COVID-19: Lessons from the Italian Reproductive Medical Experience

Inklings

7
5

Authors:

Antonio La Marca, M.D., Ph.D. (1,2), Craig Niederberger, M.D. (3), Antonio Pellicer, M.D. (4), Scott M. Nelson, M.D., Ph.D. (5,6,7)

(1) Department of Medical and Surgical Sciences for Children and Adults, University of Modena and
Reggio Emilia, Modena, Italy
(2) Clinica Eugin Modena, Modena, Italy
(3) Department of Urology, University of Illinois at Chicago College of Medicine, Chicago, Illinois
(4) Instituto Valenciano de Infertilidad (IVI) Rome, Italy
(5) School of Medicine, University of Glasgow, United Kingdom
(6) NIHR Bristol Biomedical Research Centre, Bristol, United Kingdom
(7) The Fertility Partnership, Oxford, United Kingdom


By the time you’re reading this, much will have transpired. That’s the story with the exponential spread of an infection across the globe: it all happens so fast.

On December 31, 2019, the Health Commission of Hubei Province, People’s Republic of China, announced a cluster of unexplained cases of pneumonia. The virus was isolated, its genome was sequenced, and it was identified as the 2019 novel coronavirus (2019-nCoV). On February 11, 2020, the International Committee on Taxonomy of Viruses defined the virus as ‘‘acute severe respiratory syndrome coronavirus 2’’ (SARS-CoV-2) with the associated respiratory disease COVID-19 (CO-rona VI-rus D-isease 2019). The COVID-19 pandemic brought unique challenges to the global healthcare community, with rapid escalation of the number of affected individuals and associated mortality over a handful of weeks. Clinical and public health guidance has tried to minimize the potential health impact using the best available scientific advice and evidence to inform decision making to help contain the virus, delay its spread, and mitigate its effect on those infected with it. Countries have adopted their own timing of risk-reduction strategies reflecting their differential risk assessments, with Italy having the largest number of affected cases outside of China. The impact and reorganization of clinical services that have been required by Italy will likely be faced by those around the globe in the weeks ahead given the anticipated trajectory of COVID-19.

The COVID-19 epidemic in Italy started on January 30, when two tourists tested positive. An outbreak was subsequently detected in a few patients in Lombardy on February 21, which quickly became 60 patients the next day. As of March 17, 2020, there were 31,506 positive cases from the 148,657 swabs tested, with 2,941 people who have fully recovered since testing positive and 2,503 who died. Among the measures to contain the infection, as early as February, 11 municipalities had been quarantined. Nobody could enter and leave those territories. Following the expansion of the areas with confirmed infection, the area of limitation of human activities was extended to various northern regions including Lombardy, Emilia, and Veneto, and from March 9, the entire country with 60 million citizens was placed in lockdown.

The societal and economic impact of these changes at this time is too large to assess. All schools are closed requiring childcare to be provided at home, social and professional meetings are cancelled, public spaces closed, the mobility of people is restricted to only attend work or for health reasons, and many businesses are closed, including all restaurants and entertainment venues. These measures are combined with existing recommendations from the World Health Organisation for people to wash their hands frequently; avoid touching their eyes, nose, and mouth; by covering the mouth and nose with a tissue when sneezing or coughing and disposing of the tissue immediately and washing hands; keeping an interpersonal distance of at least one meter; avoiding gatherings; and using a surgical mask in the presence of people suspected of being sick. The primary aim of these measures is to flatten the growth curve of new cases, thereby reducing the number of people who will simultaneously require intensive care as well as the overall mortality. As of March 11, 2020, 1,028 of the approximately 5,200 intensive care beds within Italy were already occupied with COVID-19 patients (1). Parallel to these governmental directives, the Ministry of Health implemented extensive reorganization of national healthcare services to facilitate the treatment of the large numbers of patients who will need intensive support therapy.

Professional bodies including the American College of Obstetrics and Gynecology (ACOG) (2) and the British Royal College of Obstetricians & Gynaecologists (RCOG) (3) have provided specific guidance for pregnant women based on very limited data and experience with prior coronaviruses including SARS-CoV and MERS-CoV: compared with the general population, pregnant women may be at higher risk of severe illness, morbidity, or mortality, and adverse perinatal outcomes including preterm birth (4, 5). There is little historical information available for women considering pregnancy or embarking on assisted conception. Given the modelling of the pandemic, including the time to peak and subsequent tail, considerable delays in conception to substantially mitigate risk may be required, which will inevitably impact overall success rates.

Reproductive medicine units in Italy that continue to offer clinical treatments necessitate specific changes to their organization. These include strict adherence to the generic health precautions with clearly visible signs within the clinics at the entrance and throughout the clinics, including private spaces, to remind patients of these general measures. Exposure by scheduled in-person meetings may be reduced by cancelling attendance, and all staff are to consider personal risk when commuting. All non-essential visits by external businesses or academic collaborators are to be avoided and replaced by telecommunications and online platforms. Patient informational events may be held via webinars. Outpatient consultations can be moved to a telemedicine model where feasible, with strict adherence to scheduled appointments for ultrasounds and lab tests to reduce waiting room exposure, coupled with a request to patients to attend alone and to wait outside in their own vehicle until the scheduled appointment to reduce overall risk of transmission. Working agendas are altered to reduce the sharing of common spaces by staff, including the creation of shift teams to reduce the risk that the whole clinic staff is affected and required to self-isolate. Managerial, administrative, and IT staff are similarly to be moved to a rotational schedule to reduce the risk of all being infected simultaneously. Access to common areas of the clinic is strictly limited, with deliveries made outside at specific entrances. All staff must be trained in the processes and protocols for dealing with COVID-19 cases and the use of general precautions and certified particulate filtering face masks to reduce transmission. Should the team members themselves present with respiratory symptoms, the Italian authorities have mandated that, if accompanied by a fever, they are required to abstain from work.

For patients, it is very useful to develop a written multi-lingual summary of the scientific evidence of pregnancy with the coronavirus, including frequently asked questions which align with international guidance and are under daily review that is available both online and within the clinics. Patients are screened by telephone prior to attendance and instructed not to come to the clinic and to postpone their treatment if they are suspected to have an acute respiratory infection with at least one of the following symptoms: fever, cough, dyspnea; or they were, in the previous 14 days, in a country with community transmission of the virus according to the CDC; or in close contact with a confirmed case of COVID-19; or have been in a hospital where COVID-19 patients were hospitalized. Websites must be updated with the most recent available information and links. When entering the clinic, patients are again interviewed regarding the presence of respiratory symptoms or at-risk behavior.

Should medical staff suspect that a patient has COVID-19, a strict protocol is invoked. The healthcare staff isolate the patient in a designated insulated room and wear the following protective health equipment: a waterproof gown, viral particulate-filtering face mask, eye protection, and double gloves; the patient is also provided with a face mask. Decisions are made based on the stage of medically assisted reproduction therapy. If the patient is positive during ovarian stimulation, the optimal solution is to cancel the cycle. If the patient has already had oocyte retrieval, then cryostorage of oocytes or embryos will be undertaken with avoidance of embryo transfer until the patient is proven disease-free due to the risks of further disease deterioration, particularly during pregnancy. On completion of the consultation and the explanation that treatment will be deferred, the patient is transported outside the clinic using a predetermined route to minimize the possible exposure of health personnel, other patients, and visitors. All rooms and areas are then carefully sanitized using an alcohol-based disinfectant containing R 75% alcohol or 5% chlorine. After use, the disposable protective devices are carefully removed, folded in on themselves with hand sanitization with alcohol gel at each stage of removal before final disposal in an appropriate container for infected waste. The patient is then directed to the appropriate regional or national center.

For patients receiving ovarian stimulation, mitigation of the risk of ovarian hyperstimulation syndrome is grave, as COVID-19 infection in a woman experiencing the hypovolemic and electrolyte imbalance typically associated with the syndrome may lead to an amplified risk of lung and kidney complications. Consequently the use of mild stimulation, GnRH antagonist control of the luteinizing hormone (LH) surge, GnRH agonist triggering, and single embryo transfer or freeze-all, are the first choice in this period for women entering in vitro fertilization.
The Italian authorities have mandated that even in the absence of evidence of transmission of the virus within reproductive cells, all donors should be interviewed regarding the presence of respiratory symptoms and for recent travel to high-risk areas. For donors who have returned from an area at risk, a 2-week suspension is required, and in the case of respiratory symptoms, a 2-week suspension from the end of symptoms is necessitated, as compared to the 28-day period recommended by the Joint United Kingdom Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee (JPAC). For homologous fertility treatments, there are no specific regulatory restrictions except for patients with symptoms in progress suggestive for COVID-19 with separate closed cryostorage systems. When importing gametes from abroad, an additional declaration is required from the sending center indicating that the risks of SARS-CoV-2 infection for the specific donor have been assessed. The declaration is necessary only for new donations and not for material cryopreserved prior to the SARS-CoV-2 outbreak. Patients are advised not to pursue fertility tourism due to the strict travel bans in place.

We have described how Italy was consumed by the COVID-19 pandemic and how we adapted our reproductive medical system to its challenges. It’s a moving target, and our processes will continue to adjust. Other countries will face this threat, and we hope that others can learn from our experience. On March 15, 2020, the European Society of Human Reproduction and Embryology (ESHRE) published a statement recommending a precautionary approach that all fertility patients considering or planning treatment, even if they do not meet the diagnostic criteria for COVID-19 infection, should avoid becoming pregnant at this time. For those patients already having treatment, it is suggested to consider deferring pregnancy with oocyte or embryo freezing for later embryo transfer.

On March 17, 2020, the American Society for Reproductive Medicine (ASRM) issued guidance for patient and clinical management during the coronavirus (COVID-19) pandemic. Key recommendations were to: 1) suspend initiation of new treatment cycles, including ovulation induction, intrauterine inseminations (IUIs), in vitro fertilization (IVF) including retrievals and frozen embryo transfers, as well as non-urgent gamete cryopreservation; 2) strongly consider cancellation of all embryo transfers whether fresh or frozen; 3) continue to care for patients who are currently ‘‘in-cycle’’ or who require urgent stimulation and cryopreservation; 4) suspend elective surgeries and non-urgent diagnostic procedures; and 5) minimize in-person interactions and increase utilization of telehealth. Recognizing that the situation is highly fluid, this guidance would be revisited periodically as the pandemic evolves.

COVID-19 is an unprecedented challenge to our healthcare systems. Italy was the first in line after China to experience the explosion in infections from this pandemic. As we write this, the United States is close behind with an infection incidence mirroring that of Italy and with a time shift of approximately a week and a half. The federal government has declared a national emergency and many states and cities are implementing measures like cancellations of entertainment and sporting events, and closures of schools, bars, and restaurants, but there is as yet no fully coordinated response. We fear the worst is yet to come. And in parts of the world, for example, Mexico with its population approximately twice that of the United Kingdom, at the time of this writing no substantial measures are underway. It is likely that we are only at the beginning of this pandemic.

We must learn from our experiences. What Italy is doing in reproductive medicine may not be enough, but taking action is the first step and communicating it to the world community is the second. Educating ourselves with the experiences of our colleagues around the world is critical. At Fertility and Sterility, we’ve created a virtual real-time conversation in our Dialog where doctors and scientists can share what they’re learning about COVID-19 and reproductive medicine. Please contribute your thoughts and observations at https://www.fertstertdialog.com/rooms/871-covid-19.   

References

1.          Remuzzi A, Remuzzi G. COVID-19 and Italy: what next? Lancet  March 13, 2020. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30627-9/fulltext

2.          Practice Advisory: Novel Coronavirus 2019 (COVID-19). American College of Obstetricians and Gynaecologists. March 13, 2020.  https://www.acog.org/Clinical-Guidance-and-Publications/Practice-Advisories/Practice-Advisory-Novel-Coronavirus2019

3.          Coronavirus (COVID-19) infection and pregnancy. Guidance for healthcare professionals on coronavirus (COVID-19) infection in pregnancy.  Royal College of Obstetricians & Gynaecologists, Royal College of Midwives, Royal College of Paediatrics and Child Health, Public Health England and Health Protection Scotland. March 13, 2020. https://www.rcog.org.uk/coronavirus-pregnancy

4.          Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet 2020;395:809-15.

5.          Zhu H, Wang L, Fang C, Peng S, Zhang L, Chang G, et al. Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia. Transl Pediatr 2020;9:51-60.

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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

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.

5 Comments

Go to the profile of Alexander Quaas
Alexander Quaas 22 days ago

Excellent and timely summary of the current COVID-19 situation, with lessons from the Italian experience.

The core problem at the moment is that the extent and the consequences of the pandemic cannot be reliably predicted. It is possible that the current precautions may be necessary for prolonged periods of time. 

That produces very challenging ethical dilemmas in all areas of life, including the area of assisted reproduction.

In our societies, quests to increase survival and decrease morbity and mortality in the population have the unwanted effect of challenging people's economic livelihoods: many people will lose their jobs, many companies will go bankrupt, many restaurants, bars, theatres etc will not survive this crisis.

 Likewise, the quest to decrease medical risk to our patients and reduce morbidity in our "real" (already existing) and unborn patients has unintended consequences. A large proportion of our patients is right at the edge of a virtual "reproductive cliff" where waiting even a few months will result in decreases in ovarian reserve that make autologous conception impossible. It is impossible to know how many couples will remain childless because of Corona precautions, but depending on the length of the precautions it will be a significant number.

This raises the question: who decides when one risk is weighed against another? Is it up to professional organizations such as ESHRE / ASRM? Up to the doctor? Or up to the patient?

When the patient is given the choice, they may prefer to proceed with treatment while taking recommended (handwashing / social distancing etc) precautions, accepting the risk of Corona exposure and its unknown effects on pregnancy, because the risk of irreversible ovarian insufficiency is perceived as a worse outcome.

Doctors may feel similarly, and may be faced with the dilemma of weighing ethical principles of patient autonomy and "do no harm" against each other.

So should it be taken out of the hands of patients and doctors, and decided by professional societies such as ASRM / ESHRE?

If that is the case, then is it appropriate to ask whether the same logic should apply to other recommendations such as elective single embryo transfer? Transferring more than one embryo exposes patients to the risk of multiple pregnancy, with the associated public health consequences. However guidelines are just a "guide", and doctors and patients can have educated discussions on how to proceed.

At what point does a "guideline" become a rigid unshakeable mandatory decree that needs to be followed by all doctors and patients? 

The next few days and weeks will tell. Until this unusual period of time, it seemed far-fetched that countries would implement laws to limit people's movement, impose curfews or enforce quarantines in exposed individuals.

All of us will be charged with the difficult task of weighing competing risks to our patients and make the best decisions for them. Staying informed and engaging in the ongoing discussion forms the basis for good treatment recommendations and guidelines, whatever they turn out to be.   

 

Go to the profile of Elena Labarta
Elena Labarta 21 days ago

Thank you very much for exposing the current situation at this time of crisis.

Obviously, the best recommendation is not to transfer embryos while the uncertainty of the effects of COVID-19 on pregnant women and foetuses continues.

I also agree that aggressive ovarian stimulation should be avoided, as this could lead to the risk of ovarian hyperstimulation syndrome and possible hospital admission at a time when hospital beds should be made available for all victims of COVID-19.

A key point is whether the virus can be present in the gametes. As stated in this manuscript: "... in the absence of evidence of transmission of the virus within reproductive cells.... But I am not sure if this has been proven already and, as is well known, "the absence of proof does not proof the absence".

Therefore, until we know this, we could not even consider vitrifying oocytes in our patients, with the consequent risk of allowing their ovarian reserve to diminish over the months.

Clearly, we are in a dramatic situation that will paralyse many things, including assisted reproduction treatments, until we are in a safe situation. Obviously, within 9 months, the birth rate will be reduced worldwide, taking into account the number of children born from assisted reproduction treatments.

We must follow all the recommendations that the health authorities send us, in order to flatten the curve and thus be able to recover as soon as possible from this situation.

Dr Elena Labarta

IVI RMA Valencia, Spain

Go to the profile of Samuel Santos-Ribeiro
Samuel Santos-Ribeiro 21 days ago

Excellent comment Elena! Just as ASRM is recommending, I also agree that cases of low ovarian reserve, while time-sensitive, should not be deemed urgent for now to mitigate COVID19 growth. I just hope however that no one starting issuing already "blank statement" on all vitrification cases as some fertility preservations should remain an option even at this time in my view. Specifically, I am concerned that such a strict decision may put in jeopardy the opportunity of fertility preservation in cases of oncofertility. I think a special consent should now be obtained for preservation, but to outright "ban" oocyte vitrification may unnecessarily limit the later options of these oncofertility patients.

Go to the profile of Zofia
Zofia about 8 hours ago

Recomendations allows us  urgent sperm, egg or embryo freezing for people with cancer or serious medical conditions requiring chemotherapy or radiotherapy that may affect their fertility. But do you have any opinion/idea  how to safty store sperm, eggs or embryos ?? Do we have to screen patients before procedure  IgG/IgA test for Covid ? Should these test be repeated and if yes when? Should we have separate freeze tank for patient who are treating during this period?

I was looking for answers – but no luck.

Go to the profile of Domenico carone
Domenico carone 21 days ago

Excellent Antonio . This is a good start for some considerations  . First of all, are we open a new era in Reproductive Medicine in Corona Virus Time ? Really as many scientists think we don't know a lot of things on Corona Virus but Italian Way to suspend new treatments is strictly realated to limit movements of population and so to reduce the risks of contagion and above all to reduce the requests of medical Care ( all pregnant in ART treatments can have need of care )  in Hospital during this emergency .

All factors related to effect on gametes of this infection in this moment is very hard to define but we have to consider that SARS COV 2  is a respiratory virus , 85% of infected are asyntomatic or have mild symptoms  , and above all  we have previous experience of SARS COV 1 and MERS on a small scale before in Pregnancy . 

It's prevalent now to find  the right balance between the individual claim of the patient and the limits of the law for a collective interest during spike of contagion and minimize the risk for the patient