The short and long term consequences of COVID-19 on IVF treatment

Lorena Lupu (Embryology Department) recently composed the below award winning essay on the short and long term consequences of COVID-19 on IVF treatment.

Abstract:

The purpose of this essay is to highlight the effects of the current pandemic in providing fertility treatments (consequences on short and long term, and measures recommended by professional organizations). Like many other industries, the assisted reproductive technology (ART) has been severely affected by this pandemic. Because this virus has a high rate of transmission between humans, and also because it can be very serious in some cases, WHO (World Health Organization) declared COVID-19 as a pandemic in the 11^th of March 2020. Afterward, most of the professional associations worldwide strongly recommended the temporary closure of specialized clinics and the postponement of fertility treatments. These measures have been taken especially for the care of patients, but also for the protection of staff.

Unfortunately, studies are limited, we are still at the beginning and there is not enough data about the potential of this virus and what its consequences are, especially in the long term. We can only analyze existing data and try to adapt in the best way we can to the current situation by implementing security measures adopted by Government/National Regulations in association with professional bodies for both, patients and staff.

Introduction:

An unprecedented global state of concern and a major change in our social and individual plans occurred because of the new type of coronavirus. This is called COVID-19 or SARS CoV-2 and it was identified for the first time in humans following an unusual outbreak of viral pneumonia in Wuhan, China in December 2019 (*WHO), and then spread rapidly in 210 countries around the world (*Worldometer). This novel coronavirus is responsible for the largest pandemic of the last 100 years and the first pandemic caused by a coronavirus (*WHO). Its characterized by high infectious rates,  high level of severity in some cases, and relatively high mortality with more than 4 million confirmed cases worldwide and more than 280.000 deaths, according to the latest figures on the 9^th of May 2020 (*Worldometer).

Genome organization, phylogenetic, and structure of SARS-CoV-2 (COVID-19):

COVID-19 is a ribovirus (RNA genome virus) that belongs to the Coronaviridae family (Chen et al., 2020). The name comes from the particular appearance of infectious viral particles (called virions), which have prominent glycoprotein (S) spikes on the coating, which forms a crown (Li, 2016). Corona virions are spherical in shape (De Haan et al.,1998), relatively large (120-160 nm in diameter), and possess the largest genomes (26.4–31.7 kb) among all known RNA viruses (Woo et al., 2010). Coronaviruses are involved in human and vertebrate's diseases and is characterized by severe acute respiratory syndrome, predominantly present with pneumonia-related symptoms (Chen et al., 2020).

Based on phylogenetic relationships and genomic structures, COVID-19 has many similarities in its genomic and phenotypic structure comparative with SARS-CoV and MERS and therefore the Coronavirus Study Group of the International Committee on Taxonomy of Viruses named the virus SARS-CoV-2 (Cascella et al.,2020).

The SARS-CoV-2 (COVID-19) genome is represented by a single-stranded unsegmented (positive-sense) RNA molecule (Mousavizadeh and Ghasemi, 2020), as opposed to that of influenza A, B, C viruses, which is segmented (Bouvier and Palese, 2008), associated with a nucleoprotein. The two components form the nucleocapsid, which has helical symmetry. The nucleocapsid has a special coating (peplos), which originates in the intracellular membranes (Endoplasmic reticulum, Golgi apparatus) (Mihaescu, 2020).

ACE2 (Angiotensin Converting Enzyme 2) is one of the major receptors that mediate the entry of COVID 19 into human cells. SARS-CoV-2 (COVID-19) binds to ACE2 (the angiotensin-converting enzyme 2) with the coronavirus Spike and a protease called TMPRSS2 cleaves the Spike glycoprotein, allowing the viral and cellular membranes to fuse. These two trans-membrane proteins, ACE2, and TMPRSS2 have expressed more abundantly especially in certain cells like testis, kidney, lungs, and other organs (Hoffmann et al., 2020).

Immediate worldwide impact of SARS-CoV-2 (COVID-19) on fertility treatment:

In line with the guidance from the ARCS/BFS (Association of Reproductive and Clinical Scientists and British Fertility Society), HFEA (Human Fertilisation and Embryology Authority) issued, in 23^rd of March 2020, the General Directions 0014 (Covid-19 Treatment Strategy), which required all clinics to have a COVID-19 treatment strategy and ceased the treatment services by 15^th of April 2020 (*HEFA).

Many other European countries that have been severely affected by SARS-CoV-2 (COVID-19) have decided to temporarily postpone fertility treatments (*ESHRE).

Infertility is a serious disease and affects a considerable percentage of the human population (*WHO) and delaying even for a short period of treatment, for some patients this decision can have dramatic consequences. But at the same time, continuing to provide fertility treatments in these difficult times without evidence that is safe to do so can have even more dramatic consequences, and that is why authorities decided to postpone the treatments until new recommendations.

After analyzing the limited literature about SARS-CoV-2 (COVID-19), there are few possible consequences on short and long-term:

·       On the very short term, the first and the most significant impact, with immediate consequences, is, obviously, the closure of specialized clinics and the postponement of fertility procedures, affecting the most vulnerable category, with immediate needs for treatment, like oncology patients and those patients at the age limit at which these treatments can be given.

·       One possible short-term, but also long-term consequence can be represented by one of the most common symptom of the infection with SARS-CoV-2 (COVID-19), the high fever, and this can produce major changes in sperm parameters. This has been proven that in feverish episodes, healthy men of reproductive age have experienced significant changes associated with decreased sperm concentration, motility, and morphology, but fortunately, this aspect has been observed to be reversible and after a while, they completely recovered (Carlsen et al., 2003).

·       The previous potential consequence was attributed only to fever, but not to other potential factors caused by SARS-CoV-2 (COVID-19) infection, which are currently unknown, and which can potentially produce other serious and irreversible effects on fertility. There are many controversies about the association between infection with SARS-CoV-2 (COVID-19) and potential testicular damage and germ cell destruction (Maya et al., 2020) but it is still too early to draw a clear conclusion. Because the virus uses ACE2 protein to infect the human body, and also because this protein is highly expressed into the Leydig cells and cells of the seminiferous tubules in the human testis, many researchers decided to alert the professionals about the potential consequences (Fan et al., 2020), that this novel coronavirus outbreak may have a serious impact on fertility. As a recommendation, patients who have experienced a SARS-CoV-2 (COVID-19) infection should undergo fertility examination after rehabilitation (Ma et al., 2020). A possible direction of study may be, in addition to sperm analysis, examination of the level of sperm DNA fragmentation. Otherwise, fortunately, one recent small study has shown that patients how was tested positive for SARS-CoV-2 (COVID-19) and proved that the virus did not reach the semen or the testicles. No positive RT-PCR (Reverse transcription-polymerase chain reaction) result was found in the semen or testicular biopsy specimen (Song et al., 2020). This discovery can be extremely valuable for fertility treatments. But this is a small study and we cannot be sure that it is accurate. We need more data on a much larger cohort to be sure of this.

·       Another major question with possible short-term consequences is about the safety of pregnant women. Even if there is no clear evidence of a direct correlation between COVID-19 and pregnancy we should be mindful that it can be more dangerous for pregnant women (Schwartz and Graham, 2020). There are very few studies in which a small number of cases have been analyzed and must be interpreted with caution but which fortunately have shown that the unborn babies can be protected by the placental barrier (Zaigham and Andersson, 2020). This has been proven by the birth of healthy babies from mothers infected with SARS-CoV-2 (COVID-19) which is positive news in the current context (Yan et al., 2020), but again, it is too early to draw conclusions. Another risk can be the fever, a common symptom of the COVID-19 infection, which if uncontrolled can be dangerous in pregnant women (Brucato et al., 2017; Waller et al., 2018). We acknowledge that some of the medication used in infection treatment may not be recommended during pregnancy and can have negative effects on the embryo development or even lead to pregnancy loss (Al-Enazy et al., 2018). Compared to the general population, pregnant women have higher mortality rates and complications associated with viral infections (Jamieson et al., 2006). One case was reported with severe preeclampsia and placental abruption in the second trimester of pregnancy with symptomatic Covid-19. It has been found the presence of SARS-CoV-2 in the placenta localized predominantly to syncytiotrophoblast cells at the maternal-fetal interface. (*MedRxiv). There are many unknowns and the precaution may be the best method until clear evidence is obtained.

·       Unfortunately, we don't know anything about the possible consequences of infection with SARS-CoV-2 (COVID-19) in early pregnancies. During the first 12 weeks of pregnancies, organogenesis takes place, the critical and defining period (Gerrard, 2016; Ye et al., 2019) in the development of the future baby. Generally, viruses rarely cross the placental barrier, but when they reach the fetus, it can result in severe birth defects (Littauer et al., 2017; Racicot and Mor, 2017). All the reports mainly refer to infection in the third trimester and at this moment there is no information on the possible effect of SARS-CoV-2 (COVID-19) infection on pregnancies in their initial stages.

·       Another concern, both in the short and long term, which emerges from the analysis of the current global situation, can be the financial part needed to cover fertility treatments, both for patients eligible for NHS (National Health Service) funding (*NHS) and patients with private funds.

·       The emotional aspect is extremely important and with immediate effects on the quality of life, but also on fertility. We are living an unprecedented, stressful, uncertain event, with a very high emotional load, with a strong impact on physical and mental health. All the above can potentially deter the couples to continue the procedures, at least for a short period. That is why it is so vital to keep our optimism, hope, and not hesitate to ask for help when we feel it is necessary.

Restarting treatment during COVID-19:

In the context of the latest data on the evolution of the pandemic, ARCS/BFS had a meeting with HFEA in an attempt to reconsider GD0014 to enable treatment to resume (*HFEA). This was encouraged particularly by the recommendations issued by other important professional associations like ESHRE (European Society of Human Reproduction and Embryology) and ASRM (American Society for Reproductive Medicine), and also because the Health Secretary announced that he planned to restart some NHS fertility services for the ‘most urgent’ services, such as cancer. At the meeting, they decided that: “fertility clinics will be able to apply to reopen in the week commencing 11^th of May 2020”(* HFEA).

Later, ARCS/BFS published good practice guidelines for the reintroduction of routine fertility treatments during the SARS-CoV-2 (COVID-19) pandemic.  All the clinics who applied for reopen need to demonstrate that they take all measures to protect staff and patients against infection had been put in place.

The ARCS/BFS COVID working group has identified five key principles, can help to minimise risk to patients and staff.

1.     “Resumption of fertility services must take place in a manner that minimises the chances of spread of COVID-19 infection to patients and fertility clinic staff.

2.     Centers should ensure a fair and transparent approach to any prioritisation policy.

3.     Resumption of treatment should not result in an undue burden on the NHS.

4.     Patients considering treatment should be fully informed about the effect of the ongoing pandemic on their treatment and give informed consent to having fertility treatment at this time.

5.     The fertility sector should adopt sustainable changes in working practices that help to build resilience against any future increases in the spread of COVID-19 in the community.”  the ARCS/BFS COVID working group said. (*BFS)

Another good news from HFEA is that the storage limit for frozen gametes and embryos was extended with 2 years during coronavirus outbreak (*HFEA).

Internationally, working ESHRE Group published on the ESHRE website on 23^rd of April 2020 a document of good medical practice proposed for the restart of activity in the ART clinic and laboratory makes it helpful to know how fertility services might be reconfigured to meet the variety of safety(*ESHRE). ESHRE recommends the centers to use this guidance having first followed the national legislation and national government advice related to SARS-CoV-2 (COVID-19). A very similar guide was developed by ASRM (American Society for Reproductive Medicine) (*ASRM).

The working ESHRE group identified six pillars: 

1.  “Discussion, agreement, and consent to the start of treatment;
2.  Staff and patient triage;
3.  Access to advice and treatment;
4.  Adaptation of ART services;
5.  Treatment cycle planning;
6.  Code of Conduct for staff and patients."(*ESHRE).

The most important aspects extracted from both guides ARCS/BFS and ESHRE are the following:

• High-risk patients should not start any treatment until it is recommended by relevant healthcare professionals;
• All patients have the right to be very well informed and to decide whether to continue or postpone treatment;
• Some patients with special conditions (cancer, those with a low ovarian reserve, advanced age) may have priority in receiving treatments;
• Patients must be comprehensively informed, clearly understand the risks related to SARS-CoV-2 (COVID-19) disease and acknowledge the increased risks in case of infection during pregnancy, and then how to reduce the risk of infection in general;
• All the patients must be clearly informed and to understand all the aspects and then to sign a new consent;
• All patients who are planning to start a fertility treatment should be asked to complete a questionnaire (paper, email, or phone) and a preliminary triage of both partners should be performed and repeated during ovarian stimulation;
• All the patients confirmed with SARS-CoV-2 (COVID-19) infection should present medical evidence of clearance and a detailed report about the received medical care (it is very important to know if they have been on respiratory support during the infection episode). Additional testing can be considered in line with the national recommendations;
• Patient support and counseling providing through social media and video conferencing;
• Other important advice, such as reducing unnecessary visits during treatment, restriction of access for accompanying persons;
• Preparation for a freeze-all policy for all patients which becomes suspected or infected after the oocytes retrieval but before embryotransfer;
• High security should be used for cryopreservation and storage tanks;
• For staff there are clear recommendations: monitoring their health status, symptoms, and lifestyle, and should be noted at the individual degree of risk. For each member of staff who is suspected of infection, or who are symptomatic, or was positive should be referred for medical advice by occupational health, should undergo testing and go into quarantine and should not re-attend work until its safe to do so and the RT-PCR test becomes negative.
• If a staff member has been diagnosed with SARS-CoV-2 (COVID-19) infection, then all contacts of both patients and colleagues should be routinely tested;
• Depending on the size of the unit, for proper functioning, the recommendation is to create mini teams that work in shifts with minimum interactions among them, thus minimizing the risk of infecting the entire unit and ensure continuity of access to fertility treatments for patients;
• Staff should minimise sharing of any equipment where possible and then must be cleaned between operators;
• If it is possible should consider using more equipment that may allow greater physical distancing like electronic witnessing systems, computer-assisted semen analysis (CASA), time-lapse technology (TLT);
• SARS-CoV-2 (COVID-19) specific training for staff and support policies;
• Reciprocal agreements between clinics to incorporate staffing, consumable provision, and general support where possible.

Conclusion:

In the context of the latest data related to the evolution and evidence of exceeding the peak of the pandemic, ART treatments for all the clinical indications, according to the National Regulations, as critical cases, will have to start as soon as possible, but everything must be done gradually and safely to minimize the risks for patients and the clinical staff.

All centers have a responsibility to implement and strictly follow all measures to reduce the risk of infection for both patients and staff.

The old protocols for good medical practice must be changed and implement a new SOP(Standard Operating Procedure) in line with the latest recommendations following the national legislation to ensure that the risk of infection is minimized for both patients and staff.

There will certainly be many changes in our medical practice but we all must try to adapt in the best way we can to the current situation and continue to provide quality health care.

Studies are limited, we are still at the beginning and there is not enough data about the potential of this virus and what its consequences are for fertility in general and also for pregnancies, especially in the long term.

We all hope a slowdown in the spread of the virus will occur as soon, as the measures recommended by the authorities are followed, and hopefully, we can return to our normal daily life in the safest possible way.

 References: 

1. Al-Enazy, S., Ali, S., Albekairi, N., El-Tawil, M., and Rytting, E., 2017. Placental control of drug delivery.Advanced drug delivery reviews, 116, pp.63-72.
2. Bouvier, N.M., and Palese, P., 2008. The biology of influenza viruses.Vaccine, 26, pp.D49-D53.
3. Brucato, M., Ladd‐Acosta, C., Li, M., Caruso, D., Hong, X., Kaczaniuk, J., Stuart, E.A., Fallin, M.D. and Wang, X., 2017. Prenatal exposure to fever is associated with autism spectrum disorder in the Boston birth cohort.Autism Research, 10(11), pp.1878-1890.
4. Carlsen, E., Andersson, A.M., Petersen, J.H. and Skakkebæk, N.E., 2003. History of febrile illness and variation in semen quality.Human Reproduction, 18(10), pp.2089-2092.
5. Cascella, M., Rajnik, M., Cuomo, A., Dulebohn, S.C. and Di Napoli, R., 2020. Features, evaluation and treatment coronavirus (COVID-19). In Statpearls. StatPearls Publishing.
6. Chen, Y., Liu, Q. and Guo, D., 2020. Emerging coronaviruses: genome structure, replication, and pathogenesis. Journal of medical virology, 92(4), pp.418-423.
7. De Haan, C.A., Kuo, L., Masters, P.S., Vennema, H. and Rottier, P.J., 1998. Coronavirus particle assembly: primary structure requirements of the membrane protein. Journal of virology, 72(8), pp.6838-6850.
8. Fan, C., Li, K., Ding, Y., Lu, W.L. and Wang, J., 2020. ACE2 expression in kidney and testis may cause kidney and testis damage after 2019-nCoV infection.MedRxiv.
9. Gerrard, D.T., Berry, A.A., Jennings, R.E., Hanley, K.P., Bobola, N. and Hanley, N.A., 2016. An integrative transcriptomic atlas of organogenesis in human embryos.Elife, 5, p.e15657.
10. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T.S., Herrler, G., Wu, N.H., Nitsche, A. and Müller, M.A., 2020. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell.
11. Jamieson, D.J., Theiler, R.N. and Rasmussen, S.A., 2006. Emerging infections and pregnancy.Emerging infectious diseases, 12(11), p.1638.
12. Li, F., 2016. Structure, function, and evolution of coronavirus spike proteins.Annual review of virology, 3, pp.237-261.
13. Littauer, E.Q., Esser, E.S., Antao, O.Q., Vassilieva, E.V., Compans, R.W. and Skountzou, I., 2017. H1N1 influenza virus infection results in adverse pregnancy outcomes by disrupting tissue-specific hormonal regulation.PLoS pathogens, 13(11), p.e1006757.
14. Ma, L., Xie, W., Li, D., Shi, L., Mao, Y., Xiong, Y., Zhang, Y. and Zhang, M., 2020. Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study.medRxiv.
15. Maya, W.D.C., Du Plessis, S.S. and Velilla, P.A., 2020. SARS-CoV-2 and the Testis: similarity to other viruses and routes of infection. Reproductive BioMedicine Online.
16. Mousavizadeh, L. and Ghasemi, S., 2020. Genotype and phenotype of COVID-19: Their roles in pathogenesis. Journal of Microbiology, Immunology and Infection.
17. Racicot, K. and Mor, G., 2017. Risks associated with viral infections during pregnancy.The Journal of clinical investigation, 127(5), pp.1591-1599.
18. Schwartz, D.A. and Graham, A.L., 2020. Potential maternal and infant outcomes from (Wuhan) coronavirus 2019-nCoV infecting pregnant women: lessons from SARS, MERS, and other human coronavirus infections. Viruses, 12(2), p.194.
19. Song, C., Wang, Y., Li, W., Hu, B., Chen, G., Xia, P., Wang, W., Li, C., Yang, X., Yao, B. and Liu, Y., 2020. Detection of 2019 novel coronavirus in semen and testicular biopsy specimen of COVID-19 patients.medRxiv.
20. Waller, D.K., Hashmi, S.S., Hoyt, A.T., Duong, H.T., Tinker, S.C., Gallaway, M.S., Olney, R.S., Finnell, R.H., Hecht, J.T., Canfield, M.A. and National Birth Defects Prevention Study, 2018. Maternal report of fever from cold or flu during early pregnancy and the risk for noncardiac birth defects, National Birth Defects Prevention Study, 1997–2011.Birth defects research, 110(4), pp.342-351.
21. Weiss, S.R. and Navas-Martin, S., 2005. Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiol. Mol. Biol. Rev., 69(4), pp.635-664.
22. Woo, P.C., Huang, Y., Lau, S.K. and Yuen, K.Y., 2010. Coronavirus genomics and bioinformatics analysis viruses, 2(8), pp.1804-1820.
23. Yan, J., Guo, J., Fan, C., Juan, J., Yu, X., Li, J., Feng, L., Li, C., Chen, H., Qiao, Y. and Lei, D., 2020. Coronavirus disease 2019 (COVID-19) in pregnant women: A report based on 116 cases.American Journal of Obstetrics and Gynecology.
24. Ye, Z., Wang, L., Yang, T., Chen, L., Wang, T., Chen, L., Zhao, L., Zhang, S., Zheng, Z., Luo, L. and Qin, J., 2019. Maternal Viral Infection and Risk of Fetal Congenital Heart Diseases: A Meta‐Analysis of Observational Studies.Journal of the American Heart Association, 8(9), p.e011264.
25. Zaigham, M. and Andersson, O., 2020. Maternal and Perinatal Outcomes with COVID‐19: a systematic review of 108 pregnancies.Acta Obstetricia et Gynecologica Scandinavica.
26. *ASRM, Patient Management and Clinical Recommendations During The Coronavirus (COVID-19) Pandemic https://www.asrm.org/news-and-publications/covid-19/statements/patient-management-and-clinical-recommendations-during-the-coronavirus-covid-19-pandemic/ 
27. *https://www.arcscientists.org/wp-content/uploads/2020/05/ARCS-BFS-COVID-19-guideline-v1.1-1.pdf 
28. *https://www.britishfertilitysociety.org.uk/2020/05/06/arcs-and-bfs-u-k-best-practice-guidelines-for-reintroduction-of-routine-fertility-treatments-during-the-covid-19-pandemic/
29. *ESHRE, Assisted reprohttps://www.who.int/emergencies/diseases/novel-coronavirus-2019duction and COVID-19 https://www.eshre.eu/Press-Room/ESHRE-News#COVID19_April2 
30. *HEFA, Coronavirus (COVID-19) guidance for professionals, https://www.hfea.gov.uk/treatments/covid-19-and-fertility-treatment/coronavirus-covid-19-guidance-for-professionals/ 
31. *Mihaescu, G., 2020, COVID-19: contagiozitate, mutații și memorie imunitară, Grigore Mihăescu https://unibuc.ro/covid-19-contagiozitate-mutatii-si-memorie-imunitara/
32. *NHS, https://www.nhs.uk/conditions/ivf/availability/
33. *SARS-CoV-2 Infection of the Placenta – Preprint article.                     https://www.medrxiv.org/content/10.1101/2020.04.30.20083907v2?fbclid=IwAR2SqgCnm373yYe_66Uk-gV09nErADP0UTe-w8JsLEZneceZi-R0cZMgfVU
34. *World Health Organization, Coronavirus disease (COVID-19) Pandemic,  https://www.who.int/emergencies/diseases/novel-coronavirus-2019  
35. * Worldometers, Real time report cases Coronavirus, https://www.worldometers.info/coronavirus/