Association between human papillomavirus infection and non-cancerous reproductive health outcomes: An umbrella review

INTRODUCTION

Human papillomavirus (HPV) is a ubiquitous spherical DNA virus that exclusively infects humans and represents the most prevalent sexually transmitted infection worldwide.^[1,2] Among healthy women, particularly those older than 30 years, the global prevalence of HPV infection is estimated at 11.7%.^[3] HPV infection is also highly prevalent in men, with more than 31% of men aged ≥ 15 years infected with at least one genital HPV genotype and 21% harboring at least one high-risk (oncogenic) type.^[4] Accordingly, HPV infection constitutes a major global public health concern.

HPV infection induces abnormal proliferation of epithelial cells in the skin and mucous membranes, leading to a spectrum of conditions ranging from benign lesions and warts to malignancies.^[5] Although most early HPV infections are asymptomatic, persistent infection can result in long-term sequelae and increased mortality risk.^[4] The probability of viral clearance decreases with prolonged infection duration.^[6,7] Mechanistically, HPV interacts with host cell receptors via viral proteins to facilitate cellular entry and integration of viral DNA into the host genome, thereby disrupting normal cellular processes.^[8] In addition, HPV can evade host immune responses, impair viral clearance, and promote persistent infection.^[9]

HPV types are broadly classified as high-risk or low-risk according to their carcinogenic potential.^[10,11] Low-risk types, such as HPV-6 and HPV-11, are typically associated with benign lesions (e.g., common, flat, and plantar warts) affecting the genitals, anus, oropharynx, esophageal mucosa, and other sites.^[12,13] In contrast, persistent infection with high-risk types, particularly HPV-16 and HPV-18, is strongly associated with multiple cancers,^[14] including breast cancer and oesophageal squamous cell carcinoma, as highlighted in a recent umbrella review (UR).^[15] However, the relationship between HPV infection and non-cancerous reproductive health outcomes remains unclear and controversial.^[16–18] For instance, the 2021 Sexually Transmitted Diseases Treatment Guidelines reported no evidence that HPV infection impairs a woman's ability to conceive or carry a pregnancy to term.^[19] In contrast, a 2023 systematic review and meta-analysis found a higher prevalence of high-risk HPV infection among women with pregnancy complications, such as preterm birth (PTB), compared with controls.^[20] These inconsistencies underscore the need for a comprehensive evaluation of the available evidence.

UR is a rigorous evidence synthesis approach that systematically re-evaluates and integrates findings from multiple systematic reviews and meta-analyses.^[21] This methodology enables a comprehensive and reliable assessment of the strength and credibility of existing evidence, thereby informing clinical practice, research priorities, and policy development.^[22] To date, while prior studies have primarily focused on cancer outcomes, no study has comprehensively assessed the association between HPV infection and non-cancerous reproductive health outcomes. Therefore, we conducted an UR to synthesize current evidence from systematic reviews and meta-analyses, with the aim of evaluating the strength and credibility of associations, as well as identifying potential sources of bias and uncertainty in the existing literature.

METHODS

This UR adhered to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) and meta-analyses of observational studies in epidemiology (MOOSE) guidelines (Supplementary Tables 1-2).^[23,24] This umbrella review was not prospectively registered in PROSPERO or a similar registry.

RESULTS

DISCUSSION

This UR comprehensively synthesizes and critically appraises evidence from 11 articles encompassing 36 associations derived from systematic reviews and meta-analyses examining the relationship between HPV infection, including specific genotypes, and non-cancerous reproductive health outcomes. Four associations were supported by suggestive evidence, indicating increased risks of PTB, LBW, female infertility, and infertility of unknown origin. Critically, the certainty of evidence according to GRADE was low or very low for all these suggestive associations, and most 95% prediction intervals crossed the null, indicating that the true effects remain uncertain and might be null in some populations. Therefore, these results should be interpreted with caution and do not prove causation.

Our findings indicate that HPV infection is associated with an increased risk of adverse pregnancy outcomes, particularly PTB and LBW, both supported by suggestive evidence. Specifically, HPV infection was associated with a higher risk of PTB (OR= 1.50, 95% CI: 1.19-1.88), consistent with previous studies. For instance, a meta-analysis of seven cohort studies reported that HPV infection may influence maternal physiology and increase the risk of PTB (OR = 1.81, 95% CI: 1.25-2.62).^[47] Similarly, a large retrospective population-based register study (1999-2016) including 400,583 women found that HPV infection shortly before or during pregnancy was associated with an elevated risk of PTB (OR = 1.19, 95% CI: 1.01-1.42).^[48] However, it is important to note that the association between HPV and PTB may be confounded by prior cervical treatments, such as loop electrosurgical excision procedure (LEEP) or conization, which are themselves independent risk factors for PTB. Most primary studies did not adequately adjust for these procedures, potentially biasing the observed associations. Future research should distinguish between untreated HPV infection, persistent infection, and post-treatment status to clarify the independent effect of HPV. Evidence also suggests that specific high-risk genotypes may confer greater risk. In the HERITAGE prospective cohort study of 1052 pregnant women, persistent HPV-16/18 infection was associated with a substantially increased risk of PTB (OR = 3.72, 95% CI: 1.47-9.39).^[49] Together, these findings support the hypothesis that HPV infection, particularly with high-risk genotypes, may contribute to the risk of PTB.

PTB and LBW frequently co-occur, as shortened gestational duration is a major determinant of reduced birth weight.^[50] Consistent with this relationship, our umbrella review also identified a suggestive association between HPV infection and increased risk of LBW (OR = 1.91, 95% CI: 1.33-2.76). This aligns with prior evidence indicating that HPV infection during pregnancy may adversely affect maternal and neonatal outcomes, including LBW, premature rupture of membranes, spontaneous abortion, and fetal death.^[51]

The biological mechanisms underlying these associations remain incompletely understood but are likely multifactorial. HPV oncoproteins E6 and E7 may disrupt placental development and function by impairing trophoblast invasion and promoting apoptosis, thereby compromising placental integrity.^[52] Such dysfunction may reduce nutrient and oxygen transfer, contributing to intrauterine growth restriction and LBW. In addition, HPV infection may ascend into the amniotic cavity, triggering inflammatory responses characterized by elevated cytokine levels.^[53] Increased production of pro-inflammatory mediators, including interleukin-6 and tumor necrosis factor-α, may further disrupt placental function and promote pathways leading to PTB and premature rupture of membranes.^[54–56] Nevertheless, the substantial heterogeneity and the fact that the 95% PIs for these outcomes cross 1.0 indicate that the associations are not consistently observed and may be non-significant in different contexts. The low or very low GRADE certainty further underscores that these findings remain tentative. Therefore, they should not be used to justify changes in clinical screening practices; instead, they highlight the need for additional prospective studies with standardized HPV exposure definitions.

Despite these findings, the results should be interpreted with caution. Substantial heterogeneity was observed, and prediction intervals often included the null value, indicating limited generalizability and potential variability across populations and study settings. From a clinical and public health perspective, these findings underscore the need for future research to investigate whether HPV prevention and monitoring strategies among women of reproductive age could clarify the observed associations. Specifically, well-designed prospective studies are warranted to evaluate whether standardized HPV assessment (including timing of infection, persistence, and prior cervical treatment history) or preventive interventions—such as vaccination—are associated with reduced risks of adverse pregnancy outcomes and infertility. Until such evidence becomes available, no changes to current clinical screening or vaccination guidelines are warranted.

Our UR also identified a suggestive association between high-risk HPV infection and increased risk of female infertility (OR = 2.33, 95% CI: 1.42-3.83). This finding is consistent with previous evidence. A nationwide population-based cohort study reported a higher risk of infertility among women with prior HPV infection, particularly those aged 26-35 years.^[57] Similarly, a case-control study involving 190 participants (95 infertile and 95 fertile women) found that HPV was the most prevalent viral agent among infertile women and was significantly associated with infertility (OR = 7.02, 95% CI: 1.52-32.3).^[58]

Several biological mechanisms may explain this association. First, high-risk HPV infection can lead to cervical intraepithelial neoplasia, which may result in cervical stenosis or obstruction, thereby impairing sperm transport and fertilization.^[59] In addition, HPV-induced chronic cervicitis may alter cervical mucus properties and disrupt sperm-mucus interactions, further compromising fertility. Second, high-risk HPV infection has been implicated in tubal factor infertility. Viral oncoproteins E6 and E7 may disrupt cell cycle regulation and induce epithelial abnormalities in the fallopian tubes, potentially leading to tubal damage or occlusion.^[60] Furthermore, HPV-associated chronic endometritis and endometrial inflammation may impair endometrial receptivity and hinder embryo implantation.^[61]

Meanwhile, our UR also identified a moderate-quality association between HPV infection and male fertility abnormality (OR = 2.98, 95% CI = 1.98-4.48), although this finding requires confirmation in larger, well-controlled studies. Given that HPV is commonly transmitted through sexual contact, evaluation of male partners—even when asymptomatic—may be important in the context of infertility assessment and management.^[62] However, these results should be interpreted cautiously due to substantial heterogeneity and the inclusion of the null value within the 95% prediction interval, suggesting limited robustness and potential variability across studies. Further well-designed studies are needed to clarify these associations. Again, the result for female infertility should be interpreted with caution because of high heterogeneity and the 95% PI including the null. The evidence does not establish that HPV infection causes infertility; rather, it signals an association that requires further validation, especially in well-controlled prospective studies.

To our knowledge, this is the first UR to comprehensively evaluate the hierarchy and credibility of evidence linking HPV infection to non-cancerous reproductive health outcomes, including adverse pregnancy outcomes, infertility, HIV coinfection, and cervical precancerous lesions. We applied rigorous and standardized criteria to assess methodological quality, strength of epidemiological evidence, and GRADE ratings. Overall, the included studies were of moderate to high methodological quality. Sensitivity analyses of excluded, overlapping meta-analyses addressing similar research questions demonstrated largely consistent findings, supporting the robustness of our results. By integrating evidence across a broad range of studies, this umbrella review provides a valuable evidence-based foundation to inform clinical practice and public health policy.

However, several limitations should be considered. First, this UR was not prospectively registered in PROSPERO or a similar registry. Although we strictly adhered to PRISMA and MOOSE guidelines and defined our protocol a priori, the lack of registration may increase the risk of selective reporting bias and should be considered when interpreting the findings. Second, as this review is based on observational studies, it is inherently subject to biases typical of such designs, including selection bias and residual confounding. Although many included studies adjusted for known confounders, unmeasured or incompletely measured factors, may still influence the observed associations. In particular, the timing of HPV infection (preconception, early vs. late pregnancy, persistent infection, or history of treated lesions) was not consistently differentiated across primary studies. This exposure heterogeneity may obscure distinct risk profiles and represents a critical gap in the literature. For pregnancy outcomes, insufficient adjustment for prior cervical excisional procedures in most primary studies could have biased the estimates. While some primary studies accounted for these variables,^[48,63] heterogeneity in data quality and adjustment methods remains, which may contribute to residual bias and partially explain the generally low GRADE ratings. Nonetheless, given the ethical and practical challenges of conducting randomized controlled trials in this context, observational evidence represents the best available source of data. Third, substantial statistical heterogeneity was observed across several meta-analyses. This may reflect variability in study populations, exposure definitions, outcome classification, and study design. In particular, misclassification of non-cancerous reproductive outcomes in registry-based studies and differences in population characteristics may have contributed to both overestimation and underestimation of associations.^[64] Fourth, the reliability of our findings depends on the quality of the included meta-analyses and their underlying primary studies. Although we verified extracted data against original studies, detailed evaluation of each primary study was beyond the scope of this review. Finally, some recently published primary studies may not have been captured;^[65,66] however, comparisons with overlapping meta-analyses suggest that their omission is unlikely to materially affect the overall conclusions.

CONCLUSIONS

This UR synthesized the existing evidence on the association between HPV infection and the risk of non-cancerous reproductive health outcomes. Our UR has provided evidence indicating that HPV or high-risk HPV infection was associated with an elevated risk of PTB, LBW, female infertility, and unknown infertility. However, the certainty of this evidence is low or very low, and most prediction intervals include the null value. These findings should not be interpreted as proof of a causal relationship. Given the limitations, this review does not support altering current clinical screening or vaccination guidelines. Instead, it identifies critical research priorities, including the need for studies that distinguish HPV exposure timing, account for cervical treatment history, and evaluate whether preventive interventions can ultimately mitigate these reproductive risks. Future larger prospective cohort studies, as well as experimental models to validate biological plausibility and potential causal mechanisms, are needed to verify these associations.