August 02, 2020

SARS-CoV2 and Reproductive Health: An update

Recently a young woman in her thirties shared that she and her husband are thinking about conceiving a baby. They are worried about Covid-19 and have put off childbirth for now. They are willing to wait for the pandemic to diminish, but are well aware that at their age they cannot put off this decision too long. Fortunately, recent research and clinical studies are shedding light on what this couple and other young adults need to know before they decide what to do about having children.

In order to appreciate the effects of the virus on reproduction it is important to understand what is known about how it invades cells and about the host immune response. Since I posted our first blog on Covid-19 and pregnancy in March, physicians and scientists have learned a great deal about these issues. It is well known that the virus, SARS-CoV2 has mutated since it first was reported to infect individuals in Wuhan, China. The mutated virus has increased spikes on its surface and has the ability to efficiently search out the host cell receptor, ACE2 and bind to it.Thus, it is highly contagious.The virus that first came to our country in Washington state was the virus from China, but the virus that infected people on the East Coast and Europe was primarily the mutated virus. Over time the mutation has become prominent.

Scientists have a good understanding of how SARS-CoV2 binds to and enters host cells. Since the host cell receptor angiotensin converting enzyme 2 (ACE2) is on many types of cells, the virus can invade and take over the cells of many organs, although it first invades lung cells. The SARS-CoV2 spike (S) glycoprotein binds to the host cell receptor, ACE2. Then the host cell protease, transmembrane serine protease 2 (TMPRSS2) cleaves the viral S glycoprotein and changes its structure or conformation to induce fusion of the virus with the cell. Another viral protein, N-terminal nonstructural protein (Nsp1) shuts down host cell protein production. This blocks the host cell immune response by several mechanisms including obstruction of mRNA entry channels of host ribosomes and blocking translation of host proteins. Thus, the host immune response, including production of interferon- beta is thwarted by the virus.

Recent studies of the initial immune response in SARS-CoV2 infected individuals is characterized by a robust activation of CD4+ T and CD8+ T cells, (CD4+ and CD8+ cells are the main inflammatory immune cells that clear viruses). Robust activation of B cells and an increase of peripheral blood neutrophils, monocytes and natural kills or NK cells occurs. All of these responses have been shown to vary among individuals. In persons with more severe disease there is a decrease of CD15 and CD16 molecules on neutrophils and decreased CD16 on NK cells along with the presence immature granulocytes and monocytes. (CD15 and CD16 are involved in the immune response to viral infections). Scientists have also used rigorous immune profiling to understand how the immune system continues to respond to SARS-CoV2. Again, the response varies among persons. Three types of responses of immunotypes appear to materialize. The first type correlates with more severe Covid-19. It is characterized by inflammation, organ failure and acute kidney disease. This immunotype shows robust CD4+ T cell activity, but modest CD8+ T cell and peripheral blood lymphocyte responses. The second immunotype is associated with pre-existing immunosuppression and mortality. Its characteristics include EM, EDMCA subtype CD8+ T cells with modest activation of CD8+ T cells, memory B cells and peripheral blood lymphocytes. The third immunotype showed no immune activation and did not correlate with any specific symptoms.

With this background we can look at what is now known regarding Covid-19 and reproduction. In the early months of the pandemic, physicians expressed concerns that infection with SARS-CoV2 would affect male fertility. In men fever is known to negatively impact spermatogenesis. Several reports indicate diminished male fertility for 72-90 days following Covid-19 infection due to decreased sperm concentration and motility caused by a high fever. Because ACE2 is expressed in the testis and data exits showing that ACE2 plays a role in spermatogenesis, physicians have been concerned that the virus could directly impact male fertility. Very recent research is reassuring and suggests that long-term harm of SARS- CoV2 on male reproduction is unlikely. Furthermore, this same study seems to indicate that transfer of the virus to offspring during fertilization is low. Specifically, using published single cell RNA sequence data the research team reported that co-expression of ACE2 and TMPRSS2 was not detected in testicular cells. (They did not query Sertoli cells). The study also evaluated the co-expression patterns of BSG/CD147, a protein that has been suggested to have the ability to mediate viral entry and cathepsin L, a cysteine protease that potentially would cleave the S protein. These molecules were also found to have low expression. This suggests that SARS-CoV2 would not be able to invade testicular cells. Co-expression of these proteins in female gametes was also evaluated. A subpopulation of oocytes in nonhuman primates did express ACE2 and TMPRSS2 but co-expression of these molecules in ovarian somatic cells was not observed. In 18 samples of human cumulus cells RNA expression of TMPRSS2 was low or absent. Oocytes in antral follicles are surrounded by cumulus cells, so they probably provide a barrier to infection with SARS-CoV2. Finally, ACE2 -TMPRSS2 co-expression was not found in either the endometrium or placenta.  Thus, there is a low risk of infection of reproductive tissue in both men and women.

Covid-19 has a lower maternal case fatality rate than that of previous coronavirus diseases, SARS and MERS. Pregnant patients have the same symptoms as Covid-19 in non-pregnant individuals and they do not appear to be more susceptible to SARS-CoV2 infection. Miscarriages seem to be rare but there is very little data regarding the first trimester and viral infection. However, severe illness may precipitate preterm labor or lead to early delivery. SARS-CoV2 has not been found in amniotic fluid, cord blood or breast milk. There is a report of viral nucleic acid in breast milk, but no evidence of infectious virus. In published reports, the majority of births were by Cesarean Section. Vaginal birth appears to be safe. Because pregnancy is an immunosuppressed condition it is important to study the immune response in depth to determine what immunotypes are observed. Taken together reports demonstrate that pregnancy and birth are safe. Assisted reproduction for infertility, including IVF is also safe.

Full-term infants born to mothers with Covid-19 have been healthy. They are normal in weight, and have good Apgar scores. No known report of confirmed vertical transmission exists currently. One case report suggests possible vertical transmission, however. A healthy infant was delivered by C-Section and placed immediately in isolation. At two hours of age a blood sample was positive for SARS-CoV2 IgM and IgG. While IgG crosses the placenta, IgM does not. This infant did have 5 negative SARS-CoV2 virus PCR tests and thus was not given the diagnosis of Covid-19.   

There is concern that an infected mother may expose her newborn at birth or after birth. The likelihood that an infant becomes positive for SARS-CoV2 as detected by PCR is the similar for infants who are separated from their infected mothers and for infants rooming in with their infected mothers. With rooming the use preventive measures of wearing a mask and using good hand washing techniques are essential. Hospitals and birth centers follow protocols suggested by professional societies and government agencies based on local epidemiology at the time of birth. Depending on the situation locally, support persons are able to be with laboring and birthing women. This person must stay in the room with the mother and not wander around the facility, must wear a mask and use proper hand hygiene. In one study 3.1% of 311 babies born to mothers with Covid-19 were positive for SARS-CoV2 within one week. The National Perinatal Covid-19 Registry has listed over 1500 maternal-infant dyads. Among these dyads, there is evidence that some newborns have become infected following birth, but there is no report of an infant death.

The young woman who talked to me about wanting another pregnancy should be reassured by these findings. However, because fertility decreases with age, waiting too long can be problematic. As the pandemic in the US continues women in their thirties need to weigh risks carefully but might not want to delay pregnancy. Protocols are constantly changing as physicians and scientist learn more about SARS-CoV2 and the clinical course of Covid-19. The American College of Obstetricians and Gynecologists, The American Academy of Pediatrics, Section on Neonatology and Perinatal Medicine, The Society of Maternal-Fetal Medicine and the Centers for Disease Control have posted up-to-date guidance on their websites. There are several national pregnancy, birth and newborn registries that are gathering data on Covid-19. The registries collect data on treatments giving insights into those that are helpful as well as caution for those that are harmful and are providing on going information to clinicians caring for pregnant women and their infants. As more is learned protocols are changing to improve care.

Selected References:

Abobaker A, Raba AA. Does Covid-19 affect male fertility?  World Urol. 2020 Apr 21:1-2 doi:10.1007/s00345-020-03208-w [Epub ahead of print]

Gatta AND, Rizzo R, Pilu G, Simonazzi G. Coronavirus disease 2019 during pregnancy: a systematic review of reported cases. Amer J Obstet Gynecol. 2020 July:36-41

Khalil A, von Dadelszen P, Draycott T, et al. Change in the Incidence of Stillbirth and Preterm Delivery During the COVID-19 Pandemic. JAMA. Published online July 10, 2020. doi:10.1001/jama.

Kuri-Cervantes L, Pampena MB, Meng W, et al. Comprehensive mapping of immune perturbations associated with severe COVID-19. Sci Immunol. 2020 5(49):eabd7114. doi:10.1126/sciimmunol.abd7114

Mathew D, Giles JR, Baxter AE, et al. Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications [published online ahead of print, 2020 Jul 15]. Science. 2020;eabc8511. doi:10.1126/science.abc8511

Muhidin S  Moghadam ZB,  Vizheh M.   Analysis of Maternal Coronavirus Infections and Neonates Born to Mothers with 2019-nCoV; a Systematic Review. Arch Acad Emerg Med

Rozycki HS, Kotecha S. Covid-19 in pregnant women and babies: What pediatricians need to know. Paediatr Respir Rev 10.1016/j.prrv.2020.06.006 [Epub ahead of print]

Segars H, Katler Q, McQueen DB et al. Prior and novel coronaviruses, Coronavirus Disease 2019 (Covid-19) and human reproduction: what is known? Fertil Steril. 2020 113:1140-9.

Stanley KE, Thomas E, Leaver M, Wells D. Coronavirus disease-19 and fertility: viral host entry protein expression in male and female reproductive tissues. Fertil Steril. 2020 114:33-43.

Trocado V, Silvestre-Machado J, Azevedo L et al. Pregnancy and COVID-19: a systematic review of maternal, obstetric and neonatal outcomes. [published online ahead of print, 2020 Jul 7]. J Matern Fetal Neonatal Med. 2020;1-13. doi:10.1080/14767058.2020.1781809J.

Youssef K, Abdelhak K. Male genital damage in COVID-19 patients: Are available data relevant?  Asian J of Urol. https:doi.org/10.1016/ajur.2020.06.005