Recent evidence shows increased preterm birth risk with human papillomavirus-16 (HPV16)infection during pregnancy. Researchers from Canada, led by Khayargoli, P. et al., published the study titled "Association between Human Papillomavirus 16 Viral Load in Pregnancy and Preterm Birth," aiming to measure the association between HPV16 viral load and preterm birth.
A strong association between a high HPV16 viral load during pregnancy and preterm birth demonstrates a biological gradient that reinforces the biological plausibility of a causal association.
The study data from participants in the HERITAGE (Human papillomavirus perinatal transmission and risk of HPV persistence among children) 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).
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.
The cohort included 1052 pregnant women, recruited between 2009 and 2016 from three academic hospitals in Montreal, Canada. The participants self-collected vaginal samples for genotype-specific HPV DNA testing at the recruitment visit (1st trimester of pregnancy) and at the third-trimester visit (32 to 35 weeks). The data from 48 participants were included in the analysis.
The study found a mean HPV16 viral load of 1.63 copies/cell (SD = 5.64) (median = 8.0 × 10−3 copies/cell) with a maximum value of 31.46 copies/cell. Among these, 35 participants remained positive in the third trimester, with a mean HPV16 viral load (±SD) of 0.32 copies/cell (±0.97) (median = 5.29 × 10−3 copies/cell) and a maximum value of 5.07 copies/cell. Ten participants cleared their infection, and three had missing data on HPV status in the third trimester.
Table 2 shows the HPV16 viral load values for each participant in the first and third trimester. Interestingly, we observed an overall decrease in the average viral load between the first and third trimester (paired t-test p-value = 0.0562). Five participants (10.4%) experienced preterm birth (four delivered at 36 weeks and one at 35 weeks), and among them, one was multiparous without a history of preterm birth. The five participants with preterm birth had a mean HPV16 viral load of 8.93 ± 13.51 copies/cell (median = 1.41 copies/cell and maximum value of 31.46 copies/cell) in the first trimester and remained positive for HPV16 in the third trimester, having 1.12 ± 1.72 copies/cell (median = 7.74 × 10−3 copies/cell and maximum value of 3.91 copies/cell). Only one participant with preterm birth (who gave birth at 36 weeks) had an increased viral load between the two trimesters while the others had decreased viral loads.
Table 3 shows the associations between HPV16 viral load and preterm birth. The viral load (as a continuous variable) in the first trimester was significantly associated with preterm birth; each unit increase in first-trimester viral load was associated with an increased risk of preterm birth by 13% (aOR [95% CI]: 1.13 [1.03–1.25]). When the viral load measures were dichotomized using a cutoff of 1 copy/cell, the highest viral load values measured in both the first and third trimester were associated with preterm birth with aORs of 15.03 [95% CI: 1.75–129.26] and 14.02 [95% CI: 1.28–153.48], respectively. Similar results were obtained for the other categorization, although they were not always statistically significant.
Findings from in vitro studies suggest that HPV can alter trophoblast physiology and morphology with an increasing rate of apoptosis in the placenta, possibly causing abnormal placentation and compromised gestation. HPV infection has also been suspected of disturbing the vaginal microbiome increasing its heterogeneity, which could in turn increase the production of pro-inflammatory cytokines and lead to early delivery. Nevertheless, it seems that the vaginal HPV viral load during pregnancy is an important parameter to consider. A higher viral load may cause greater cellular reactions in the cervix and disrupt the regular cellular pathways of parturition, which may either increase the risk of HPV transmission to the placenta or disrupt the vaginal microbiome during pregnancy and lead to preterm birth. On the other hand, a high viral load may be a marker of an immunologic dysfunction that may be linked to a higher risk of preterm birth.
Given that preterm birth remains a major health concern, it is important to better understand its etiology. If a causal relationship exists between HPV16 and preterm birth, mass HPV vaccination with the currently available vaccines will have a significant impact in reducing the number of preterm births globally.
Reference:
Khayargoli, P. et al. Association between Human Papillomavirus 16 Viral Load in Pregnancy and Preterm Birth. Viruses 2024, 16, 298.
