key: cord-0970978-2wrtl1uw
authors: Yang, Ming; Wang, Jing; Chen, Yidong; Kong, Siming; Qiao, Jie
title: Effects of SARS-CoV-2 infection on human reproduction
date: 2021-05-18
journal: J Mol Cell Biol
DOI: 10.1093/jmcb/mjab025
sha: 438e79e8de0b2a8ae6eb330cee1fc3abd8a53e88
doc_id: 970978
cord_uid: 2wrtl1uw

The worldwide infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacts human health and life on multiple levels. People infected with SARS-CoV-2 suffer from physical disorders and psychological distress. At present, no direct evidence indicates that SARS-CoV-2 negatively influences human reproduction, and the possibility that gametes and embryos are affected requires further investigation. To evaluate the potential effects of SARS-CoV-2 infection on human reproduction and fetal health, this review summarizes the basic and clinical research of SARS-CoV-2 on reproduction up to date, hoping to offer guidance and advice to people at reproductive age and provide clues for the prevention and treatment of associated diseases.

Since the first identification of coronavirus disease-19 in December 2019 , the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a major threat to the public health system. The confirmed cases reported around the world have exceeded 110 million until March 12, 2021, and the number of deaths is over 2 million. This is the third coronavirus infection outbreak of the 21 st century. Every country has adopted various strategies to combat the pandemic and to restore the world's prosperity. The incubation period of SARS-CoV-2 infection is 1-14 days (Lin and Li, 2020) . Fever, dry cough, nasal congestion, runny nose, sore throat, myalgia, and pneumonia are the main clinical symptoms. Diarrhea or conjunctivitis are the first symptom in a small number of patients Mehta et al., 2020) . Among them, the elderly with chronic diseases is more likely to become critically ill. No effective medicine specific for COVID-19 has been developed yet.

Zinc metallopeptidase angiotensin-converting enzyme 2 (ACE2), first discovered in 2000 (Zisman et al. 2003) , is a cellular receptor for SARS-CoV and SARS-CoV-2 (Turner et al., 2004; Yushun et al., 2020) . ACE2 is expressed in many systems (Zou et al., 2020) and correlates with several tissue functions (Tikellis et al., 2003; Zisman et al., 2003) . Lung alveolar epithelial cells, enterocytes of the small intestine (Hamming et al., 2004) , type II alveolar cells (AT2) , respiratory epithelial cells, myocardial cells, epithelial cells of ileum and oesophagus, proximal tubule cells of kidney, and bladder urothelial cells (Zou et al., 2020) all express ACE2.

Organs and tissues with ACE2 are believed to have a higher susceptibility to SARS-CoV-2 infection (Zou et al., 2020) . The analysis of ACE2 expression patterns in embryos and gonads is valuable for further investigate into potential effects and mechanisms of SARS-CoV-2 on reproduction.

Autopsy results have showed the presence of SARS-CoV-2 in the reproductive system of infected patients (Bian and The COVID-19 Pathology Team, 2020; Ma et al., 2021) . Whether SARS-CoV-2 affects human reproduction and embryonic development remains to be clarified. Therefore, this review hopes to give some insights into the effects of SARS-CoV-2 infection on human reproduction (Figure 1 ).

The female reproductive system is composed of ovaries, fallopian tubes, and uterus. The functional cooperation of these organs allows steroid hormones production, oocytes maturation, successful fertilization, as well as embryo development (Mancini and Pensabene, 2019) . The molecular functions of ACE2, angiotensin Ⅱ (AngⅡ), Ang-(1-7), and mitochondrial assembly 3 (Mas) are connected closely (Santos et al., 2003; Santos et al., 2013; Turner et al., 2004) . ACE2 and Mas are expressed in human ovaries (Reis et al., 2011) . Previous studies reported that Ang-(1-7)

and Mas co-localized to primordial, primary, secondary, and antral follicles and were present in the stroma and corpora lutea of human reproductive-aged ovaries; Ang-(1-7) was also detectable in follicular fluid.

To our knowledge, the female reproductive system is susceptible to many other viruses, such as HSV-2, HIV, and Zika virus (Counotte et al., 2018; Keller et al., 2019) . Pathology Team (2020) detected SARS-CoV-2 in uterus and ovary by polymerase chain reaction (PCR), immunohistochemistry (IHC), and transmission electron microscopy (TEM) for the first time. Vaginal swab samples from 10 women diagnosed with COVID-19 were collected and proved to be negative for SARS-CoV-2 (Qiu et al., 2020) . In 35 female severe COVID-19 patients who were in the postpartum and postmenopausal stage, no presence of the virus in vaginal fluid and exfoliated cells was found (Cui et al., 2020) . Considering the limited sample size, an infection risk of female reproductive system and the possibility of vertical transmission of SARS-CoV-2 cannot be completely ruled out.

SARS-CoV-2 needs entry factors ACE2 (Turner et al., 2004; Yushun et al., 2020) , TMPRSS2 (Djomkam et al., 2020) , CatB/L (Djomkam et al., 2020) , and CD147 to promote its invasion. In theory, organs with a high expression level of cell entry factors can be susceptible to SARS-CoV-2. ACE2 has been confirmed to express widely in ovaries, uterus, and vagina in the female reproductive system. In the uterus, (Vaz-Silva et al. (2009) found a higher ACE2 expression in epithelial cells compared to stromal cells and in secretory phase compared to proliferative phase.

Moreover, data from the Human Protein Atlas and GeneCards also confirmed the presence of ACE2 in the uterus and vagina (Jing et al., 2020) . On the contrary, at a single-cell level, the results appeared to be different. Single-cell sequencing data from normal cells in ovaries, fallopian tube, and uterus showed no significant expression of either ACE2 or TMPRSS2. The co-expression of ACE2 with TMPRSS2, CTSB, and CTSL was also not detected (Goad et al., 2020) . Therefore, it might be hard for SARS-CoV-2 to attack normal uterus and vagina cells. These organs tend to be strong against infection, which could also explain the absence of the virus reported in some studies.

Henarejos-Castillo et al. (2020) studied endometrium gene expression throughout the menstrual cycle from 112 COVID-19 patients. The findings showed that although low expression levels of ACE2 and TMPRSS2 suggested a safe environment against the virus entry into host cells, expression levels of proteases such as TMPRSS4, CTSB, and CTSL significantly increased during the early and middle secretory phases, which might confer a susceptibility of infection through different mechanisms. In addition, virus-related gene expression was shown to increase with age, suggesting higher risk of infection to the reproductive system for older women (Henarejos-Castillo et al., 2020) .

Overall, the existing studies are limited by small sample sizes and individual differences. The potential influences of the virus require further valiation. More completed and detailed diagnoses and autopsies of female reproductive organs in COVID-19 patients may provide more insights to explore the true influence of the virus.

Currently, the infection of SARS-CoV-2 in the male reproductive system is still uncertain and controversial. Majority of the researches revealed that no SARS-CoV-2 was detected in testes or semen in COVID-19 patients Ruan et al., 2021) . Nevertheless, three researches reported the detection of SARS-CoV-2 in testes and semen of COVID-19 patients (Yang et al., 2020; Li et al., 2020a; Ma et al., 2021) . To be specific,6 of 38 COVID-19 patients were detected SARS-CoV-2 positive in semen ; 1 of 12 COVID-19 patients was detected SARS-CoV-2 positive in testes of postmortem examination (Yang et al., 2020) ; and SARS-CoV-2 Spike S1 protein was stained positive in COVID-19 patients' testes (Ma et al., 2021) . Considering the risk of sample contamination, some researchers were skeptical to SARS-CoV-2-positive test in semen (Paoli et al., 2020a; Paoli et al., 2020b) . Up to now, no study has reported the presence of SARS-CoV-2 in the prostate. TMPRSS2 exists in different parts and cells of normal prostate and prostate cancer (Afar et al., 2001) , so the possibility of prostatitis caused by SARS-CoV-2 cannot be excluded. More details about the SARS-CoV-2 existence in the male reproductive system are shown in Table 1 .

Notably, orchitis was found in the testicles of male COVID-19 patients through autopsy (Nunes Duarte-Neto et al., 2020) , raising the question of whether SARS-CoV-2 affects sperm quality. A research reported that all 5 cases of male patients with COVID-19 had suffered from severe spermatogenesis damage compared with the normal control group. In addition, the study also observed significant infiltration of immune cells in testes of COVID-19 patients (Ma et al., 2021) . Holtmann et al. (2020) reported that, compared with the mildly infected group and the control group, sperm quality (sperm concentration, counts of sperm per ejaculate, counts of progressive motility, and counts of complete motility) was significantly different in the moderately infected group.

Moreover, although the differences in volume, complete motility, and amount of immotile sperms were of statistical significance between fever-positive and fever-negative groups, the values were still within normal range. Segars et al. (2020) indicated declined sperm concentration and motility for 72-90 days due to fever after SARS-CoV-2 infection. 21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   5 Pathological examinations and hormones were also studied in COVID-19 patients.

Pathological examinations in infected males showed a series of changes in seminiferous tubules.

Sertoli cells displayed severe injuries, including swelling, vacuolation, cytoplasmic rarefaction, and detachment from tubular basement membranes. Cell clusters in the lumen also decreased and shed in number. Leydig cells reduced and the basement membrane thickened with peritubular fibrosis along with mild inflammatory infiltration in the interstitium (Deshmukh et al., 2020; Yang et al., 2020) . SARS-CoV-2 infection may also affect male hormone production. Schroeder et al. (2020) found lower testosterone and dihydrotestosterone levels in most male participants with intensive care. Rastrelli et al. (2020) reckoned that most COVID-19 patients had lower total testosterone levels. While serum luteinizing hormone (LH) was higher in the 81 infected patients, testosterone to LH (T/LH) ratio and follicle stimulating hormone (FSH) to LH (FSH/LH) ratio were lower. The T/LH ratio in COVID-19 patients was negatively associated with disease severity, aspartate transaminase concentration, and c-reactive protein (CRP) levels and was positively associated with serum AMH level .

There is still no strong evidence to support that COVID-19 infection directly leads to male infertility. To understand long-term influences of SARS-CoV-2 on the male reproductive system, more thorough studies are needed.

Autopsy of COVID-19 victims in China has confirmed SARS-CoV-2 infection in uterus and ovaries (Bian and The COVID-19 Pathology Team, 2020), indicating the possible severe scenario of vertical transmission. It is worth noting that using TEM, Algarroba et al. (2020) first found the virus invading human placenta, but the infant was tested negative for SARS-CoV-2. SARS-CoV-2 was also identified to localize predominantly in syncytiotrophoblast cells (Hosier et al., 2020) , amniotic and placental (Richtmann et al., 2020) . In addition, compared to healthy individuals, the placentas of infected pregnant women have common abnormalities such as villous agglutination, subchorionic thrombi, focal avascular villi, and thrombi in larger fetal vessels (Dong et al., 2020a; Mulvey et al., 2020; Smithgall et al., 2020; Zeng et al., 2020a) . In a study that 29 infected women accepted SARS-CoV-2 detection by reverse transcription (RT)-PCR using their amniotic fluid, placenta, breast milk, and cord blood, all samples were negative (Schwartz 2020) . Throat swab samples of 16 newborns delivered by 15 infected pregnant women were tested negative for SARS-CoV-2 Zhu et al., 2020) . However, in one case, nasopharyngeal swabs obtained from the neonate on the day of birth, day 2, and day 7 were all SARS-CoV-2-positive, neonatal plasma tested positive on day 4, and stool was positive on day 7 (Kirtsman et al., 2020) . In addition, 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 6 some neonates were confirmed with SARS-CoV-2 infection at 16 (Alzamora et al., 2020) , 24 (Sisman et al., 2020; Zeng et al., 2020b) , and 36 (Marzollo et al., 2020; Wang et al., 2020b; Yu et al., 2020) h after birth. Although placenta, cord blood, and breast milk were tested negative Yu et al., 2020) and the detection was not carried at once after birth, the possibility of vertical transmission cannot be excluded. Moreover, two studies reported that IgM and IgG antibodies of novel coronavirus existed in the newborns, but the virus was tested negative in the fetus (Dong et al., 2020b; Zeng et al., 2020a) . Since IgM antibodies generally cannot be transmitted through the placenta to the fetus and the production of IgM usually takes 3-7 days after infection, there might be an intrauterine infection. Another study reported 3 of 11 neonatal placentas tested positive for SARS-CoV-2, but the neonatal virus test was negative (Penfield et al., 2020) .

A recent study reported for the first time that SARS-CoV-2 was detected to transmit from mother to child through the placenta (Vivanti et al., 2020) . A 23-year-old pregnant woman with a fever (38.6°C) and severe cough at 35+2 weeks of pregnancy tested positive for SARS-CoV-2 in blood, throat swabs, and vaginal swabs. Five days later, a cesarean section was performed. During the cesarean section, transparent amniotic fluid was collected before rupture of the amniotic membrane, and it was positive for SARS-CoV-2. The mother was discharged from the hospital six days after delivery and was in good condition. Six hours after birth and extubation, the newborn's blood, non-bronchial, and bronchoalveolar lavage fluid were found SARS-CoV-2-positive. Throat swab and rectal swab were collected after cleaning the newborn 1 h after birth, and then repeated on day 3 and day 18 after birth: SARS-CoV-2 tests were all positive. RT-PCR of two SARS-CoV-2 genes in the placenta showed positive results. Therefore, vertical transmission of SARS-CoV-2 infection was suggested to exist in this case (Vivanti et al., 2020) .

However, this case only confirmed SARS-CoV-2 vertical transmission in the third trimester.

Due to a paucity of evidence, caution should be undertaken to draw the link between vertical transmission and SARS-CoV-2 infection. Pregnant women with COVID-19 may have risk of death, premature delivery, and infection of newborns. As such, pregnant women with COVID-19 need to be closely observed and cared for. More details about the outcome of COVID-19 pregnant women and newborns are shown in Table 2 .

The potential mechanism of SARS-CoV-2 affecting the reproductive system ACE2 and TMPRSS2 are important for SARS-CoV-2 invasion (Djomkam et al., 2020) . ACE2 is expressed in several spermatogenic cell types, with Sertoli cells having the highest expression level. TMPRSS2 is also expressed in the male reproductive system, but has a different expression pattern compared to ACE2 (Liu et al., 2020a) , suggesting the potential danger of SARS-CoV-2 to 7 spermatogenesis.

Because the blood-testis barrier cannot completely block the virus, males infected by SARS-CoV-2 would present an increase in LH and a decrease in T/LH ratio and FSH/LH ratio Wang et al., 2020a) . Furthermore, COVID-19 induced oxidative stress at cellular level, leading to sperm DNA fragmentation and reduced sperm motility (Anifandis et al., 2020; Homa et al., 2019) . SARS-CoV-2 infection can cause fever and elevated testicular temperature (Li et al., 2020c) , which may impair spermatogenesis (Jung and Schuppe, 2007) . Male patients with severe COVID-19 who have a secondary cytokine storm syndrome (hemophagocytic lymphohistiocytosis) (Mehta et al., 2020 ) may undergo immunomodulatory therapy; the patient might experience a deviation of the cytokine microenvironment in the testis and risk the development of testicular cancer, all of which related to male infertility (Mehta et al., 2020; Tveito, 2020) .

SARS-CoV-2 has been proved to exist in the uterus, ovaries, and placenta (Algarroba et al., 2020; Bian and The COVID-19 Pathology Team, 2020; Ferraiolo et al., 2020; Hosier et al., 2020) .

ACE2 is expressed in female follicles, endometrium (Algarroba et al., 2020; Hosier et al., 2020) , and throughout different developmental stages of preimplantation embryos. The co-expression level of ACE2 and TMPRSS2 is highest on day 6 during the embryonic development in trophectoderm (TE) cells, indicating that TE cells may be relatively susceptible to SARS-CoV-2 during that time window. Thus, the potential risk of SARS-CoV-2 infection during embryo transfer process in clinical in vitro fertilization (IVF) should be properly evaluated.

ACE2 expression in endometrium may allow SARS-CoV-2 to enter endometrial epithelial and stromal cells, impairing in vivo decidualization, embryo implantation, and placentation (Chadchan et al., 2020) . ACE2-positive-expressing cells are also distributed at the maternal-fetal interface. The co-expression of ACE2 and TMPRSS2 mainly exists in the extravillous trophoblast cells (EVTs_24W) and syncytial trophoblast cells (STB_8W) of the decidua, making vertical transmission possible in the early and second trimester. Therefore, women with COVID-19 may have a higher risk of miscarriage .

SARS-CoV-2 infection has significant impacts on physical and mental health. In this review, potential effects of COVID-19 on human reproduction and the possibility of SARS-CoV-2 vertical transmission are discussed (Figure 1 ).

The incidence of infertility has been increasing recently, and miscarriage rate cannot be ignored in the natural pregnancy population. In the past few decades, although the success rate of infertility treatment has been greatly improved, the live birth rate of assisted reproductive technologies (ARTs) such as IVF still cannot exceed 50%. The above studies have confirmed that SARS-CoV-2 existed in human reproductive system of COVID-19 patients, and SARS-CoV-2 infection may affect sperm motility and T/LH and FSH/LH ratios. Thus, clarifying the impacts of SARS-CoV-2 infection on human reproduction will provide suggestions for people of childbearing age and construct a theoretical framework for IVF and embryo transfer process.

Pregnant women are susceptible to respiratory pathogens and may develop severe pneumonia.

This makes them especially vulnerable for contracting SARS-CoV-2, even more so if they have chronic diseases or maternal complications. To enhance the protection for pregnant women, they should be informed about prenatal check-up items, check-up time intervals, and check-up content during pregnancy. It is not recommended for pregnant women to listen to fetal heart rate at home instead of having regular pregnancy check-up. During the epidemic, for women within 28 weeks of pregnancy, the time intervals for their prenatal check-ups can be appropriately extended if there is no noticeable discomfort in the first and second trimester. Women with over 28 weeks of pregnancy, however, should follow their doctor's advice to go to the hospital for check-up. Pregnant women with chronic diseases or maternal complications should pay more attention to their health conditions. Pregnant women with severe or critical COVID-19 should consider terminating the pregnancy, and caesarean sections is recommended. Labour and delivery should be managed in a designated negative pressure room with experienced staff on personal protective equipment. Neonates should be isolated in a designated unit for at least 14 days after birth, and breastfeeding should be minimized to avoid close contact with the mother suspected or confirmed with COVID-19. Males and females are advised to engage in reproduction at least 3-6 months after recovering from COVID-19. More follow-up studies should be conducted to further evaluate the safety and health of pregnant women and newborns with COVID-19.

Currently, few studies pay attention to the long-term health status of neonates. More are tended to evaluate the status of newborns at birth using the Apgar score, which is mostly between 8-10 points (Schwartz, 2020; Wu et al., 2020; Yan et al., 2020; Yu et al., 2020) . Although some cases suffered complications like premature birth, neonatal distress, and so on, none of the conditions has anything to do with COVID-19. A cohort study observed 116 COVID-19 pregnant women and conducted a follow-up on 82 neonates (Salvatore et al., 2020) . None of the newborns showed symptoms of COVID-19. In addition, researchers from China also conducted prospective analysis of clinical characteristics and prognosis of 19 newborns from Wuhan (Liu et al., 2020b) , monitoring the newborns' vital signs, blood oxygen saturation, etc. The result indicated that the health status of the newborns was not affected. According to the present results, there is no evidence to support that pregnant women infected with SARS-CoV-2 would affect their neonates. To reach a concrete 

Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia

Visualization of severe acute respiratory syndrome coronavirus 2 invading the human placenta using electron microscopy

Severe COVID-19 during Pregnancy and Possible Vertical Transmission

COVID-19 and fertility: a virtual reality

Autopsy of COVID-19 patients in China

The SARS-CoV-2 receptor, angiotensin converting enzyme 2 (ACE2) is required for human endometrial stromal cell decidualization

Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records

SARS-CoV-2 Entry Factors: ACE2 and TMPRSS2 Are Expressed in Peri-Implantation Embryos and the Maternal

Sexual transmission of Zika virus and other flaviviruses: A living systematic review

Severe acute respiratory syndrome coronavirus 2 detection in the female lower genital tract

Histopathological observations in COVID-19: a systematic review

Commentary: SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a

Possible Vertical Transmission of SARS-CoV-2 From an Infected Mother to Her Newborn

Antibodies in the breast milk of a maternal woman with COVID-19

Report of Positive Placental Swabs for SARS-CoV-2 in an 10

Female reproductive tract has low concentration of SARS-CoV2 receptors

Absence of SARS-CoV-2 in semen of a COVID-19 patient cohort

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

SARS-CoV-2 infection risk assessment in the endometrium: viral infection-related gene expression across the menstrual cycle

Assessment of SARS-CoV-2 in human semen-a cohort study

A Comparison Between Two Assays for Measuring Seminal Oxidative Stress and their Relationship with Sperm DNA Fragmentation and Semen Parameters

SARS-CoV-2 infection of the placenta

Potential influence of COVID-19/ACE2 on the female reproductive system

Influence of genital heat stress on semen quality in humans

Impact of Herpes Simplex Virus Type 2 and Human Immunodeficiency Virus Dual Infection on Female Genital Tract Mucosal Immunity and the Vaginal Microbiome

Probable congenital SARS-CoV-2 infection in a neonate born to a woman with active SARS-CoV-2 infection

Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease

Impaired spermatogenesis in COVID-19 patients

COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis

Interpretation of 'Guidelines for the Diagnosis and Treatment of Novel Coronavirus (2019-nCoV) Infection by the National Health Commission (Trial Version 5

Clinical characteristics of 19 neonates born to mothers with COVID-19

Single-cell transcriptome analysis of the novel coronavirus (SARS-CoV-2) associated gene ACE2 expression in normal and non-obstructive azoospermia (NOA) human male testes

Evaluation of sex-related hormones and semen characteristics in reproductiveaged male COVID-19 patients

Pathological and molecular examinations of postmortem testis biopsies reveal SARS-CoV-2 infection in the testis and spermatogenesis damage in COVID-19 patients

Organs-On-Chip Models of the Female Reproductive System

Possible Coronavirus Disease 2019 Pandemic and Pregnancy: Vertical Transmission Is Not Excluded

COVID-19: consider cytokine storm syndromes and immunosuppression

Analysis of complement deposition and viral RNA in placentas of 11

COVID-19 patients

Pulmonary and systemic involvement in COVID-19 patients assessed with ultrasound-guided minimally invasive autopsy

Study of SARS-CoV-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab

SARS-CoV-2 presence in seminal fluid: myth or reality

Detection of SARS-COV-2 in Placental and Fetal Membrane Samples

SARS-CoV-2 Is Not Detectable in the Vaginal Fluid of Women With Severe COVID-19 Infection

Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients

Angiotensin-(1-7), its receptor Mas, and the angiotensinconverting enzyme type 2 are expressed in the human ovary

Fetal deaths in pregnancies with SARS-CoV-2 infection in Brazil. Case Rep

No detection of SARS-CoV-2 from urine, expressed prostatic secretions, and semen in 74 recovered COVID-19 male patients: A perspective and urogenital evaluation

Neonatal management and outcomes during the COVID-19 pandemic: an observation cohort study

Angiotensin-(1-7) is an endogenous ligand for the G proteincoupled receptor Mas

Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system

The majority of male patients with COVID-19 present low testosterone levels on admission to Intensive Care in Hamburg, Germany: a retrospective cohort study

An Analysis of 38 Pregnant Women with COVID-19, Their Newborn Infants, and Maternal-Fetal Transmission of SARS-CoV-2: Maternal Coronavirus Infections and Pregnancy Outcomes

Prior and novel coronaviruses, Coronavirus Disease 2019 (COVID-19), and human reproduction: what is known?

Intrauterine Transmission of SARS-COV-2 Infection in a Preterm Infant

Third Trimester Placentas of SARS-CoV-2-Positive Women: Histomorphology, including Viral Immunohistochemistry and in Situ Hybridization

Characterization of Renal Angiotensin-Converting Enzyme 2 in Diabetic Nephropathy

ACE2: from vasopeptidase to SARS virus receptor

Cytokine storms in COVID-19 cases？Tidsskr

The vasoactive peptide angiotensin-(1-7), its receptor Mas and the angiotensin-converting enzyme type 2 are expressed in the human endometrium

Transplacental transmission of SARS-CoV-2 infection

CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells

A Case Report of Neonatal 2019 Coronavirus Disease in China

scRNA-seq Profiling of Human Testes Reveals the Presence of the ACE2 Receptor, A Target for SARS-CoV-2 Infection in Spermatogonia

Neonatal outcome in 29 pregnant women with COVID-19: a retrospective study in Wuhan, China

Coronavirus disease 2019 in pregnant women: a report based on 116 cases

Pathological Findings in the Testes of COVID-19 Patients: Clinical Implications

Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study

Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus

Antibodies in Infants Born to Mothers With COVID-19 Pneumonia

Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan

Single-Cell RNA Expression Profiling of ACE2, the Receptor of SARS-CoV-2

Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia

Increased angiotensin-(1-7)-forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme Homologue ACE2

Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

We thank professor Liying Yan for guiding us and giving us comments on this review. We also thank our lab members Xixi Liu, Xi Chen, Jianting An, Lingyue Hua, and Feiyin Zhu for material searching on this review and Jiaxi Chen and Yiru Zhu for the help of language polishing.

This project is funded by the National Key Research and Development Program (2019YFA0801400) and the National Natural Science Foundation of China (81730038).