Negative Impact of Elevated DNA Fragmentation and Human Papillomavirus (HPV) Presence in Sperm on the Outcome of Intra-Uterine Insemination (IUI).

We wanted to determine the sperm DNA fragmentation index (DFI) cutoff for clinical pregnancies in women receiving intra-uterine insemination (IUI) with this sperm and to assess the contribution of Human Papillomavirus (HPV) infection on sperm DNA damage and its impact on clinical pregnancies. Prospective non-interventional multi-center study with 161 infertile couples going through 209 cycles of IUI in hospital fertility centers in Flanders, Belgium. Measurement of DFI and HPV DNA with type specific quantitative PCRs (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66 and 68) in sperm before its use in IUI. Clinical pregnancy (CP) rate was used as the outcome to analyze the impact on fertility outcome and to calculated the clinical cutoff value for DFI. A DFI criterion value of 26% was obtained by receiver operating characteristic (ROC) curve analysis. Couples with a male DFI > 26% had significantly less CPs than couples with DFI below 26% (OR 0.0326; 95% CI 0.0019 to 0.5400; p = 0.017). In sperm, HPV prevalence was 14.8%/IUI cycle. Sperm samples containing HPV had a significantly higher DFI compared to HPV negative sperm samples (29.8% vs. 20.9%; p = 0.011). When HPV-virions were present in sperm, no clinical pregnancies were observed. More than 1 in 5 of samples with normal semen parameters (17/78; 21.8%) had an elevated DFI or was HPV positive. Sperm DFI is a robust predictor of clinical pregnancies in women receiving IUI with this sperm. When DFI exceeds 26%, clinical pregnancies are less likely and in vitro fertilization techniques should be considered.

Infectious human papillomavirus virions in semen reduce clinical pregnancy rates in women undergoing intrauterine insemination.

OBJECTIVE: To study the influence of human papillomavirus (HPV) virions present in different sperm fractions of male partners of women undergoing IUI on fertility outcome. DESIGN: Prospective noninterventional multicenter study. SETTING: Inpatient hospital fertility centers. PATIENT(S): Seven hundred thirty-two infertile couples undergoing 1,753 IUI cycles with capacitated sperm. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Biochemical and clinical pregnancy rate in IUI cycles with HPV-positive or HPV-negative semen. RESULT(S): Five hundred seventy-three infertile couples undergoing 1,362 IUI cycles were enrolled. Work-up of the 1,362 sperm samples that were used for IUI generated 3,444 separate sperm fractions. Each of the sperm fractions was tested with quantitative polymerase chain reaction for 18 different HPV types (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, and 68). HPV prevalence in sperm was 12.5%/IUI cycle. When infectious HPV virions were detected in sperm, a significant decrease in clinical pregnancies was observed when compared with HPV-negative cycles (2.9% vs. 11.1 %/cycle). Above a ratio of 0.66 HPV virions/spermatozoon no pregnancies occurred (sensitivity 100%, specificity 32.5%). CONCLUSION(S): Women inseminated with HPV-positive sperm had 4 times fewer clinical pregnancies compared with women who had HPV-negative partners. Detection of HPV virions in sperm is associated with a negative IUI outcome and should be part of routine examination and counseling of infertile couples. EUROPEAN CLINICAL TRIALS DATABASE NUMBER: 2017-004791-56.

Linear viral load increase of a single HPV-type in women with multiple HPV infections predicts progression to cervical cancer.

Persistent high-risk human papillomavirus (HPV) infection is strongly associated with development of high-grade cervical intraepithelial neoplasia or cancer (CIN3+). In single type infections, serial type-specific viral-load measurements predict the natural history of the infection. In infections with multiple HPV-types, the individual type-specific viral-load profile could distinguish progressing HPV-infections from regressing infections. A case-cohort natural history study was established using samples from untreated women with multiple HPV-infections who developed CIN3+ (n = 57) or cleared infections (n = 88). Enriched cell pellet from liquid based cytology samples were subjected to a clinically validated real-time qPCR-assay (18 HPV-types). Using serial type-specific viral-load measurements (≥3) we calculated HPV-specific slopes and coefficient of determination (R(2) ) by linear regression. For each woman slopes and R(2) were used to calculate which HPV-induced processes were ongoing (progression, regression, serial transient, transient). In transient infections with multiple HPV-types, each single HPV-type generated similar increasing (0.27copies/cell/day) and decreasing (-0.27copies/cell/day) viral-load slopes. In CIN3+, at least one of the HPV-types had a clonal progressive course (R(2) ≥ 0.85; 0.0025copies/cell/day). In selected CIN3+ cases (n = 6), immunostaining detecting type-specific HPV 16, 31, 33, 58 and 67 RNA showed an even staining in clonal populations (CIN3+), whereas in transient virion-producing infections the RNA-staining was less in the basal layer compared to the upper layer where cells were ready to desquamate and release newly-formed virions. RNA-hybridization patterns matched the calculated ongoing processes measured by R(2) and slope in serial type-specific viral-load measurements preceding the biopsy. In women with multiple HPV-types, serial type-specific viral-load measurements predict the natural history of the different HPV-types and elucidates HPV-genotype attribution.

Human Papillomavirus Positivity in Women Undergoing Intrauterine Insemination Has a Negative Effect on Pregnancy Rates.

BACKGROUND: Sexually transmitted infections are a major cause of infertility. Human papillomavirus (HPV) infection is one of the most common viral infections of the female genital tract. Only a limited number of studies have investigated the influence of HPV on fertility and its impact remains controversial. OBJECTIVE: We investigated the relationship between cervical HPV infection and pregnancy outcome after intrauterine insemination (IUI). Since other sexually transmitted infections could also influence outcome, we also analyzed the influence of Trichomonas vaginalis (TV) and Chlamydia trachomatis (CT) on pregnancy outcome. METHODS: We performed a retrospective analysis of 590 women who underwent 1,529 IUI cycles at AML between 2010 and 2014. Positivity of 18 different HPV types (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68) and TV was assessed by PCR in cervical cytology specimens. CT status was ascertained by detection of IgA/IgG antibodies on serum samples or by PCR on cervical swabs. RESULTS: The HPV prevalence per IUI cycle was 11.0 and 6.9% for CT; none of the women tested positive for TV. HPV-positive women were six times less likely to become pregnant after IUI (1.87 vs. 11.36%; p = 0.0041). There was no significant difference in pregnancy rates between women with or without a history of CT (8.51 vs. 11.10%; p > 0.05). CONCLUSION: Detection of HPV is associated with a negative IUI outcome.