SARS-CoV-2 and the reproductive system: assessment of risk and recommendations for infection control in reproductive departments

ABSTRACT

The World Health Organization has declared the outbreak of the coronavirus disease COVID-19, caused by SARS-CoV-2, a pandemic. This novel infectious disease has rapidly become a global health threat. Currently, there are limited data on the extent of reproductive system damage caused by COVID-19. We reviewed the potential risks for complications in the reproductive system caused by COVID-19 infection. In addition, based on the latest American Society for Reproductive Medicine (ASRM), and European Society of Human Reproduction and Embryology (ESHRE), recommendations regarding clinical and patient management, we provide a series of suggestions for infection control measures in reproductive medicine departments. With the gradual restoration of reproductive care services, reproductive departments in epidemic areas should actively seek to minimize COVID-19 infection of both healthcare workers and patients.

KEYWORDS:

• COVID-19
• SARS-CoV-2
• reproduction
• control measures

Introduction

The world is currently experiencing an outbreak of the 2019 novel coronavirus disease (COVID-19) infection. As of 14 June 2020, the World Health Organization has reported more than 7,700,000 confirmed cases across more than 100 countries and described the coronavirus outbreak as a pandemic.

Previous studies have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV viruses have very similar spike protein (S protein) 3D structures, which are considered to have a strong binding affinity with the human cell receptor angiotensin-converting enzyme 2 (ACE2) (Wrapp et al. 2020). ACE2 is an important active enzyme in the renin-angiotensin aldosterone system, which, has emerged as a target.  It is widely expressed in somatic cells, such as those in the lung, myocardium, and kidney.

Results and discussion

The potential risk of reproductive complications caused by COVID-19 infection

Recently, a series of studies have reported high levels of ACE2 expression in the testes, spermatids, ovaries, fallopian tubes, and placenta, and similar levels of ACE2 expression in the human uterus and lungs (Hamming et al. 2007; Caibin Fan et al. 2020; Shen et al. 2020; Wang and Xu 2020; Zhang et al. 2020). Although further clinical laboratory tests are needed to confirm the distribution of SARS-CoV-2 infection in the human body, the high expression of ACE2 in testicular, uterine, placental, and sperm cells indicates a high risk of SARS-CoV-2 infection in the human reproductive system.

ACE2 deficiency has been identified as inhibiting gestational weight gain and restricting fetal growth during pregnancy in mice (Bharadwaj et al. 2011). Previous studies of SARS-CoV have shown that infection during pregnancy is related to a high incidence of adverse maternal and neonatal complications, such as intrauterine growth restriction, preterm delivery, spontaneous miscarriage, disseminated intravascular coagulopathy, and renal failure (Lam et al. 2004; Wong et al. 2004).

For SARS-CoV-2, the latest clinical evidence identified two cases of fetal distress among nine monitored pregnancies, although no cases of intrauterine infection have been reported (Chen et al. 2020). Mehan et al. have also reported adverse perinatal outcomes for pregnant women infected with SARS-CoV-2, but it is unclear whether these results are directly related to SARS-CoV-2 (Mehan et al. 2020). Although data available from a limited number of case reports do not indicate the presence of maternal-to-infant transmission of SARS-CoV-2, a study by Zeng et al. using reverse transcriptase–polymerase chain reaction (RT-PCR) reports that six infants, of six different mothers with COVID-19, tested positive for SARS-CoV-2-specific antibodies and were also presenting with elevated inflammatory cytokine (IL-6) levels (Zeng et al. 2020). Similarly, another case report describes the presence of immunoglobulin M (IgM) antibodies to SARS-CoV-2 in the blood of an infant at birth, and suggests that vertical transmission of the virus is possible (Dong et al. 2020). In addition, SARS-CoV-2 was found to have invaded the syncytial trophoblast in the placental villi in a rapidly deteriorating COVID-19 patient at 28 weeks gestation (Algarroba et al. 2020). In conclusion, considering the limited published data available, we cannot, at present, exclude the possibility of SARS-CoV-2 transmission from mother to infant via the placenta.

In men, some viral infections, including those caused by the mumps virus, the human immunodeficiency viruses, and the Zika virus (Liu et al. 2018), may lead to long-term complications of the tests and other reproductive organs, such as orchitis and infertility. One study analyzed pathological changes in the tests of six SARS patients and found that SARS-CoV caused orchitis (Xu et al. 2006). In addition, another study reported that SARS-CoV was found in the testicular epithelial cells and Leydig cells of two patients who died of SARS (Zhao and Sun 2003). In fact, the data on the presence of SARS-CoV-2 in semen are conflicting. Current evidence suggests that the main pathways for coronavirus entry into cells include the viral S protein attaching to ACE2, and the initiation of S proteins via transmembrane serine protease 2 (TMPRSS2), and both ACE2 and TMPRSS2 are present in the testes (Hoffmann et al. 2020; Pan et al. 2020). A study using RT-PCR testing showed that the SARS-CoV-2 virus was not present in the semen of 34 men with COVID-19 (Pan et al. 2020). Interestingly, the authors also reported scrotal discomfort in 17.6% (6/34) of these SARS-CoV-2 positive patients. Further studies are needed to confirm whether this observation is related to virus infection. However, in another recent study evaluating the semen of 38 COVID-19 patients from China, 15.8% (6/38) of the patients were positive for SARS-CoV-2 in the semen (Li et al. 2020). In addition, a recent autopsy report for 91 COVID-19 victims described varying degrees of spermatogenic cell reduction and damage, and SARS-COV-2 RNA and virus particles were detected in the testes of several patients (Bian and Team 2020).

In summary, despite a lack of additional clinical evidence, SARS-CoV-2 infection may carry a potential risk of reproductive system damage. Therefore, it would be beneficial to monitor the functionality of the reproductive system of patients infected with COVID-19. In addition, the possibility of vertical transmission and sexual transmission should be considered.

Current infection control measures in reproductive medicine departments

Globally, most reproductive departments and clinics are extremely busy and crowded because of the increasing incidence of infertility. In addition, reproductive departments typically conduct multiple examinations of men and women, including physical examination, ultrasound, blood series, semen series, genetics, and electrophysiology. All these procedures potentially increase the risk of cross-infection between patients and healthcare workers in reproductive departments. Therefore, in the early stages of the COVID-19 pandemic, the European Society of Human Reproduction and Embryology (ESHRE), American Society for Reproductive Medicine (ASRM), British Fertility Society/Association of Reproductive and Clinical Scientists (BFS/ARCS) and Canadian Fertility and Andrology Society (CFAS) recommended that all but the most urgent of reproductive care cases be delayed. With the emergence of successful mitigation strategies and more data in some regions, our global professional bodies have issued a series of recommendations for the judicious and gradual resumption of full reproductive care (Patient Management and Clinical Recommendations During The Coronavirus (COVID-19) Pandemic 2020). There is no denying that COVID-19 will remain a factor to be managed in reproductive care practice for a long time. It is therefore necessary that reproductive departments strengthen infection control measures in order to minimize the risk of SARS-CoV-2 transmission. Based on the latest management and clinical recommendations of ASRM, ESHRE, BFS/ARCS, and CFAS, the following comprehensive management measures should be considered.

Firstly, before restarting reproductive care services, hospitals should monitor and evaluate local conditions, including the prevalence of diseases, the status of government regulations, and the availability of medical resources. The reproductive department should maintain active risk mitigation strategies, and formulate or perfect a sound contingency plan to reduce the risk of virus transmission.

Secondly, in terms of prevention strategies for patients, reproductive departments should consider the benefits and risks associated with treating patients. In addition to considering COVID-19 prevalence in the region, and current recommendations regarding social distancing, an additional factor to be considered is the urgency of treatment (for example, the age of the donor/recipient, the age of the prospective parent, and possible progression of the disease). Hospitals should formulate systematic screening strategies, such as pre-screening for symptoms (e.g. shortness of breath, cough, sore throat, fever, and anosmia), taking epidemiological histories via telephone or telehealth visits, implementing temperature screening at hospital entrances, and possible COVID-19 testing. The number of family members accompanying patients on hospital visits should be strictly limited, and all patients and visitors should be advised to wear masks. The widespread availability of reliable COVID-19 testing is essential to prevent further infection and control the outbreak. Testing for the virus (via nucleic acid or protein antigen tests) or immunity to it (via antibody serology tests) helps to identify patients, and their close contacts, who have had COVID-19.

However, the guidelines provided by our global professional institutions, (ASRM, ASRM, ESHRE, BFS/ARCS and CFAS), are obviously different in the deployment and interpretation of SARS-CoV-2 test strategies. As the recent resurgence of COVID-19 cases in some previously affected areas and new places in the United States threatens the ability to continue to provide reproductive health care safely, the ASRM COVID Taskforce proposed in the latest update (July 10, 2020) that baseline PCR testing for COVID-19 should be encouraged before starting any type of fertility treatment or surgical intervention. Moreover, patients who tested negative for COVID-19 were encouraged to isolate themselves throughout the reproductive treatment. In addition to the ASRM’s recommendation, the ESHRE COVID Taskforce believes that testing for SARS-CoV-2 is crucial and can be used to decide whether to continue or postpone reproductive treatment. However, the first hurdle at present is the availability of tests. Most countries are experiencing great pressure in maintaining the supply chain of test reagents and the capacity of the infrastructure required for testing. In fact, most of these resources are managed by government agencies, which may further reduce the availability of testing for patients receiving assisted reproductive treatment. For example, in the ‘Guiding Principles to assist Canadian ART clinics to resume services and care’ (June 3rd, 2020), the CFAS suggested that the testing guidelines for SARS-CoV-2 should include who is eligible, under what circumstances, and the associated turnaround times stipulated by the provincial/state/regional government. In the ‘best practice guidelines for reintroduction of routine fertility treatments during the COVID19 pandemic’ (June 12, 2020), the BFS/ARCS pointed out that there are currently no widely available and reliable serological tests in Britain. Regarding coronavirus detection, the BFS/ARCS suggested that the centers should follow local and national guidelines.

Thirdly, prevention strategies for clinical staff should be considered. The current principle is that the safety of patients and staff be maximized while ensuring the capacity to provide care. All staff should receive infection control training, including on hand hygiene and the use of personal protective equipment. All employees should be encouraged to report their body temperature and any abnormal physical condition promptly. The availability of personal protective equipment, required to reduce the risk of infection, is an important factor for the recovery of routine reproductive care, and procedures should be established to maintain an adequate supply. Guidelines for the use of personal protective equipment to reduce the risk of infection in reproductive health environments are continuously updated in the ASRM patient management and clinical recommendations (Patient Management and Clinical Recommendations During The Coronavirus (COVID-19) Pandemic 2020).

The number of COVID-19 cases and deaths continues to increase. Current data indicate that the COVID-19 pandemic may continue for a long time. Therefore, all health care workers, including reproductive doctors, should be prepared to continue the fight against COVID-19.

Author contributions

Conceived and designed: GL, YC; Drafting of the manuscript: GL, WL; Data collection: BS, HW, DT, CW; Supervision: XH, YC. All authors approved the revisions and final manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was funded by the Non-profit Central Research Institute Fund, grant number 2019PT310002.