Antonio La Marca, M.D., Ph.D.1,2, Scott M. Nelson, MRCOG, Ph.D.3,4,5
1Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
2Clinica Eugin Modena, Modena, Italy
3School of Medicine, University of Glasgow, United Kingdom
4NIHR Bristol Biomedical Research Centre, Bristol, United Kingdom
5The Fertility Partnership, Oxford, United Kingdom
The devastating clinical impact of COVID-19 has led governments across the world to introduce desperate social isolation or “lockdown” measures to try to reduce the viral reproduction number (R0), prevent overwhelming the existing healthcare systems and reduce morbidity and mortality. These repressive public health measures have been accompanied with capacity building within the healthcare systems including redeployment of clinical staff to front line areas, cessation of routine clinical and research activity, expedited graduation of nursing and medical students and repurposing theaters and recovery areas to intensive care units. These comprehensive strategies to flatten the curve and protect our health services from being overwhelmed have come at a price for many patients with cancellation of elective clinical procedures. Recognizing the potential contribution of assisted conception to the overall clinical workload, both ESHRE and ASRM recommended the discontinuation of all non-emergency ovarian stimulation, with national authorities and regulators like the Human Fertilization and Embryology Authority (HFEA) underlining the need to comply.
At present in many European Countries these measures have had their desired impact with the SARS-CoV-2 R0 now at 1 or less, and classically infectious disease outbreaks will fade out if either interventions maintain R0 below 1 or the susceptible part of the population has been depleted sufficiently to maintain R0 below 1. As estimates of infection are only at 2-4%, long-term strategies to maintain the R0 < 1 are critical while vaccines are developed and distributed. So, what are the options that will enable routine care to begin to be provided again and what exit strategies may be feasible. Inevitably different countries will be able to experience these at different time points and potentially use different strategies, based on how successful they were in the initial stages of this pandemic. The mortality data discordances between developed countries is striking; as of the 24th April Kuwait has only 15 deaths, New Zealand 17, Denmark 403, the UK 19,566, Italy 25,969, and 50,890 in the USA. These differences reflect the different trajectories of these countries, but more importantly their respective success in early recognition of the virus and upscaling of widespread testing, contact tracing, quarantining, and containment measures.
At present heavy-handed nationalist responses still predominate. Alongside curfews, lockdowns, and requisitioning, governments are closing borders and using wartime rhetoric to rally their populations. Global supply chains and trade are being disrupted not just by lockdowns, but also by wealthy countries’ competition for supplies. So how do we get beyond this, restart the economy, enable patient care and once again recommence fertility provision? At present a variety of scenarios are being contemplated with many focusing on gradual stratified relaxation of lock down measures with continued shielding of those at greatest risk, monitoring of hospital admissions as the virus continue to pervade society to evaluate measures, ramping up of both diagnostic testing with novel measures for contact tracing and serological testing to facilitate safe return to work for those who have been infected. All of these measures are ongoing while the pursuit of a vaccine continues.
The shutdown of ART: cure or harm?
It is conceivable that many IVF units from western countries, if not from all over the world, have stopped since mid-March, with some countries such as Denmark now recommencing treatment for specific cases. This is despite continued recommendations from ESHRE and ASRM guidelines that all activity should still be discontinued. Eloquent arguments have been vocalized by many of our colleagues as to why our professional bodies should recognize the importance of the overall healthcare system. However, whether continued cessation of activity will meaningfully impact on utilization of healthcare resources in all settings across the globe is unclear, but it is easier to estimate the immediate consequence of this lack of activity. An unknown but certainly very high number of missed pregnancies. In Italy in 2017, 13,973 born (3% of children born in 2017) were born thanks to ART techniques, with we can therefore expect that one month of absolute non-activity will lead to the absence of at least a thousand children in 9 months from now. In the USA, 76,930 ART infants were born in 2016 equating to ~6,410 per month of inactivity. Therefore, although the various professional societies have considered IVF as a non-urgent medical practice, an exit strategy for ART from this pandemic is now not only urgent, but of paramount public health importance.
Treatment of infertility: elective or urgent?
Consideration of what is perceived by urgent when routine clinical care across all specialties is disrupted is difficult to define. The ASRM suggested that “ While age and diminished ovarian reserve are time-sensitive, at present these should not be included in the definition of urgent care”, while in the first revision of 30th March the task force stated (point 5) that as the pandemic continues, reproductive care professionals will have to consider reassessing the criteria of what represents urgent and non-urgent care. For example, this may include reassessing the care of patients with diminished ovarian reserve, as well as for other conditions where extended delays may impact patient outcomes.” Given the decline in success rates with advancing maternal age or in younger women with diminished ovarian reserve related to comorbidities like endometriosis, many women and their partners will perceive their care as time-sensitive and urgent.
The concept of time-sensitivity also applies to many other conditions that we routinely treat. We all recognize that fertility treatment is a process that can take months or even years to reach. While many couples may have a predicted good or high prognosis, the vast majority of couples in western countries have a medium to low or very low prognosis principally due to maternal age, with multiple treatment cycles likely to be required(1). Inevitably the current indefinite delays, will only further reduce their prognosis as age is an independent variable in prognostic models for couples with severe male factor, couples with already known low fertilization rate, couples with recurrent implantation failure or miscarriage, couples with chromosomal disorders, women with endometriosis or congenital or acquired uterine malformation. For all couples in which the prognosis is low, time becomes essential, and adding delay may only increase the risk for the couple of remaining childless. Treatment of human infertility must always be considered urgent.
IVF clinics also treat fertile patients to reduce the risk of transmission. For example, serodiscordant HIV couples, and those at risk of vertical transmission of genetic diseases. In the absence of appropriate and timely care these couples may choose to conceive naturally with potentially devastating consequences. Furthermore, in the absence of active fertility care providers, women may increase the self-administration of ovulation inducing drugs increasing the risk of multiple pregnancies and or may increase the adoption of non-regulated practices such as home insemination with unscreened donor sperm.
Mechanisms to restart
We and others have previously highlighted the potential pathways that can be adopted to minimize the risk to staff and patients, with a focus on standard infection control procedures, telemedicine, symptom ascertainment and social distancing within clinics(2, 3). As validated serological testing becomes routinely available, the potential for different teams to be developed within the clinic based on initial serological stratification may be feasible(4). If staff are known to be immune, they would rapidly return to work and provide screening at the initial point of contact along with other routine investigations. Subsequently non-infected patients could be treated by immune staff and immune patients are treated by non-exposed staff, would help protect both groups provided that viral titers are no longer detectable in those who are deemed immune. Inevitably some patients may become symptomatic during treatment and the issue will be whether to continue treatment or discontinue until resolved with the necessary financial burden. As diagnostic testing capacity is ramped up the ability to confirm the diagnosis in a timely manner will become more feasible.
For maternal outcomes the data is increasingly reassuring, with the absolute risk of complications low5. Emerging evidence suggests that individuals admitted to hospital with COVID-19 are hypercoagulable, and which may sit on the background of the enhanced maternal hypercoagulable state associated with pregnancy. Steps to avoid OHSS would be warranted, with early recourse to coagulation modifying agents if symptomatic. Lastly although some pregnant women have required intensive support, within the UK the rate of current/recent pregnancy amongst all individuals admitted to critical care (2.3%) remains similar to the reported rate for non-COVID viral pneumonia during 2017-19 (3.3%).
For perinatal outcomes, there are currently no data suggesting an increased risk of miscarriage or early pregnancy loss in relation to COVID-19 or of Teratogenicity5. Although there is some evidence of potential vertical transmission the outcomes are generally favorable. With respect to potential increased risk of preterm birth that has been reported it is unclear whether this is partially iatrogenic for maternal or fetal indications related to the viral infection, or whether some were spontaneous. Liberal use of elective single embryo transfer would ensure that we were not contributing to this risk.
Infertility treatment is time-sensitive, with accumulating data on reassuring pregnancy outcomes and the ability to modify practices extensively to maintain a low R0, the time may have come for those who were early and successful in flattening the curve to reopen and recommence treatment.
1. Smith AD, Tilling K, Nelson SM, Lawlor DA. Live-Birth Rate Associated With Repeat In Vitro Fertilization Treatment Cycles. JAMA 2015;314:2654-62.
2. La Marca A, Niederberger C, Pellicer A, Nelson SM. COVID-19: lessons from the Italian reproductive medical experience. Fertility and Sterility.
3. Meseguer M, Niederberger C, Pellicer A. Deep inside the pandemic, from inactivity to action: let´s be ready. Fertil Steril 2020;(in press).
4. Abbasi J. The Promise and Peril of Antibody Testing for COVID-19. JAMA 2020.
5. Royal College of Obstetricians and Gyneacologists. Coronovirus (COVID-19) Infection in pregnancy. Version 8: Published Friday 17 April 2020. https://www.rcog.org.uk/globalassets/documents/guidelines/2020-04-17-coronavirus-covid-19-infection-in-pregnancy.pdf