key: cord-0852771-z1fj5n5l
authors: Li, Rong; Yin, Tailang; Fang, Fang; Li, Qin; Chen, Jiao; Wang, Yixin; Hao, Yongxiu; Wu, Gengxiang; Duan, Peng; Wang, Yuanyuan; Cheng, Dan; Zhou, Qi; Zafar, Mohammad Ishraq; Xiong, Chengliang; Li, Honggang; Yang, Jing; Qiao, Jie
title: Potential risks of SARS-Cov-2 infection on reproductive health
date: 2020-04-30
journal: Reprod Biomed Online
DOI: 10.1016/j.rbmo.2020.04.018
sha: 518d02f4a29d97c597870f9f0d16a37487511566
doc_id: 852771
cord_uid: z1fj5n5l

Abstract The outbreak of 2019 novel coronavirus disease (COVID-19) has been a major epidemic threat all over the world. Such a public health emergency can greatly impact various aspects of people's health and lives. This paper focused on its potential risks on reproductive health, including reproductive system and function, as well as gamete and embryo development, which was underpinned by the virus, drugs, chemical disinfectants and panic psychology during the outbreak of COVID-19.

Reproduction is the most precious wealth and continuity of human beings.

Reproductive health refers to all factors and processes, including physical, mental and social health, and is the significant of maintaining the quantity and quality of the birth population. The current epidemic situation, treatment, prevention and control measures, associated with 2019 novel coronavirus disease , lead to people's worry caused by viruses, treatment medicines and environmental disinfectants, anxiety caused by isolation conditions, and panic psychologic status caused by public health emergencies. All of these factors affect reproductive health.

In order to respond to people's concerns about the possible impact of these special events on reproductive health, this paper reviewed the relevant literature to protect the overall situation of reproductive health.

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV2) , which shares 76% amino acid sequence homology with SARS-COV and enters into target host cells by the same cellular receptor, angiotensin-converting enzyme 2 (ACE2), and cellular protease, transmembrane protease serine (TMPRSS) (Lukassen et al., 2020) . In theory, organs with high expression of ACE2 or TMPRSS2 are more vulnerable to be infected. Currently, respiratory, cardiovascular, digestive and urinary systems have been reported as potential target organs of COVID-19 infection(Xin Zou, 2020) . The scRNA-seq raw sequencing data and immunohistochemistry (IHC) indicated that there is high expression of ACE2 in testis (Fan et al., 2020, Wang and Xu, 2020) , however, there is no report on the 5 expression of ACE2 in the female reproductive system until now. The potential risk of COVID-19 infection on fertility should be given more attention.

Wang Z et al (Wang and Xu, 2020) investigated the expression pattern of ACE2 and TMPRSS2 in adult male testis at the level of single-cell transcriptomes. The results indicated that ACE2 was predominantly enriched in spermatogonia, Leydig and Sertoli cells, while TMPRSS2 was expressed only in spermatogonia and spermatids.

The GO analysis has showed that genes associated with viral reproduction and transmission were highly enriched in ACE2-positive spermatogonia, while the genes associated with male gamete generation were down-regulated. The intercellular junction and immune-related genes were increased in ACE2-positive Leydig and Sertoli cells, but mitochondria and reproductive-related genes were decreased. In addition, Fan C et al (Fan et al., 2020) found that ACE2 was highly expressed in renal tubular cells, Leydig cells and cells in seminiferous ducts in testis. Also, Xu J et al found that orchitis is a complication of SARS and further indicated that the reproductive functions should be followed and evaluated in the recovered male SARS patients (Xu et al., 2006) . These findings may suggest that the testis might be a high-risk organ vulnerable to be attacked by SARS-COV2. Once infected, functional abnormalities in male germ cells or supporting somatic cells could cause spermatogenic failure and male infertility. Considering the potential pathogenicity of SARS-COV2 to testicular tissues, we proposed that clinicians should pay attention to the assessment and appropriate intervention in young patients' fertility, including the sperm analysis and sperm cryopreservation in the early stage of disease, and follow-up of the reproduction functions in the following months. 6 To date, the damage to the female reproductive system in COVID-19 patients has not been reported. There was an evidence that the renin-angiotension-aldosterone system (RAS) was involved in female reproductive processes, such as folliculogenesis, steroidogenesis, oocyte maturation, and ovulation. Reis FM et al (Reis et al., 2011) confirmed the existence of an Ang-(1-7)-Mas receptor-ACE2 axis and the ACE2 markers in all levels of follicles in the human ovary. ACE2 was also expressed in the endometrium, and more in epithelial cells than stromal cells, moreover, the expression of ACE2 was changed with the menstrual cycle, and more abundant in secretory phase than in proliferative phase, which may interfere with the local Ang-II homeostasis and regulate the endometrial regeneration (Vaz-Silva et al., 2009 ). In addition, previous studies showed that ACE2 expressed in bovine and rat ovarian granulosa cells, which was regulated by gonadotropins, and involved in follicular development (Barreta et al., 2013 , Pereira et al., 2009 . Based on the previous researches, we speculated the possible ways of SARS-COV2 affecting female fertility: (i) SARS-COV2 might attack ovarian tissue and granulosa cells, and decrease ovarian function and oocyte quality, leading to female infertility or miscarriage; (ii) SARS-COV2 might damage endometrial epithelial cells and affect early embryo implantation. However, there is still a lack of evidence about the effect of SARS-COV2 on fallopian-tube, which should be paid more attention in the future.

Recently, Chen H et al reported there was currently no evidence for vertical transmission of SARS-COV2 in the third trimester (Chen, 2020) . However, the effect of SARS-COV2 on early pregnancy is still unknown. An individual participant data meta-analysis showed pregnancy was a risk factor for severe influenza infection (Mertz et al., 2019) , and influenza vaccination reduces the risk of mild to moderately severe LCI disease during pregnancy (Thompson et al., 2019) . Furthermore, limited information associated with SARS might provide insights into COVID-19's effects 7 during pregnancy. SARS during pregnancy could be associated with a high incidence of adverse maternal and neonatal complications, such as spontaneous miscarriage, preterm delivery, intrauterine growth restriction and disseminated intravascular coagulopathy (DIC), Wong et al reported seven women infected with SARS in the first trimester, four had a spontaneous abortion (Wong et al., 2004) . During early pregnancy, human placental RAS was upregulated and played an important role in placental vascular development (Pringle et al., 2011) . Another research showed a high level of ACE2 mRNA in the placenta in early pregnancy, which was located in syncytiotrophoblast (STBs) and villous stroma, and ACE2 also regulated the release of Ang1-7, which was beneficial for maternal-fetal circulation vasodilation, and favorable for virus spread(la Pena et al., 2018) . Zheng QL et al analyzed the mRNA expression profile, and found that ACE2 had a very low expression in the different cell types (STB cells, decidual stromal cells and epithelial glandular cells) of maternal-fetal interface, except slightly high expression in decidual perivascular cells cluster 1 (PV1)(Zheng QL, 2020). So, we presumed the potential effect of COVID-19 on early pregnancy as follows: (i) Due to the lack of "susceptible cells" at the interface between mother and infant in early pregnancy, the rate of mother to infant transmission might be very low; (ii) SARS-COV2 might change the expression of ACE2 at the interface between mother and infant in early pregnancy, leading to a pregnancy loss.

Drugs for the treatment of COVID-19 mainly include antiviral drugs (such as interferon, ribavirin, lopinavir/ritonavir), antibiotics (such as moxifloxacin, azithromycin), and steroidal drugs like glucocorticoids. In addition, in order to stop the spread of the virus, a large scale disinfection was carried out in medical institutions including hospitals, centralized isolation points, the homes of infected 8 people's families, the homes of those in close contact with infected individuals or their families, communities, key units (including supermarkets, hotels), bazaars, public toilets, garbage transfer stations, and more. This section focuses on the effects of first-line drugs and disinfectants currently used to combat COVID-19 on reproductive health.

According to the latest "Coronavirus Pneumonia Diagnosis and Treatment Program (Sixth Edition)," (thereafter referred to as Sixth Edition) issued by the National Health Commission of China, interferon-alpha, and ribavirin (combine with interferon or lopinavir/ritonavir), arbidol (umifenovir), and chloroquine phosphate were recommended for use. Ribavirin is a broad-spectrum antiviral drug. Animal experiments have reported that the ingestion of ribavirin decreased the testosterone level and impaired spermatogenesis (Almasry et al., 2017) , and could cause sperm abnormalities in rats (Narayana et al., 2002b) . However, this toxic effect was reversible (Narayana et al., 2005 , Narayana et al., 2002a . Clinical studies have shown that ribavirin combined with interferon treatment could affect male fertility, manifested through a decrease in sperm counts (Bukhari et al., 2018, Drobnis and Nangia, 2017) . Pharmacokinetic studies showed that the concentration of the drug in seminal plasma during serum antiviral therapy was twice that in the serum, so contraception was strongly recommended during medication period (Hofer et al., 2010) . Moreover, ribavirin could lead to sperm DNA fragmentation for up to 8 months (Pecou et al., 2009) , so contraception was also recommended for a period after cessation of antiviral treatment. There were relatively few studies on the effects of ribavirin on the female reproductive system, but there was a clinical case about a 36-year-old woman injected with ribavirin intramuscularly due to a suspected SARS infection during the first trimester of pregnancy, whose baby girl had a normal development at 8 months postpartum (Rezvani and Koren, 2006) . Lopinavir/ritonavir 9 was recommended for pregnant women with HIV infection to reduce HIV transmission, and no increase in the risk of birth defects was observed(U.S.

Department of Health and Human Services. 2019). But for the male, lopinavir/ritonavir was reported to impair spermatogenesis possibly by oxidative damage in rats (Adaramoye et al., 2015) . Chloroquine phosphate has also been shown to impair spermatogenesis and epididymal function in male rats (Adeeko and Dada, 1998, Asuquo et al., 2007) . To date, none of the studies has explored the impact of arbidol on the reproductive system.

Glucocorticoids can expand the interstitial space of the spermatogenic epithelium, destroy cell connections, affect the blood-testis barrier, thus allowing harmful substances to enter testicular tissue. Glucocorticoids can also cause germ cell apoptosis through its receptor on germ cells. There is currently no literature demonstrating the effect of glucocorticoids on follicular development. It is recommended that glucocorticoids only are used for a short time in patients with progressive deterioration of oxygenation indicators, rapid imaging progress, and excessive activation of inflammatory reactions in the body. Small doses in a short period have less impact on the reproductive system.

Avoiding the inappropriate use of antimicrobials, especially the combination of broad-spectrum antimicrobials, although most antibiotics, especially the new generation of drugs that are highly specific and cause less damage to the human reproductive system.

At present, the commonly used chemical disinfectants can be divided into the following 8 types: alcohol disinfectants, chlorine disinfectants, biguanide and quaternary ammonium disinfectants, iodine disinfectants, aldehyde disinfectants, phenol disinfectants, peroxide disinfectants, and ethylene oxide. 75% alcohol is the most-used and safe disinfectant in medical institutions. But compared with quaternary ammonium, 75% alcohol results in significantly higher volatile organic compounds (VOCs) in IVF laboratory, which may increase the risk of egg fertilization failure, induce embryonic retardation and reduce developmental potential, leading to adverse IVF outcomes (Brown, 1999) . However, no alcohol is contained in the present disinfectants used in IVF laboratories. Chlorine disinfectants are widely used. This kind of disinfectant has been shown to increase abnormalities in the sperm heads of mice (Meier et al., 1985) . Peroxyacetic acid, also known as acetic acid, has a wide range of antibacterial activities, in both gaseous and solution forms. Some studies have found that zebrafish embryos exposed to 0.75mg/L peracetic acid for 2 to 4 hours after fertilization had an average mortality rate of 89.6 ± 3.4%, and there was a positive correlation between the peracetic acid concentration and embryo mortality (Marchand et al., 2013) . Phenolic disinfectants are mainly used for the disinfection of livestock buildings, cages, sites and vehicles. A large number of animal experiments demonstrated phenolic disinfectants could cause embryonic developmental deformities and even resulted in fetal arrest (El-Dakhly et al., 2018 , Ton et al., 2012 . The iodine-containing disinfectants include iodine tincture and povidone-iodine. The most important component of iodine-containing disinfectants is iodine. Excessive intake of iodine may lead to a decrease in sperm density (Sakamoto et al., 2004) .

Previous studies have shown that the outbreak of emerging infectious diseases (like SARS, MERS, and H1NI) was associated with panic psychology among patients, health workers and the public, such as depression, anxiety, fear, posttraumatic stress 11 disorder (PTSD) and so on (Liao et al., 2014 , Blendon et al., 2004 , Park et al., 2018 , Hawryluck et al., 2004 , Wu et al., 2009 , Wang et al., 2011 . When confronted with a stressor of such emergent crisis as COVID-19 outbreak, people's risk perception and psychological distress can be aroused of high level and lead to irrational nervousness or scare (Shi et al., 2003, Sim and Chua, 2004) . The consequence is an immediate disruption the body's homeostasis and activation of the central stress response system (primarily regulated via the hypothalamic-pituitary-adrenal (HPA) axis). Although the acute HPA response to stressors is a self-protective mechanism, constant activation of the HPA axis by chronic or traumatic stressors may result in a dysregulation of the HPA axis, which can inhibit the body's reproductive function, alter fetal development, and hence lead to poor reproductive outcome (Joseph and Whirledge, 2017) .

Furthermore, there are sex differences in the regulation of stress response, mainly due to the interaction between the HPA axis and the hypothalamic-pituitary-gonadal (HPG) axis; Such interaction could lead to abnormalities of stress responses, and the latter may in turn affect the former and thereby exacerbate psychological disorders (Oyola and Handa, 2017) . Therefore, there are many complex mechanisms between stressors and psychological disorders, and it is necessary to pay special attention to the impacts of panic psychology on human reproductive health during the outbreak of COVID-19.

There is growing evidence on the association between psychological disorders and male poor fertility. Men with psychological disorders (e.g., major depression) were less likely to make their female partners achieving conception than those without psychological disorders (Evans-Hoeker et al., 2018) . We can link the poor fertility performance during a psychological crisis period with decreased sperm quality and induced sexual dysfunction. Stress and negative moods (e.g., depression and anxiety) are able to influence detected seminal parameters at both macroscopic and 12 cellular/subcellular levels, including lower total sperm count, lower sperm concentration, lower semen volume and increased sperm DNA fragmentation (Zou et al., 2018 , Gürhan et al., 2009 , Vellani et al., 2013 . Activation of the HPA axis and subsequent change of hormones level plays a critical moderating role between psychological disorders and poor sperm quality. For example, Eskiocak et al. indicated that psychological stress can lead to an increase of nitric oxide level and a decrease of arginase activity in the L-arginine-nitric oxide pathway (Eskiocak et al., 2006) ; Wdowiak et al. concluded that depression and anxiety among subfertile males are associated with lower secretion of SHBG and DHEA-S, and higher secretion of cortisol and prolactin (Wdowiak et al., 2017) . Besides poor sperm quality, the other important cause of the poor fertility performance among men with psychological disorders is sexual dysfunction, including less sexual activity, hypoactive sexual desire, erectile difficulties and so on. For instance, Yehuda et al. established a model of sexual dysfunction in PTSD underpinned by an inability to regulate and redirect the physiological arousal needed for healthy sexual function (Yehuda et al., 2015) .

Likewise, other negative moods, such as depression, anxiety and fear, have been proved to be related with sexual dysfunction (Brotto et al., 2016) .

Similar to males, stress and psychological disorders also leads to both direct and indirect impacts on female reproductive system. Through activating the HPA axis, a close association between stress and women's reproductive function can be highlighted by body-stress response and hormones involvement, and such association seemed more likely reported in infertile women rather than fertile women, although with gaps in evidence on a precise cause-effect relationship due to conflicting results and the lack of objective evaluation indicators (Palomba et al., 2018) . Based on the theory and previous studies, Prasad et al. also established a pathway of how stress impacts the biology of female reproduction: stress leads to increased level of reactive 13 oxygen species (ROS) in ovary, accumulation of ROS further beyond physiological level leads to oxidative stress (OS), which reduces growth and development of follicular and induces apoptosis of oocyte, finally leading to poor reproductive outcomes (Prasad et al., 2016) . If an woman's panic psychology of the COVID-19 pandemic develops a chronic or traumatic dysfunction, such negative impacts on her oocyte quality and reproductive outcomes may happen. For example, an internet-based preconception cohort study conducted in the United States and Canada reported an association between women's severe depressive symptoms and greater prevalence of irregular menstrual cycles as well as decreased fecundability (compared with no or low depressive symptoms: prevalence ratio 1.80, 95% CI: 1.48 to 2.19; fecundability ratio 0.62, 95% CI: 0.43 to 0.91,) (Nillni et al., 2016 , Nillni et al., 2018 .

Another example is that a lot of markers for stress and anxiety (such as adrenaline, noradrenaline, adrenocorticotropic hormone, natural killer cells, cardiovascular reaction to provoked stress and so on) have been proved to be relevant for lower pregnancy rates in IVF cycles (Campagne, 2006) . Therefore, it can be concluded that stress and psychological disorders can impact oocyte quality and reproductive outcomes via complicated physiological mechanisms. Furthermore, similar to their male partners, women with stress and psychological disorders are also troubled with sexual dysfunction. It has been proved by increasing evidence that women with negative moods and PTSD are more likely to experience sexual dysfunction (Yehuda et al., 2015 , Brotto et al., 2016 , McCabe et al., 2016 . Therefore, sexual dysfunction may be a common symptom, although not specific, which should be paid more attention among both men and women with panic psychology.

Panic psychology during early pregnancy may impact embryonic development and then lead to adverse maternal and fetal outcomes. Early pregnancy is a special period susceptible to neuroendocrine and immune dysregulation, which is common in the 14 process of body's stress response and also primarily regulated by the HPA axis (Parker and Douglas, 2010) . Neuroendocrinal and immunologic changes play a critical mediating role between stress exposures and early pregnancy risk (for example, pregnancy loss), via affecting arterial formation, placental development, and uterine-fetal interaction (Frazier et al., 2018) . Besides early pregnancy risk in the short term, psychological stress also can lead to long-term impacts on pregnant women and offspring. For instance, D'Souza et al. associated increased oxidative stress during early pregnancy with developing preeclampsia (D'Souza et al., 2016) . Hantsoo et al. proposed that inflammation is a mediator between maternal stress and offspring neuropsychiatric risk, through reviewing both human and animal studies (Hantsoo et al., 2019) . Except for these pathological mechanisms and outcomes of panic psychology during early pregnancy which have been discussed above, pregnancy termination without medical indicators, especially among pregnant women in the first trimester, is also atragic consequence of panic psychology. During the outbreak of infectious diseases, some pregnant women may make a choice of pregnancy termination, especially in early pregnancy, due to excessive worries and fears of either known or unknown risks on themselves and offspring (Meaney-Delman et al., 2017 , Wong et al., 2004 . Evidence has showed that pregnant women with severe depression had a higher risk perception of teratogenic risk and a higher rated likelihood to terminate the pregnancy (Walfisch et al., 2011) . Therefore, it is necessary to timely provide reliable information and mental counseling to pregnant women, avoiding unnecessary fears and overloaded stress.

The pandemic of COVID-19 is rapidly spreading all over the world. As of April 13, 2020, there are over 1.7 million confirmed cases of COVID-19 globally, and the total deaths from this disease has surpassed 100, 000(World Health Organization, 2020).

Many clinicians and the public are very concerned about its impact on reproductive health. Based on limited evidence so far, we have considered that the potential pathogenicity and attack of COVID-19 on testicular tissues, ovarian tissue and granulosa cells, might affect testicular and ovarian function, sperm, oocyte quality and pregnancy outcomes. We should pay attention to the assessment and appropriate intervention in young couples' fertility during and even after this pandemic, especially for those infected SARS-Cov-2. The potential risk of SARS-Cov-2 infection on fertility should be given more attention. Maternal or paternal massive pneumonia and its treatment are prone to influence embryo development, fetal health, and endangers pregnancy safety. It is strongly suggested that contraception must be emphasized during the anti-viral treatment of COVID-19 and it should be continued for a period of time after the treatment. There is no evidence to suggest that termination of pregnancy is required for patients in early pregnancy. At present, the main disinfectants used during prevention and control are 75% alcohol and chlorine disinfectants which are both used at safe concentrations and will not cause damage to the reproductive system, gametes, and zygotes. During the outbreak of COVID-19, the couples should be provided with reliable information and psychological consultation in time to avoid irrational fear and excessive stress, especially for the patients with COVID-19.

COVID-19 also calls for an urgent demand of specific procedures and measures in assistant reproductive technology (ART) centres. According to practical experiences from ART centres China, there are several recommendations that should be seriously pay more attention: (1) providing adequate personal protective equipments (PPEs) for medical staff; (2) strengthening hygiene and disinfection in the settings, and re-arrangement of procedures and physical spaces to avoid crowding and space constraints, in order to reduce the risk of nosocomial infection; (3) screening all patients on arrival, including epidemiological history, routine temperature measurement and inquiry of COVID-19 common symptoms; (4) providing online counselling and following up to avoid unnecessary visiting during the pandemic, if possible; (5) initiating rapid training mechanisms for key response capacities, including diagnosis, triage, clinical management, and essential infection prevention and control; and (6) promoting health education for patients of basic infection-prevention measures, such as hand hygiene, respiratory etiquette (wearing masks when face-to-face talking with others, never sneezing to others, etc.), physical distancing and so on, as well as keeping a healthy lifestyle during the pandemic.

Furthermore, previous studies have indicated that the new coronavirus might have a potential impact on the reproductive system of the two sexes, mainly due to changes in the use of drugs and the environment. Medical professionals should make comprehensive assessments based on their fertility needs and disease conditions, so as to give reasonable guidance and advice on fertility. At the same time, further study should be needed to evaluate the long-term effects of SARS-Cov-2 infection (male, female or both) on human fertility, pregnancy outcomes, and the growth and development of their offspring, so as to accumulate more evidence for the reproductive effects of similar diseases.

All authors declare that they have no competing interests. Completed disclosure of interest forms are available to view online as supporting information.

RL organized the working group, interpreted the results of reviewing literatures and wrote the final manuscript. TY, FF, QL, JC, Yixin W, YH, GW, PD, Yuanyuan W, DC, QZ and MIZ searched literatures, interpreted the results and drafted the 17 manuscript. CX interpreted the results and revised the manuscript. HL, JY and JQ conceived, planned, and designed the study, and contributed equally to this work.

No ethical approval was required for this study.

This work was funded by grants from Peking University Health Science Center (BMU2020HKYZX001), Chinese Academy of Engineering (2020-KYGG-01-06), and HUST COVID-19 Rapid Response Call (2020kfyXGYJ057).

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