ART during the SARS-CoV-2 pandemic: a new context, new challenges, and new recommendations

Deconfinement measures are being planned in many countries, which leads us as a group to consider the practicality of reinitiating infertility treatments with protective measures tailored to these new conditions.

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Authors:

Dominique de Ziegler, MD1, 2, Paul Pirtea, MD1, Richard T. Scott Jr., M.D.3, 4, Laura Rienzi, Ph.D.5, Marine Poulain, Pharm.D., Ph.D.1, Jean Marc Ayoubi, M.D., Ph.D.1

1Dept of OB Gyn Hospital FOCH – University of Paris Ouest (UVSQ), Paris, France

3IVIRMA New Jersey, Basking Ridge, NJ, USA.

4Thomas Jefferson University, Philadelphia, PA, USA.

5Clinica Valle Giulia, GENERA Center for Reproductive Medicine, Rome, Italy

Introduction

In December 2019, an outbreak of viral pneumonia emerged in Wuhan, China.  On January 9, 2020 the World Health Organization (WHO) officially announced a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.  Since January 2020, the COVID-19 disease has spread world-wide affecting over 26 countries.  Globally, by now, according to the WHO, more than 2.4 million cases have been confirmed and more than 165,000 patients have died (1).

The definition of COVID-19 – the disease caused by SARS-CoV-2 – is evolving over time with criteria varying between countries.  After an exponential spread of the outbreak, the authorities have recommended different risk-management strategies, from simple respect of barrier gestures, such as social distancing, to strict confinement policies, as in the case of France and Italy for example.  Faced with an unknown virus and a sudden large number of hospitalized patients, the health care system had to be reorganized.  All scheduled medical procedures including fertility treatments and notably, ART, have been stopped in many countries notably, in France and Italy. 

Recently, ASRM updated their guidelines, acknowledging that infertility is an essential treatment and that the window of opportunity for many infertile patients is finite (2).  Postponing fertility treatments indefinitely could compromise certain patients’ ability to become pregnant.  Therefore today, on April 27 – approximately 8 weeks into the disease’s outbreak – when the pandemic seems to have reached its peak and confinements orders are about to be lifted in many countries, it is appropriate to query about the modalities of reinitiating ART activity.  Hence us as group of practitioners – not a national society – have mustered the following thoughts regarding the practice of ART in COVID-19 times.

Disease transmission – what do we know and what we don’t know

COVID-19 viral transmission occurs predominantly through respiratory droplets, but since the apparition of the first 5 reported cases (3), the virus or virus-linked particles have been also isolated in blood samples, urine and feces.  This has raised questions about the potential viral presence in other bodily fluids, including semen, as well as alternate modes of transmission (4).  Human to human transmission is established and it is estimated that in the absence of control and prevention measures, each patient infects between 2 and 3 people.  Contagiousness seems to start a few days before the appearance of symptoms and lasts longer in those individuals who present lasting symptoms such as coughing (5-9).

Looking back to the coronaviruses history, we can see that SARS-CoV-2 is similar to SARS-CoV and that the viral entry into target cells by SARS-CoV-2 is likely mediated by the interaction between the viral spike (S) protein and cellular angiotensin-converting enzyme 2 (ACE2) (10, 11).  ACE2 is expressed in multiple organ systems including type II alveolar cells of the lungs, intestine, heart, kidney, testis and ovary (10-12). Until now, SARS-CoV-2 was not detected in semen of COVID-19 patients and based on a recent study on ACE2 and TMPRSS2 expression ACE2-mediated viral entry of SARS-CoV-2 into target host cells, is unlikely within the human testicle (13).

The COVID 19 epidemic differs from other viral cases usually encountered in ART

Among the viral cases usually handled in IVF we commonly include cases where one or both members of the couple suffer from sexually transmitted viral disease such as hepatitis (B or C) or HIV.  These pathologies are chronic, with a lasting risk of viral presence in the sperm or blood.  Due to their chronic nature and active viral particles in male semen, vaginal fluid and blood, these viral cases have been handled in different facilities of habilitated laboratories following distinct viral pathways.

The situation regarding conducting ART in times of COVID-19 pandemic is drastically different.  Indeed, COVID-19 is not a chronic sexually transmitted disease but a short-lived disease that is communicated by air droplets.  The disease leads to an acute episode which can be more or less symptomatic, evolving at times to major pulmonary deficiency and possibly death.  The short-lived characteristics of COVID-19 is however the essence of its difference with other classical ‘viral’ cases handled in ART.  Experience gained during the current pandemic crisis has indicated that 14 days after having tested positive and being symptomatic for COVID-19, people who became asymptomatic are less susceptible of being contagious.  These individuals are therefore authorized to regain contact with the general asymptomatic population. 

At the time when confinement measures are about to be lifted by most countries, infertility, declared an essential medical concern, ought to be treated provided that the challenges and disposition described below are properly addressed.  As outlined above, COVID-19 is in no way similar to other classical cases associated with hepatitis or HIV and therefore needs to have a dedicated management, different from simply isolating gametes and embryos of viral patients.  During the COVID-19 pandemic, we will only treat healthy patients – either untouched or cured from COVID 19 infection.  It would be therefore inappropriate to expose these embryos to risk of contamination by handling them through a dedicated viral path designed for Hepatitis and HIV patients.  On the contrary, one must ascertain that infertile couples being treated in time of COVID-19 are free of the disease at the time of treatment.

Challenges in undertaking ART in COVID-19 times

The female patient ought to be disease free when starting ovarian stimulation (OS).  For this, symptoms and body temperature must be recorded for two weeks prior to initiating OS and monitored by online consultation.  Specific PCR testing should be advised while social distancing and the wear of protective masks must be mandatory.  The male partner needs to be free of symptoms and in doubt tested negative for COVID-19 when providing the sperm sample.  

Patients undergoing ART must be protected from the risk of being exposed to COVID-19 during the treatment course, including during the ultrasound monitoring, oocyte retrieval and embryo transfer procedure.

Data from China have raised the possibility of obstetrical complications in case of pregnancy developing in COVID-19 infected women.  As described below, dispositions need to be undertaken in order to avoid this to occur by only transferring embryos to women who have been symptom free for 2 weeks prior to the transfer.  This risk obviously is not limited to ART-induced pregnancies but concerns all pregnancies developing while the COVID-19 pandemic is still active (14).

The OS prescribed to the female patient must be such that it practically excludes the risk of ovarian hyper stimulation syndrome (OHSS), which could constitute an aggravating risk if the woman contracts COVID-19 infection. 

Recommendation regarding performing ART in COVID-19 times

Infertile patients should benefit from clinical and psychological support via teleconsultations, with extensive updates on this new disease and the advised safety measures.  ART clinics should provide teleconsultation appointments for both current and new patients thereby minimizing the number of person-to-person consultations.

Specific hygiene measures should be enforced such as notably, in between patient disinfection of the treatment premises.  Safety and quality procedures should be familiar to the entire staff who should be trained for these new measures.

ART ought to be conducted exclusively in symptom free and in case of suspicion negative COVID-19 PCR-tested couples, including at the time of sperm collection, oocyte retrieval and embryo transfer.  Patients and staff should be actively monitored for COVID-19 exposures and symptoms, by phone, email, teleconsultation, before and at arrival to the clinic.

The clinical facility ought to be practically adapted for allowing to respect the needed social distancing.  Scheduling of ultrasounds and other procedures must be spread out sufficiently throughout the day so that no accumulation of patients ensues in different waiting areas.  Ideally, patients should come alone.  Also, they should receive text messages indicating that their turn has arrived for their given procedure, thus reducing patient waiting time.  Reports and results for patients should be given via email, to avoid paper use and virus transmission.

Patients must be wearing protective masks, shoe covers at all time when in the institution.  The caring team must wear similar protective elements adding gowns and visual protective gears when performing procedures (blood draw, oocyte retrieval and embryo transfers).  Universal precautions should be mandatory for patients, doctors, nurses, biologists, secretaries, as anyone could potentially be a carrier.  Disinfection of the retrieval and transfer rooms ought to be reinforced with stricter procedures than in non COVID-19 times.  

As said above, utmost effort should be deployed for avoiding the risk of OHSS.  This can be safely and reliably accomplished by exclusively conducting antagonist OS protocol using GnRH-a for triggering ovulation (Lupron® or Decapeptyl®), with freeze all and deferred ET protocols. 

Anesthesia consultation should be conducted via teleconsultation to identify patients at risk.  No use of non-steroidal anti-inflammatory medication should be made, as this could possibly aggravate a potential COVID-19 infection.

Frozen embryo transfers (FET) can be scheduled as early as 4-5 weeks following the oocyte retrieval after assuring again that the patient remained free of COVID-19 symptoms (analysis of symptoms, recording of body temperature monitored by teleconsultation) or delayed after the end of COVID-19 outbreak. 

Before each step discussed above, we recommend the large use of teleconsultations for verifying that the patient is free of symptoms.  Also, patients should be informed about the risk of mandatory cancelation if one member of the couple is contaminated during the OS.

Finally, patients presenting suspicious symptoms should be immediately guided towards specific COVID-19 departments.

Laboratory measures to ensure safety of patients and staff

While there is no evidence suggesting transmission of COVID-19 through ART-related laboratory procedures, the activity of the laboratory within the context of COVID-19 pandemic is worthy of discussion.

Laboratory activity will be modified mainly in relation to technical staff risk management who could represent vectors of SARS-Cov-2 and in relation to patient pathways reorganization.  Laboratory staff will be monitored to ensure minimal risk of transmission of the virus by an employee of the laboratory.  Work schedules will have to be modified in order to be able to have several shifts in rotation and to avoid concentrating too many operators in one place while ensuring that work is carried out in accordance with good practice recommendations (15, 16).  The laboratory team must wear, as usual, a cleanroom uniform and mask.  Gloves and masks should always be worn in the laboratory and not only when handling follicular fluid, oocytes, embryos and semen.  Routine cleaning procedures use embryo tested products that are viricidal and normally suitable for the removal of SARS-CoV-2.  This procedure should be updated according to relevant recommendations of authorities.

The central issue in the laboratory is the management of frozen samples, particularly in the case of freeze-all strategy, which is widely recommended in the current context by the various medical societies. Viruses are resistant to the freeze/thaw process.  Therefore, particles of SARS-CoV-2 could either end up in the vitrification medium through i) contaminated gametes or ii) operators.  First hypothesis has not yet been demonstrated and studies on a small number of patients have not found any viral particles in vaginal secretions, semen or testicular tissue (17, 18).  It is assumed that COVID-19 isn’t a sexually transmitted disease and that sperm, oocytes and embryos are unlikely to be contaminated.  Furthermore, the zona pellucida represents a high level of protection for oocytes and embryos.  However, viral particles may derive from a contaminating operator during the various laboratory manipulations.  This risk is limited by screening operators and wearing masks and gloves.  Finally, commercial liquid nitrogen may have been contaminated during manufacture, transport and filling of storage tanks.  The use of sterile nitrogen to wash the devices at thawing/warming may be advisable (19).  Moreover, repeated washing steps required by thawing and warming protocols will reduce the presence of viral particles in the culture media by high dilution (20) and avoid potential contamination through this pathway.

Conclusions

We must accept that these unexpected times of COVID-19 will last.  This will be our new reality for at least several months if not years.  The end of containment will not sound the end of the pandemic, but it is needed, so that the preventive measures against COVID-19 do not become worse than the disease itself.  The disease will tend to be less virulent than what we have been experiencing, but rebounds may occur.  The reopening of countries and return to nearly normal life style will have to be accompanied by the maintenance of social distancing measures, adapted, improved, more intelligent.  Hence, the management of infertility – including ART – in times of COVID-19 should adopt new strategies dictated by the specific nature of the existing threat of this new situation. 

References:

1.              Worldometers.

2.              ASRM. Patient management and clinical recommendations during the coronavirus (COVID-19) Pandemic update #2 (April 13, 2020 Through April 27, 2020).

3.              Lescure FX, Bouadma L, Nguyen D, Parisey M, Wicky PH, Behillil S et al. Clinical and virological data of the first cases of COVID-19 in Europe: a case series. Lancet Infect Dis 2020.

4.              Wang W, Xu Y, Gao R, Lu R, Han K, Wu G et al. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA 2020.

5.              Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med 2020;382:1199-207.

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8.              Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med 2020.

9.              Liu Y, Yan LM, Wan L, Xiang TX, Le A, Liu JM et al. Viral dynamics in mild and severe cases of COVID-19. Lancet Infect Dis 2020.

10.           Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-4.

11.           Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3.

12.           Goncalves PB, Ferreira R, Gasperin B, Oliveira JF. Role of angiotensin in ovarian follicular development and ovulation in mammals: a review of recent advances. Reproduction 2012;143:11-20.

13.           Pan F, Xiao X, Guo J, Song Y, Li H, Patel DP et al. No evidence of SARS-CoV-2 in semen of males recovering from COVID-19. Fertil Steril 2020.

14.           Chen L, Li Q, Zheng D, Jiang H, Wei Y, Zou L et al. Clinical Characteristics of Pregnant Women with Covid-19 in Wuhan, China. N Engl J Med 2020.

15.           La Marca A, Niederberger C, Pellicer A, Nelson SM. COVID-19: lessons from the Italian reproductive medical experience. Fertil Steril 2020.

16.           Vaiarelli A, Bulletti C, Cimadomo D, Borini A, Alviggi C, Ajossa S et al. COVID-19 and ART: the view of the Italian Society of Fertility and Sterility and Reproductive Medicine. Reprod Biomed Online 2020.

17.           Qiu L, Liu X, Xiao M, Xie J, Cao W, Liu Z et al. SARS-CoV-2 is not detectable in the vaginal fluid of women with severe COVID-19 infection. Clin Infect Dis 2020.

18.           Song C, Wang Y, Li W, Hu B, Chen G, Xia P et al. Absence of 2019 Novel Coronavirus in Semen and Testes of COVID-19 Patients. Biol Reprod 2020.

19.           Parmegiani L, Accorsi A, Bernardi S, Arnone A, Cognigni GE, Filicori M. A reliable procedure for decontamination before thawing of human specimens cryostored in liquid nitrogen: three washes with sterile liquid nitrogen (SLN2). Fertil Steril 2012;98:870-5.

20.           ESHRE. Assisted reproduction and COVID-19. Updated statement dated 17 April 2020. In, 2020.

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Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

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