A clinicopathological study of episomal papillomavirus infection of the human placenta and pregnancy complications

Abstract

Viral infections are known to adversely affect pregnancy, but scant attention has been given to human papilloma virus (HPV) infection. We aimed to determine the molecular and histopathological features of placental HPV infection, in association with pregnancy complications including fetal growth restriction, pre-maturity, pre-eclampsia, and diabetes. Three hundred and thirty-nine placentae were selected based on the presence or absence of pregnancy complications. Five independent methods were used to identify HPV in the placenta, namely, immunohistochemistry for L1 viral capsid, in situ hybridization to high-risk HPV DNA, PCR, western blotting, and transmission electron microscopy. Pregnancy complications and uterine cervical smear screening results were correlated with placental HPV histopathology. In this study, which was deliberately biased towards complications, HPV was found in the decidua of 75% of placentae (253/339) and was statistically associated with histological acute chorioamnionitis (P o0.05). In 14% (35/253) of the HPV positive cases, HPV L1 immunoreactivity also occurred in the villous trophoblast where it was associated with a lymphohistiocytic villitis (HPV-LHV), and was exclusively of high-risk HPV type. HPV-LHV significantly associated with fetal growth restriction, preterm delivery, and pre-eclampsia (all P o0.05). All cases of pre-eclampsia (20/20) in our cohort had high-risk placental HPV. A further 55 cases (22%, 55/253) of HPV positive placentae had minimal villous trophoblast HPV L1 immunoreactivity, but a sclerosing pauci-immune villitis, statistically associated with diabetes (49.1%, 27/55, Po 0.05). For women with placental HPV, 33% (69/207) had an HPV-related positive smear result before pregnancy compared with (9.4% 8/85) of women with HPV-negative placentae (P = 0.0001). Our findings support further investigations to determine if vaccination of women and men will improve pregnancy outcomes. Modern Pathology (2015Pathology ( ) 28, 1369Pathology ( -1382 doi:10.1038/modpathol.2015 published online 21 August 2015 In the immune and hormonal modulated milieu of pregnancy, viruses are well known to infect the placenta, developing fetus, and neonate. The most common and important neoplastic driver of the lower uterine tract, human papillomavirus (HPV), 1 has been detected in the uterine cervix of 15-25% of pregnant women 2-6 and a cervical HPV infection during pregnancy has been associated with a higher incidence of spontaneous abortions, 7-9 premature rupture of the membranes, 10 spontaneous preterm labor, 11,12 pre-eclampsia, 13 and placental 'villitis' not otherwise specified. 12 HPV DNA has been detected in the placenta and amniotic fluid. 7,11,[14][15][16][17]11,16,18,and 31 have been shown to replicate in trophoblast cell lines, [18][19][20] where HPV infection decreased trophoblast number and trophoblast-endometrial cell adhesion in vitro. 19,20 We investigated for the presence of HPV in the placenta and carried out a histopathological and molecular cross-sectional study of 339 ...

Human papillomavirus infects placental trophoblast and Hofbauer cells, but appears not to play a causal role in miscarriage and preterm labor

“…We observed HPV signals in decidual tissue and close to HPV‐positive trophoblast cells of placental villi, leading to speculations on a maternal origin of placental HPV infection. Slatter et al investigated placental HPV infection in association with pregnancy complications and found a higher HPV prevalence in the decidua than in the villous trophoblast, the latter in agreement with our results . Nevertheless, their data may point towards a more critical role of decidual HPV infections concerning pregnancy outcome.…”

Risks associated with viral infections during pregnancy

“…While not herpesviruses, human papillomaviruses HPV6, -11, -16, -18, and -31 can also infect the extravillous trophoblast (18,19); HPV16 and HPV62 have been identified in gestational week-12 chorionic villus (20); and HPV16, -6, -83, and -39 have been characterized full-term placenta (19,(21)(22)(23). Zika virus (ZIKV) can also infect multiple cell types of the decidua and placenta and will be discussed in further detail in a later section.…”

Defense and infection of the human placenta

“…The virus appears to bypass the syncytiotrophoblast, and may utilize syncytiotrophoblast transcytosis of IgG to gain entry via immune complex formation . CMV, like HPV, can be detected by sensitive molecular techniques from a surprising number of placentas . Differences in HLA genes may effect susceptibility of the fetus to neurologic injury from congenital CMV infection .…”