesters. Our findings suggest a strong association between a high HPV16 viral load during pregnancy and preterm birth, demonstrating a biological gradient that reinforces the biological plausibility of a causal association.

Association between the Mode of Delivery and Vertical Transmission of Human Papillomavirus.

Human papillomavirus (HPV) can be vertically transmitted. Our objective was to measure the association between the mode of delivery and the detection of HPV in infants. We used data collected from pregnant women during the HERITAGE study. Self-collected vaginal samples from the first and third trimester were obtained for HPV testing. Specimens from oral, pharyngeal, conjunctival and anogenital mucosa were collected from infants 36-48 h after delivery and at 3 months of age. All samples were tested for HPV DNA by the Linear Array assay. Adjusted odd ratios (aOR) and 95% confidence interval (CI) were estimated using multivariate logistic regressions. From the 282 women revealed to be HPV-positive in both the first and third trimesters, 25 infants were born HPV-positive. The overall probability of transmission was 8.9% (25/282); 3.7% (3/81) in participants with a caesarean section and 10.9% (22/201) for those who delivered vaginally. Vaginal delivery increased the risk of HPV in infants compared to caesarean (aOR: 3.63, 95%CI: 1.03-12.82). Infants born after a caesarean with ruptured membranes were not at increased risk of HPV compared to infants born after an elective caesarean section with intact membranes (aOR: 1.31, 95%CI: 0.10-17.76). Our results support the hypothesis that transmission occurs mostly during the passage in the vaginal canal.

Human Papillomavirus Transmission and Persistence in Pregnant Women and Neonates.

Importance: The prevalence of human papillomavirus (HPV) infection during pregnancy and its risk of transmission to newborns are not well documented. Objective: To ascertain the prevalence of HPV in pregnant women, the risk of HPV detection in the placenta and in children at birth, and the probability that HPV detected at birth may persist in newborns. Design, Setting, and Participants: The Human Papillomavirus Perinatal Transmission and Risk of HPV Persistence Among Children (HERITAGE) study was a prospective cohort study that recruited participants between November 8, 2010, and October 16, 2016. Participant follow-up visits were completed on June 15, 2017. Participants, which included pregnant women of at least 18 years of age and at 14 weeks or earlier of gestation, were recruited from 3 academic hospitals in Montreal, Québec, Canada. Laboratory and statistical analysis were completed on November 15, 2022. Exposures: HPV DNA testing on self-collected vaginal and placental samples. Among children of mothers positive for HPV, conjunctival, oral, pharyngeal, and genital samples were collected for HPV DNA testing. Main Outcomes and Measures: Vaginal HPV DNA testing was done on self-collected vaginal samples obtained among pregnant women recruited during their first trimester of pregnancy and in the third trimester for those who had HPV-positive samples in the first trimester. HPV DNA testing was also done on placental samples (swabs and biopsies) collected after birth in all participants. HPV DNA testing among children included conjunctival, oral, pharyngeal, and genital samples collected in children of HPV-positive mothers at birth, 3 months, and 6 months of age. Results: A total of 1050 pregnant women (mean [SD] age, 31.3 [4.7] years) were included in this study. Prevalence of HPV in pregnant women at recruitment was 40.3% (95% CI, 37.3%-43.3%). Among the 422 HPV-positive women, 280 (66.4%) harbored at least 1 high-risk genotype, and 190 (45.0%) were coinfected with multiple genotypes. HPV was detected in 10.7% of placentas (92 of 860; 95% CI, 8.8%-12.9%) overall, but only 3.9% of biopsies (14 of 361) on the fetal side under the amniotic membrane were positive. Neonatal HPV detection (at birth and/or at 3 months) was 7.2% (95% CI, 5.0%-10.3%) overall, with the most frequent site of infection being the conjunctiva (3.2%; 95% CI, 1.8%-5.6%), followed by the mouth (2.9%; 95% CI, 1.6%-5.2%), the genital area (2.7%; 95% CI, 1.4%-4.9%), and the pharynx (0.8%; 95% CI, 0.2%-2.5%). Importantly, all HPV detected in children at birth cleared before the age of 6 months. Conclusions and relevance: In this cohort study, vaginal HPV was frequently detected in pregnant women. Perinatal transmission was infrequent, and in this cohort, no infection detected at birth persisted at 6 months. Although HPV was detected in placentas, it remains difficult to differentiate contamination vs true infection.

Association Between Human Papillomavirus Infection Among Pregnant Women and Preterm Birth.

Importance: Preterm birth remains a leading cause of perinatal mortality and lifelong morbidity worldwide. The cause of most preterm births is unknown, although several infectious processes have been implicated. Objective: To assess whether human papillomavirus (HPV) infection, a frequent infection among women of childbearing age, is associated with preterm birth. Design, Setting, and Participants: The prospective HERITAGE cohort study was conducted at 3 academic hospitals in Montreal, Québec, Canada, among 899 pregnant women recruited between November 8, 2010, and October 16, 2016. Follow-up was completed on June 15, 2017. Statistical analysis was conducted from February 6, 2020, to January 21, 2021. Exposures: Vaginal HPV DNA detection in the first and third trimesters of pregnancy and placental HPV infection. Main Outcomes and Measures: The main outcome was preterm birth (defined as a live birth or stillbirth between 20 weeks and 0 days and 36 weeks and 6 days of gestation). The association between HPV DNA detection and preterm birth was measured using logistic regression. Odds ratios (ORs) and 95% CIs were adjusted by inverse probability of treatment weights of the propensity score. Results: The study included 899 women (mean [SD] age, 31.3 [4.6] years [range, 19-47 years]) with singleton pregnancies. A total of 378 women (42.0%) had HPV DNA detected in vaginal samples collected during the first trimester, and it was detected in 91 of 819 placentas (11.1%) at delivery. Fifty-five participants experienced preterm birth (38 spontaneous and 17 medically indicated). Persistent vaginal HPV-16/18 detection was significantly associated with all preterm births (adjusted OR [aOR], 3.72; 95% CI, 1.47-9.39) and spontaneous preterm births (aOR, 3.32; 95% CI, 1.13-9.80), as was placental HPV infection (all preterm births: aOR, 2.53; 95% CI, 1.06-6.03; spontaneous preterm births: aOR, 2.92; 95% CI, 1.09-7.81). Results were similar when restricting the analysis to participants without a history of cervical intraepithelial neoplasia treatment. Conclusions and Relevance: The study's results suggest that persistent HPV-16/18 infection is associated with an increased risk of preterm birth, independent of cervical treatment. Future studies should investigate the association of HPV vaccination and vaccination programs with the risk of preterm birth.

Antibodies to human papillomavirus types 6, 11, 16 and 18: Vertical transmission and clearance in children up to two years of age.

Background: There is a paucity of data on the dynamics of human papillomavirus (HPV) antibodies in children. We aimed to describe the vertical transmission and clearance of antibodies against HPV6, 11, 16 and 18 in children. Methods: We used data from pregnant women recruited into the HERITAGE cohort study between 2009 and 2012 who were positive for HPV-DNA at baseline. Dried blood spots were collected during the first trimester in pregnant participants, and at birth, 6, 12, and 24 months of age in children. The level of total immunoglobulin G (IgG) against HPV6, 11, 16 and 18 were measured using Luminex immunoassays. Spearman's coefficients were used to correlate HPV antibody levels between newborns and mothers. Panel and Kaplan-Meier graphics described antibody dynamics in the first 24 months of life. Findings: Antibodies from newborns and mothers (n = 58 pairs) were moderately to highly correlated with coefficients of 0·81 (95% confidence intervals (CI):0·70-0·88), 0·68 (95% CI:0·5-0·80), 0·90 (95% CI:0·83-0·94) and 0·85 (95% CI:0·76-0·91) against HPV6, 11, 16 and 18, respectively. In newborns seropositive at birth, anti-HPV antibodies were cleared by 80% and 100% at 12 and 24 months, respectively. Only two children presented detectable HPV antibodies at 24 months. The first child had no detectable antibodies at birth and the second presented increasing levels after two undetected measures. Interpretation: Correlation between mother and newborn IgG antibodies against HPV suggests vertical transfer. Most children cleared anti-HPV antibodies within six to 12 months. Funding: The Canadian Institutes of Health Research (CIHR).

Exploration of the effect of human papillomavirus (HPV) vaccination in a cohort of pregnant women in Montreal, 2010-2016.

HPV vaccination efficacy has been shown in clinical trials but it is important to verify population level vaccine effectiveness (VE). We aimed to explore VE and herd effect using HPV infection data from a cohort study of Canadian pregnant women. We analyzed the baseline data of the HERITAGE study, which includes pregnant women recruited in Montreal between 2010-2012 and 2015-2016. Cervicovaginal samples self-collected in the first trimester were tested for 36 HPV types. Vaccination status was self-reported. VE and 95% confidence intervals (CI) were estimated by comparing the prevalence of HPV between vaccinated and unvaccinated women. Herd effect was explored by comparing HPV prevalence in unvaccinated women between the 2 recruitment periods. Adjusted ORs (95%CI) were estimated using exact logistic regression. The proportion of vaccinated women with at least one dose of 4vHPV was 7.5%. Although most of them were vaccinated after the onset of sexual activity, a high VE was found for HPV-16/18 (86.1% (95%CI: 15.0-99.7)). For HPV-6/11/16/18 and for HPV-31/33/45, VE was 61.9% (-23.5-92.6) and 57.0% (-47.7-92.0%), respectively. We also observed a non-statistically significant reduction in the prevalence of HPV-6/11/16/18 and HPV-31/33/45 among unvaccinated women recruited during the second recruitment period (adjusted OR: 0.8 (0.4-1.8) and 0.8 (0.3-1.7), respectively).

The association between adverse pregnancy outcomes and maternal human papillomavirus infection: a systematic review protocol.

BACKGROUND: Human papillomavirus (HPV) is the most prevalent genital infection, especially in young women of reproductive age. In vitro and animal model experiments provide compelling evidence of the harmful effect of HPV on pregnancy outcomes, but results from epidemiologic studies are inconclusive. We aim to determine the strength of the relationship between adverse pregnancy outcomes (APO) and HPV infection and assess its consistency across studies, by systematically reviewing the literature. METHODS: The search strategy has been developed on the basis of the PICOS framework: Population (pregnant women); Exposure (HVP infection confirmed by HPV testing); Comparator (pregnant women without HPV infection); Outcomes (miscarriage, spontaneous preterm birth, low birth weight, preterm premature rupture of membranes, pregnancy-induced hypertensive disorders and intrauterine growth restriction) and Study design (observational studies). We will search three information sources: (1) electronic databases (MEDLINE, EMBASE, and EBM Reviews databases); (2) Grey literature (Google Scholar and Web of Science conference proceedings); and (3) citing and cited articles of included studies. Two reviewers (JN, NZ) will independently and in duplicate screen identified articles, select eligible studies, and extract data. Discrepancies will be resolved by consensus and otherwise by discussion with the other authors (MHM, HT). Quality of included studies will be assessed using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies. We will narratively synthesize extracted data whether meta-analysis is conducted or not. Meta-analysis of each outcome will be performed, and where appropriate, an average measure of association will be computed. We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess and grade the strength of confidence in cumulative estimate. DISCUSSION: Comprehensive and high-quality evidence of a negative effect of HPV on pregnancy outcomes might be an additional motivation for HPV vaccination. Absence of such relationship could dispel anxiety and reassure HPV-infected pregnant women and clinicians. Findings of a poor level of confidence will allow identification of current knowledge gaps on HPV-pregnancy outcome relationship that need further research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016033425.

Human papillomavirus (HPV) perinatal transmission and risk of HPV persistence among children: Design, methods and preliminary results of the HERITAGE study.

Perinatal route of transmission of human papillomavirus (HPV) has been demonstrated in several small studies. We designed a large prospective cohort study (HERITAGE) to better understand perinatal HPV. The objective of this article is to present the study design and preliminary data. In the first phase of the study, we recruited 167 women in Montreal, Canada, during the first trimester of pregnancy. An additional 850 are currently being recruited in the ongoing phase. Cervicovaginal samples were obtained from mothers in the first trimester and tested for HPV DNA from 36 mucosal genotypes (and repeated in the third trimester for HPV-positive mothers). Placental samples were also taken for HPV DNA testing. Conjunctival, oral, pharyngeal and genital samples were collected for HPV DNA testing in children of HPV-positive mothers at every 3-6 months from birth until 2 years of age. Blood samples were collected in mother and children for HPV serology testing. We found a high prevalence of HPV in pregnant women (45%[95%CI:37-53%]) and in placentas (14%[8-21%]). The proportion of HPV positivity (any site) among children at birth/3-months was 11%[5-22%]. HPV was detected in children in multiple sites including the conjunctiva (5%[10-14%]). The ongoing HERITAGE cohort will help provide a better understanding of perinatal HPV.

Risk factors for the development and severity of juvenile-onset recurrent respiratory papillomatosis: a systematic review.

OBJECTIVES: Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare yet aggressive disease caused by human papillomavirus (HPV). Although many newborns are likely exposed to HPV, few develop JoRRP and the clinical course of the disease varies from one child to another. This systematic review seeks to provide an up-to-date understanding of the risk factors for acquisition and severity. METHODS: We conducted a comprehensive literature search in EMBASE, MEDLINE and EBMR databases using various combinations of keywords related to JoRRP etiology, risk factors and severity. We also searched Google Scholar and the reference lists of eligible studies. Our search was limited to original studies published in French or English between 1995 and July 2012 and to patients under 20 years of age. RESULTS: Of 1362 citations, we retrieved 102 articles and found 14 additional studies. We retained 32 studies meeting inclusion criteria. All were observational and together included 2296 JoRRP cases. Risk factors could be classified mainly as maternal and birth history, viral genotype, and host factors. A history of genital warts during pregnancy and delivery was strongly linked to the development of JoRRP. Depending on ethnicity, specific human leukocyte antigen class II alleles and immune response factors were important determinants of JoRRP acquisition and severity. HPV-11 genotype and younger age at onset of JoRRP were important predictors of severity. CONCLUSIONS: Genetic and immunological profiles underlying the acquisition and clinical course are not readily modifiable. Thus, preventing condylomas in women of childbearing age could reduce the burden of this life-threatening disease.