NLRP3 inflammasome: A joint, potential therapeutic target in management of COVID-19 and fertility problems.

To overcome COVID-19 long-term consequences, one possible approach is to control inflammasomes activation, because SARS-CoV-2 can induce humoral and cellular immune responses. In this opinion article we hypothesized that if it is proven with convincing and unmistakable evidence that firstly, SARS-CoV-2 can enter cells and damage them through its common receptors in the reproductive tissues, and secondly, inflammasome pathway activation is responsible for the damages caused, then the inflammasome inhibitors might be considered as suitable candidates in preventing the pathological effects on the germ cells and reproductive tissues and subsequent fertility.

COVID-19 screening during fertility treatment: how do guidelines compare against each other?

Various fertility scientific societies have published pathways and recommendations for COVID-19 screening during fertility treatments. As there is currently very limited research evidence on how to best deliver this screening, it is not surprising that there are noticeable differences between their recommendations. This paper compares the screening pathways recommended by these guidelines, in the light of the emerging evidence. It proposes the more liberal use of viral testing for improving detection of asymptomatic or mildly symptomatic fertility patients. It also argues that a negative test result on symptomatic individuals should not be over-relied upon for allowing the treatment to proceed. In these cases, a low threshold for cancellation may still need to be maintained.

SARS-CoV-2 testing in infertile patients: different recommendations in Europe and America.

The incorporation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing into patient care algorithms has been proposed to mitigate risk. However, the two main professional societies for human reproduction (ESHRE and ASRM) appear divergent on their clinical utility and whether they should be adopted. In this opinion paper, we review the currently available tests and discuss the strengths and weaknesses of the proposed clinical care pathways. Nucleic acid amplification tests are the cornerstone of SARS-CoV-2 testing but test results are largely influenced by viral load, sample site, specimen collection method, and specimen shipment technique, such that a negative result in a symptomatic patient cannot be relied upon. Serological assays for SARS-CoV-2 antibodies exhibit a temporal increase in sensitivity and specificity after symptom onset irrespective of the assay used, with sensitivity estimates ranging from 0 to 50% with the first 3 days of symptoms, to 83 to 88% at 10 days, increasing to almost 100% at ≥ 14 days. These inherent constraints in diagnostics would suggest that at present there is inadequate evidence to utilize SARS-CoV-2 testing to stratify fertility patients and reliably inform clinical decision-making. The failure to appreciate the characteristics and limitations of the diagnostic tests may lead to disastrous consequences for the patient and the multidisciplinary team looking after them.

Potential risks of SARS-CoV-2 infection on reproductive health.

The outbreak of 2019 novel coronavirus disease (COVID-19) has become a major pandemic threat worldwide. Such a public health emergency can greatly impact various aspects of people's health and lives. This paper focuses on its potential risks for reproductive health, including the reproductive system and its functioning, as well as gamete and embryo development, which could be affected by the virus itself, drug treatments, chemical disinfectants and psychological effects related to panic during the COVID-19 outbreak.

Maternal and neonatal infections of herpes simplex virus-1 and cytomegalovirus in Saudi Arabia.

It is common practice to screen for human cytomegalovirus (CMV) and herpes simplex virus (HSV) among women with infertility problems, recurrent abortion or exhibiting intrauterine growth restriction during pregnancy. Nonetheless, limited information exists about the incidence of these viruses in Saudi Arabia. The IgG and IgM antibodies of 761 women and 85 of neonates who showed intrauterine growth retardation (IUGR) were reviewed against cytomegalovirus and herpes simplex virus-1. Tests were repeated only for those with positive results. Recent infection of herpes simplex virus-1 and cytomegalovirus was evidenced by the presence of IgM in the female patients: incidence was 1.1% and 1.3% respectively. None of the neonates showed positive IgM for cytomegalovirus, but a single case showed a positive result for herpes simplex virus-1 IgM. Among the female patients, however, the presence of IgG indicated previous exposure to cytomegalovirus in 92% of cases and herpes simplex virus in 80.8%. It was concluded that although previous exposure to CMV and HSV-1 were found in high percentages in women experiencing infertility problems but did not appear to be associated with neonates exhibiting intrauterine growth retardation.

HHV-6A infection of endometrial epithelial cells affects immune profile and trophoblast invasion.

PROBLEM: We first reported human herpesvirus (HHV)-6A DNA presence in 43% of endometrial cells from women with idiopathic infertility, whereas no fertile control women harbored the virus. We investigated the effect of HHV-6A infection on the immunological status of the endometrium. METHOD OF STUDY: Endometrial biopsies, uterine flushing, and whole blood samples were collected from 67 idiopathic infertile women (mid-secretory phase). We analyzed the endometrial immunological status evaluating: (a) the effect of HHV-6A infection on endometrial immune profile analyzing the ratio of interleukin (IL)-15/ fibroblast growth factor-inducible 14 (Fn-14) and IL-18/ TNF-related weak inducer of apoptosis (TWEAK) mRNA as a biomarker of endometrial (e)natural killer activation/maturation, angiogenesis, and Th1/Th2 balance; (b) endometrial receptivity to trophoblasts in endometrial 3D in vitro model; (c) natural killer (NK) cells and T cells percentage and subpopulations by flow cytometry. RESULTS: We confirmed the presence of HHV-6A infection in a 40% of idiopathic infertile women, characterized by an immune profile reflecting eNK cell cytotoxic activation and a decrease in CD4+ CD25+ CD127dim/- regulatory T cells. The co-culture of endometrial epithelial cells with spheroids generated from the extravillous trophoblast-derived cell line JEG3 showed a twofold expansion of spheroids on endometrial epithelial-stromal cells (ESC) culture surface from HHV-6A negative women while no expansion was observed on the surface of ESC from HHV-6A positive women. CONCLUSION: The identification of an effect of HHV-6A infection on endometrial immune status opens new perspectives in idiopathic infertile women care management. In addition, it would be possible to select antiviral therapies as novel, non-hormonal therapeutic approaches to those idiopathic infertile women characterized by the presence of endometrial HHV-6A infection, to increase their pregnancy rate.

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.

Mechanisms linking bovine viral diarrhea virus (BVDV) infection with infertility in cattle.

Bovine viral diarrhea virus (BVDV) is an important infectious disease agent that causes significant reproductive and economic losses in the cattle industry worldwide. Although BVDV infection is known to cause poor fertility in cattle, a greater part of the underlying mechanisms particularly associated with early reproductive losses are not clearly understood. Previous studies reported viral compromise of reproductive function in infected bulls. In females, BVDV infection is thought to be capable of killing the oocyte, embryo or fetus directly, or to induce lesions that result in fetal abortion or malformation. BVDV infections may also induce immune dysfunction, and predispose cattle to other diseases that cause poor health and fertility. Other reports also suggested BVDV-induced disruption of the reproductive endocrine system, and a disruption of leukocyte and cytokine functions in the reproductive organs. More recent studies have provided evidence of viral-induced suppression of endometrial innate immunity that may predispose to uterine disease. Furthermore, there is new evidence that BVDV may potentially disrupt the maternal recognition of pregnancy or the immune protection of the conceptus. This review brings together the previous reports with the more recent findings, and attempts to explain some of the mechanisms linking this important virus to infertility in cattle.

Assessing access to assisted reproductive services for serodiscordant couples with human immunodeficiency virus infection.

OBJECTIVE: To understand the barriers that serodiscordant couples with human immunodeficiency virus (HIV) face in accessing services for risk reduction and infertility using assisted reproductive technology (ART). DESIGN: Two-arm cross-sectional telephone "secret shopper" study. SETTING: Infertility clinics designated by the Society for Assisted Reproductive Technology (SART), 140 from 15 American states with the highest prevalence of heterosexual HIV-infected men. PATIENT(S): Clinical and nonclinical staff at SART-registered clinics. INTERVENTION(S): Standardized telephone calls to SART-registered clinics by investigators in the roles of physician and patient callers. MAIN OUTCOME MEASURE(S): Availability and difference in services offered to callers and the rate of referral if the clinic did not provide these services. RESULT(S): Of the 140 sampled SART clinics across 15 states, callers in both patient and physician roles spoke to a staff member at greater than 90% of targeted clinics (127 clinics total). Of the physician callers 63% were told that the clinic could offer services, as compared to 40% of patient callers. Of the 55 clinics that were unable to provide services to the patient caller, 51% referred to other clinics with confidence that they could offer these services; 67% of clinics would provide services for both prevention and infertility purposes. CONCLUSION(S): Risk reduction services for HIV were more available at the sampled fertility clinics than previously reported in the literature. However, the responses depended on the person calling. The clinics demonstrated low rates of concordance with the American Society for Reproductive Medicine's guidelines, which endorse referral of patients to other facilities from sites unable to offer services.

Descriptive Study of Rubella Titer Status in Infertility Patients.

INTRODUCTION: There is a 6.4 percent incidence of rubella exposure during pregnancy in the U.S. Given the severe effects rubella can have on a developing fetus, vaccination of women prior to pregnancy is important. Women seeking fertility treatment therefore present a population of patients primed for the vaccination. This study collected and analyzed rubella-specific immunoglobulin G (RV-IgG) titer statuses and corresponding demographics of infertility patients to identify patients at risk of rubella nonimmunity. METHODS: The study consisted of a retrospective review of electronic medial records (EMR) of female patients, ages 18 to 50, who were new patients receiving an infertility workup at a Midwestern reproductive endocrinology clinic from Jan. 1, 2010 through Dec. 31, 2014. Of those patients who had RV-IgG titers noted in their EMR, the following demographics were collected: age, race, gravidity and parity, state of residence, and community size. RESULTS: There were 750 patients included in the study. Rubella titers were drawn on 72.7 percent of the patients. Of those drawn, 90.8 percent had a positive rubella titer. Most of the participants (92.3 percent) were identified as Caucasian/White. Caucasians/Whites, Asians, and African Americans/Blacks had the highest rates of rubella immunity, while American Indians/Alaskan Natives had the lowest rates of immunity (p=0.0006). Nulligravida participants had a positive rubella titer rate of 94.1 percent, while primigravida participants had a rate of 89.8 percent (p=0.04). Participants living in the largest sampled communities had the lowest rates of positive rubella titers, while those living in the smallest communities had the highest rates of positive rubella titers, although these findings were not statistically significant. CONCLUSIONS: Of the infertility patients, 27.3 percent did not have an RV-IgG titer drawn as part of their fertility workup. Of the 72.7 percent of patients for whom titers were checked, nearly 10 percent were not immune to rubella. While there are a couple reasons why a patient may not have a positive titer, lack of immunization is the most common reason. Data analysis identified significance in the difference in titer status only with respect to race and gravidity, and those findings, particularly race, must be viewed critically in light of the study population. While the statistical significance of the study may be limited, there is clinical significance in identifying infertility patients at highest risk of rubella nonimmunity so vaccination education and efforts can be focused accordingly.

Other Extrahepatic Manifestations of Hepatitis C Virus Infection (Pulmonary, Idiopathic Thrombocytopenic Purpura, Nondiabetes Endocrine Disorders).

Extrahepatic manifestations of hepatitis C virus (HCV) infection are a rare but serious condition. This article summarizes the current literature on the association between HCV and endocrine and pulmonary manifestations, as well as idiopathic thrombocytopenic purpura (ITP). HCV may directly infect extrahepatic tissues and interact with the immune system predisposing for obstructive and interstitial lung disease, ITP, autoimmune thyroiditis, infertility, growth hormone and adrenal deficiencies, osteoporosis, and potentially lung and thyroid cancers. However, in many cases, the current evidence is divergent and cannot sufficiently confirm a true association, which emphasizes the need for future targeted projects in this field.

Zika virus detected in amniotic fluid and umbilical cord blood in an in vitro fertilization-conceived pregnancy in Venezuela.

OBJECTIVE: To describe the consequences of Zika virus infection at 10 weeks of gestation in an IVF-conceived pregnancy in Venezuela. DESIGN: A case report. SETTING: Private assisted reproduction unit. PATIENT(S): A 36-year-old patient who conceived her first pregnancy through IVF and became infected with Zika virus at 10 weeks' gestation in Venezuela. INTERVENTION(S): In vitro fertilization with fresh ET. Clinical, laboratory, and imaging Zika diagnostic methods. MAIN OUTCOME MEASURE(S): Zika virus detection by real-time polymerase chain reaction (PCR) in maternal plasma, PCR in amniotic fluid and umbilical cord blood. Ultrasonography findings of anatomic abnormalities. RESULT(S): Zika infection was confirmed at 10 weeks' gestation by real-time PCR; ultrasound results appeared normal. At 19 weeks' gestation, an ultrasound revealed biometry on three SDs below the means for all parameters but with no apparent anatomic abnormality. Zika virus was positive in maternal urine and amniotic fluid by PCR at 19 weeks' gestation. Ultrasound at 21 weeks + 4 days of gestation showed fetal cerebellar hypoplasia with ventricular dysmorphia, particularly marked on the left, consistent with microcephaly and ventriculomegaly. Because of the poor prognosis, pregnancy was interrupted at 24 weeks' gestation, in France. The PCR in umbilical cord blood taken in this procedure was positive for Zika virus. CONCLUSION(S): Initial ultrasound findings in pregnancy may not be informative. Only at 21 weeks + 4 days of gestation did an ultrasound reveal fetal microcephaly and ventriculomegaly. Combined clinical, laboratory, and imaging findings provided a complete picture of the severe damage caused by Zika infection.

Hepatitis B virus infection status and infertility causes in couples seeking fertility treatment-Indicator of impaired immune response?

PROBLEM: The relationship between hepatitis B (HBV) infection in infertile couples seeking in vitro fertilization (IVF) treatment and infertility causes is unknown. METHODS OF STUDY: A total of 831 infertile couples attending our unit seeking IVF during January to December 2015 were recruited. RESULTS: HBV infection was found in 6.3% and 7.3% of female and male partners, respectively, and infection in one or both partners was associated with less primary infertility (44.2% vs 55.1%, P=.038). Infected female partners had increased tubal (69.2% vs 43.2%, P<.001) and uterine (13.7% vs 3.1%, P<.001) causes and reduced idiopathic infertility, while infected male partners were associated with increased tubal (62.3% vs 43.4%, P=.004) causes and reduced endometriosis (62.3% vs 73.9%, P=.050). CONCLUSION: Our results suggest HBV infection in either partner was associated with tubal infertility. HBV infection in either partner probably increases the risk of pelvic infection in female partner through impaired immune response to sexually transmitted infections, with consequent tubal damage and infertility.

Impact of Bovine Herpesvirus 4 (BoHV-4) on Reproduction.

Bovine herpesvirus 4 (BoHV-4) is increasingly considered as responsible for various reproductive troubles. This virus infects blood mononuclear cells and displays a specific tropism for vascular endothelia, mammary tissue, endometrium and foetal tissues. Viral multiplication can be reactivated by corticosteroids or stress, both factors present at calving. BoHV-4 has been isolated in a large variety of clinical cases, primarily metritis, vaginitis and mastitis, but also endometritis, abortion and orchitis. Its impact on reproductive performance has been suggested by several epidemiological studies: seroprevalence against BoHV-4 is higher in aborted females and in repeat breeders. Nevertheless, its intrinsic pathogenic power seems low, symptoms developing only when BoHV-4 cooperates with bacteria: within the uterus or mammary gland. BoHV-4 is rather currently considered as a cofactor for the development of an inflammatory reaction initiated by bacteria.

[Fertility and HIV: equal opportunity for everyone].

Highly active antiretroviral treatment (HAART), the increase in life expectancy and improved HIV viral detection methods, have all led to a change in attitude towards fertility in people living with HIV. There is now acknowledgment of the fundamental rights of HIV patients to parenthood and growing implementation of assisted fertility in this group. The aims of fertility treatment are prevention of infection in HIV-discordant couples, and treatment for fertility problems, identical to the general population. We review the influence of HIV on the reproduction systems of males and females, conditions requiring fertility intervention, various methods that are possible and describe the optional treatment existing in Israel for patients with viral infection, and specifically HIV.

Vascular dysfunction in young, mid-aged and aged mice with latent cytomegalovirus infections.

Human cytomegalovirus (HCMV) is associated with vascular diseases in both immunosuppressed and immunocompetent individuals. CMV infections cycle between active and latent phases throughout life. We and others have shown vascular dysfunction during active mouse CMV (mCMV) infections. Few studies have examined changes in physiology during latent CMV infections, particularly vascular responses or whether the negative effects of aging on vascular function and fertility will be exacerbated under these conditions. We measured vascular responses in intact mesenteric and uterine arteries dissected from young, mid-aged, and aged latently mCMV-infected (mCMV genomes are present but infectious virus is undetectable) and age-matched uninfected mice using a pressure myograph. We tested responses to the α(1)-adrenergic agonist phenylephrine, the nitric oxide donor sodium nitroprusside, and the endothelium-dependent vasodilator methacholine. In young latently mCMV-infected mice, vasoconstriction was increased and vasodilation was decreased in mesenteric arteries, whereas both vasoconstriction and vasodilation were increased in uterine arteries compared with those in age-matched uninfected mice. In reproductively active mid-aged latently infected mice, mesenteric arteries showed little change, whereas uterine arteries showed greatly increased vasoconstriction. These vascular effects may have contributed to the decreased reproductive success observed in mid-aged latently mCMV-infected compared with age-matched uninfected mice (16.7 vs. 46.7%, respectively). In aged latently infected mice, vasodilation is increased in mesenteric and uterine arteries likely to compensate for increased vasoconstriction to mediators other than phenylephrine. The novel results of this study show that even when active mCMV infections become undetectable, vascular dysfunction continues and differs with age and artery origin.

Presence of DNA of adeno-associated virus in subfertile couples, but no association with fertility factors.

BACKGROUND: Based on previous reports suggesting a role of adeno-associated virus (AAV) in miscarriage, the prevalence of AAV DNA in genital tracts of male and female partners of subfertile couples was determined to assess a potential association of AAV infection with clinically relevant parameters of male and female fertility. METHODS: A prospective study was performed in the outpatient infertility clinic of a university-based hospital. Semen samples and endocervical material obtained from 146 male and 134 female partners of asymptomatic subfertile couples were analyzed for the presence of AAV DNA (using nested PCR). Patients' medical histories and details of clinical examinations were recorded. Semen quality, including sperm functional capacity and the presence of antisperm antibodies (ASA) and seminal white blood cells (WBC), was assessed in aliquots of the same ejaculate. Detailed examinations of the cervical factor and other variables of female subfertility were performed. Both partners were screened for bacterial infection. RESULTS: The presence of AAV DNA in semen was not significantly related to semen quality, including sperm functional capacity or local ASA, nor was it coupled to the presence of AAV in the endocervical material of female partners. The presence of AAV DNA was not associated with the presence of other micro-organisms of the lower genital tract or with seminal WBC in men. AAV DNA in endocervical material was not related to a reduced quality of cervical mucus or to other female infertility factors. CONCLUSIONS: The presence of AAV DNA in semen samples or endocervical swabs showed no significant association with clinically relevant infertility factors. However, longitudinal studies may clarify previous suggestions of an influence of AAV infection on early pregnancy problems.

A side effect of decreased fertility associated with vaccination against bluetongue virus serotype 8 in Holstein dairy cows.

Inactivated virus vaccines have been widely used to control bluetongue after introduction of serotype 8 of the bluetongue virus (BTV) in northern Europe in 2006. To evaluate vaccination, quantitative knowledge of its possible side effects is needed. One current adverse reaction with inactivated vaccines is a rise in body temperature, which could reduce cow reproductive performance. The objective of this study was to quantify a possible side effect of vaccination on fertility before the implantation of the embryo of dairy cows under field conditions. The study was performed on herds that were not exposed to BTV. Fertility was assessed by return-to-service following artificial insemination (AI). Biological assumptions for a possible side effect of vaccination were conception failure and embryonic death. Associations between return-to-service rates and vaccine injections were assessed using mixed-logistic regression models and survival analysis. Two models were considered: a 3-week-return-to-service model comparing cows vaccinated between 3 days before and 16 days after AI and unvaccinated cows (assuming an effect on conception failure or early embryonic death), and a 90-day-return-to-service model comparing cows vaccinated between 3 days before and 42 days after AI and unvaccinated cows (assuming an effect on conception failure, early or late embryonic death). Only cows receiving a second vaccine injection between 2 and 7 days after AI had a significantly higher risk of 3-week-return-to-service (RR=1.19 [1.07-1.33]). This corresponds to an increase of return-to-service by 4 percentage points. A side effect of vaccination could be due to early embryonic death. The slight side effect on fertility associated with vaccination was low compared to effects of BTV-8 exposure on fertility.

Seroprevalence of cytomegalovirus infection in pregnant women and associated role in obstetric complications: a preliminary study.

The objective of this study was to determine the seroprevalence of cytomegalovirus (CMV) infections through antenatal screening data and the association of this virus with obstetric complications. Serum samples from 125 apparently healthy pregnant women sent for antenatal screening from various hospitals in Malaysia between January 2007 and December 2008, were examined for CMV specific IgM and IgG antibodies using an enzyme-linked immunosorbent assay method. Of the 125 pregnant women tested, anti-CMV IgG antibody was found in 105 (84%) of the cases and anti-CMV IgM in 9 cases (7.2%). Both CMV IgM and IgG were also found in another 37 women whose serum samples were sent for investigation of various obstetric complications: 17 cases of spontaneous abortions, 15 cases of fetal anomalies detected during ultrasound examination, 1 case of incomplete abortion, 3 cases with premature delivery of infant with congenital anomalies and 1 case of infertility. Our preliminary data which only represented a small study group has shown the prevalence of CMV infection among the local population and the association of CMV in obstetric complications.