Lauren Verrilli, M.D., Kellie Woodfield, M.D., Joseph Letourneau, M.D., and Erica B. Johnstone, M.D., M.H.S.
University of Utah
Objective: To identify factors that contributed to proceeding with ART following the COVID-19 clinical shutdown.
Design: Retrospective cohort study
Setting: Academic REI clinic
Patients: All patients who had planned an IVF cycle or frozen embryo transfer between March 2019 and April 27th, 2020 but had not yet undergone treatment prior to the COVID-19 shutdown.
Intervention: With the reopening of our center, all patients whose cycles had been cancelled were invited to resume treatment after standardized counseling from their primary IVF physician.
Main Outcome Measure: Resuming treatment immediately upon clinic reopening.
Results: A total of 145 patients planning FET and 133 patients planning a fresh cycle were offered the option to restart treatment. In total, 62% of all patients desired to initiate treatment. Of the 133 fresh cycles, 69 (52%) patients proceeded immediately, compared to 104 of the 145 FET cycles (72%). Among the fresh cycles, there was a trend toward older age among those who moved forward (37 vs 35; p=0.05). FET cycles using a gestational carrier were more likely to continue to delay treatment (7% vs 1 % p=0.04).
Conclusion: The majority of patients whose IVF treatment was delayed with the COVID-19 pandemic shut down desired to resume treatment immediately when able. Those proceeding and delaying were similar with regards to most prognostic factors. Further research is needed to understand the reasons patients choose to proceed with fertility treatment in the setting of a pandemic.
In December of 2019, a cluster of severe pneumonia cases of unknown cause were discovered in Wuhan, China. By early January 2020, Coronavirus Disease 2019 (COVID-19) was identified and the first documented case in the United States occurred in January 2020. In response to rapidly increasing case numbers and evidence of severe respiratory illness, the WHO declared a public health emergency on January 30, 2020 (1). A global pandemic was later declared on March 11, 2020 (2).
COVID-19 is part of the coronavirus family, which contains seven subtypes that can cross species barriers and infect human hosts (3). The coronavirus family contains human strains that range from conditions such as the common cold to highly fatal subtypes including Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) (3). Both SARS-CoV and MERS-CoV demonstrate severe and exacerbated disease course in pregnant women compared to non-pregnant patients (4) (5), however, the spread of the disease was more contained than COVID-19.
Given the history of coronaviruses and reproductive morbidity, the early days of the COVID-19 pandemic were marked by significant uncertainty. Little was known about how the virus would affect the general population and even less about the implications for pregnancy. Among the concerns were that pregnant women or infants may be more suspectable to the virus, increased rates of congenital anomalies, preterm births or spontaneous abortions and potential for vertical or sexual transmission. Initial case reports from China were unable to demonstrate vertical transmission of COVID-19, however, severe maternal morbidity was noted and an increase in preterm delivery related to decompensating maternal status (6) (7).
On March 17, 2020, following publication of Opinion #1 from the COVID-19 Task Force of the American Society of Reproductive Medicine (ASRM), the Utah Center for Reproductive Medicine (UCRM) chose to suspend all new IVF cycles and frozen embryo transfers; suspend all intrauterine inseminations; cancel elective procedures; and pursue patient care via telemedicine whenever possible (8). Fresh cycles underway were completed and frozen embryo transfers in which the patient had started progesterone were also completed. Oncofertility patients were able to pursue treatment based on clinical urgency. On April 27, 2020, the ASRM task force released Opinion #3 that reaffirmed the essential nature of infertility services and recommended reopening clinics for infertility treatment, provided there were appropriate risk assessments in place, adequate consideration of resources and extensive patient counseling (9). UCRM subsequently reopened care to patients on May 4th, 2020. Not all patients, however, opted to continue to treatment.
Several studies have examined reproductive choices during pandemics. For example, during the Zika epidemic, one study conducted in Brazil showed that birth rates decreased by 5 to 27%, with the greatest decline occurring in younger women aged 20-30 (10). During the COVID-19 pandemic, an Italian web survey distributed to reproductive aged men and women in heterosexual relationships assessed how the desire for parenthood changed before and during Italy’s mandatory quarantine. They found that 37% of people who had a desire for future pregnancy prior to the pandemic later abandoned that desire, citing economic concerns and the potential effects of COVID-19 on pregnancy as the primary reasons (11).
Importantly, neither of these studies have examined the reproductive desires of patients undergoing fertility treatment. Knowing that infertility represents a significant psychosocial stressor for many patients, and that for some infertile patients, significant delays can change prognosis, we hypothesized that most of our patients would opt to continue treatment amid the COVID-19 pandemic (12). In this study, we aim to determine which factors predict the desire to proceed with fertility treatment during the COVID-19 pandemic.
Materials and Methods:
Based on recommendations from ASRM in their COVID-19 task force opinion #1 on March 17th 2020(13), the Utah Center for Reproductive Medicine (UCRM) chose to suspend all new IVF cycles and frozen embryo transfers, suspend all intrauterine inseminations, cancel elective procedures and pursue patient care via telemedicine whenever possible. Fresh cycles underway were completed and frozen embryo transfers in which the patient had started progesterone were also completed. Oncofertility patients were able to pursue treatment based on clinical urgency. Following the ASRM task force update #3(9), UCRM reopened our clinic to previously suspended fresh and frozen IVF cycles.
A list of patients who had completed an IVF consult between March of 2019 and March of 2020 with plans to either undergo a fresh IVF cycle of a frozen embryo transfer (FET) was generated. Patients undergoing a planned oocyte cryopreservation cycle were included while those undergoing urgent oncofertility cycles were excluded. We chose to include patients whose initial consult dated back up to twelve months because it is not uncommon in our patient population that the lapse in time from initial consult to initiation of an IVF cycle is 6-9 months. Patients were then contacted individually by their primary IVF physician. Each patient was given the option to resume treatment and extensive standardized counseling was performed. This counseling included a discussion regarding the steps being taken at UCRM to limit risk of transmission in the clinic, unknown risks of COVID-19 in pregnancy, the possibility that with a surge in cases the clinic could be subject to close again and the possibility of cycle cancellation should a patient contract COVID-19 during stimulation or prior to embryo transfer. Prior to reopening, all physicians met as a group and agreed upon standardized counseling and protocols.
Retrospectively, data was collected on these patients after completion of the counseling visit and their decision had been logged. Demographic information was collected on all patients including age, parity, anti-Mullerian hormone (AMH), antral follicle count (AFC), history of prior IVF cycle or FET, number of frozen blastocysts, gamete source and use of gestational carrier. Fresh and frozen cycles were analyzed separately.
Statical analysis was performed using STATA (Version 16.1, Plano, TX) and categorial variables were analyzed using the chi square statistic while continuous variables were analyzed with either a t-test or Wilcoxon Rank Sum, depending on if the variables were parametrically or non-parametrically distributed. Odds ratios and confidence intervals were reported with corresponding p values. P-values <0.05 were considered statistically significant.
In total, 133 patients planning a fresh IVF cycle and 145 patients planning a frozen embryo transfer (FET) had cycles paused due to the COVID shut down and were included in this study. Overall, 62% (n=172) patients desired to proceed with treatment immediately upon clinic reopening (Figure 1).
Among those planning fresh IVF cycles, patients proceeding with and delaying treatment were similar in all collected variables (Table 1). Of the 133 patients planning a fresh IVF cycle, 52% (n=69) desired to proceed immediately with treatment where as 48% (n=64) continued to pause. Patients moving forward immediately with treatment were older than those who continued to pause (median age 37 vs 35, p=0.05) with a p value approaching statistical significance. Otherwise, approximately 25% of all patients in the fresh IVF group had previously undergone an IVF cycle and the majority of cycles were autologous with plan for autologous transfer as well. Nine months later, a follow up analysis demonstrated that 44% (n=28) of those who had chosen to pause treatment (or 21% of total cohort) had subsequently completed their fresh IVF cycle.
Table 1: Decision to proceed with treatment amid pandemic among Fresh IVF cycles
In the 145 patients planning a frozen embryo transfer (FET), 72% (n=104) desired to proceed immediately with treatment whereas 28% (n=41) continued to pause (Table 2). Baseline characteristics among those proceeding and those pausing were mostly similar in the FET group and the median number of frozen blasts in both groups was four. Cycles using a gestational carrier, however, were more commonly represented in the group that continued to pause treatment (1% in treatment group vs 7% in paused group, p=0.04). Nine months later, 49% (n=20) of those who had paused their FET (14% of total cohort) had returned to undergo an embryo transfer.
Table 2: Decision to proceed with treatment amid pandemic among frozen embryo transfer cycles
In our retrospective cohort study following the COVID-19 shutdown, we found that the majority of patients awaiting fertility treatment desired to proceed with treatment immediately when able. At the time of the clinic reopening (May 2020), the COVID-19 pandemic remained a threat both in our local community and on a national level. For context, at the time of the clinic closure, the average daily positive case rate in the state of Utah was under 100 cases daily statewide and approximately 140-160 cases daily when we reopened six weeks later (14). The reopening of our fertility center, as well as many others throughout the US, was not due to a decline in COVID cases, but rather an emphasis on the necessity of fertility treatment while the pandemic persists. The steps taken to reopen the clinic included converting all consults to telemedicine, testing IVF patients prior to cycle start and again prior to oocyte retrieval, temporal spacing of the in-person visits and ultrasounds, closing the waiting room and ensuring adequate personal protective equipment (PPE) for all staff members.
Our data add to the growing body of both qualitative and quantitative research emerging about the desire to pursue reproductive treatments amid a pandemic. A recent survey among infertility patients identified infertility as an equal stressor to the COVID-19 pandemic, with both issues identified as a top three stressor in two thirds of all survey respondents (15). In addition, only 6% of survey respondents felt infertility treatment should not be offered during the pandemic, whereas 64% of respondents felt it should be offered on a case by case basis and 30% felt all patients should have access during the pandemic (15). A survey study performed in Italy of 627 infertility patients during the COVID-19 pandemic noted that 40% of respondents reported high anxiety about the possibility of being pregnant during a pandemic (16). Nonetheless, 65% of patients reported a desire to continue pursuit of assisted reproductive technology, 29% felt uncertain and 6% had abandoned their desires. Those respondents who had experienced greater duration of infertility were more likely to report desire for immediate treatment. Eleven percent of respondents reported abandoning or delaying treatment owed to economic and financial concerns (16). Though these studies focused on different influences on treatment desire, such as finances and duration of infertility, they further affirm our results that the majority of fertility patients desire treatment during the COVID-19 pandemic.
In our fresh IVF cycles, no single data point was predictive of desire to proceed with treatment. Older age was trending toward significance but ultimately did not reach a significant p value. In the Italian survey study, longer duration of infertility was positively correlated with desire to proceed with treatment(16). While we did not study duration of infertility in our patients, this may have been a prognostic factor in moving forward with treatment.
In our frozen embryo transfer (FET) cycles, use of a gestational carrier was associated with continuing to pause on treatment (1% vs 7%, p<0.05). This makes sense from a coordination of care standpoint, in that, cycles using a gestational carrier required consent from a third party and often travel for the carrier from out of state. It is important to note, however, that we did not hold gestational carrier cycles to any extra restrictions compared with autologous transfers.
Nine months later (February 2021), we conducted a basic follow up evaluation of those who had initially chosen to pause treatment. At that time, roughly 50% of the patients who initially put treatment on hold had returned to our clinic, in both the fresh and frozen cycles. Those who had not returned after the additional nine months were due to a smattering of reasons including ongoing uncertainty about pregnancy in the pandemic, transferring care to other clinics, spontaneous pregnancies, or no response.
Our study has several strengths and limitations. Our biggest strength is the ability to provide real time, quantitative data about patient behavior immediately following the COVID-19 fertility center shutdown. To our knowledge, this is the first time ASRM has recommended near cessation of fertility treatment on a national level. This recommendation was not taken lightly, by clinics or patients, and was met with serious counterarguments-- including a petition to the task force to reconsider their criteria for restarting cycles signed by over 20,000 individuals (17). Several large survey studies support the notion that fertility patients saw their treatment as essential and non-elective and did desire to proceed despite having little knowledge about the ongoing effects of COVID-19 or the timeline the pandemic would take within the US (18) (19) (20). Our study, however, is the first to provide quantitative data about patient behavior upon clinic reopening.
Our study is not without limitations. The data presented comes from a relatively small number of patients from a single fertility clinic in a state that, at the time of reopening, had low overall incident COVID cases. It is possible that with a larger number of patients, certain prognostic factors would have yielded statistical significance as predictors of moving forward. In addition, we were not able to access financial information on our patients. Knowing that other data suggests finances or concern for economic downturn may influence fertility treatment and reproduction (21, 22), having information about financial status or financial uncertainty could have been a potential prognostic factor as well. Lastly, consideration of unmeasured variables may have changed results. We did not review duration of infertility or infertility diagnosis, both of which could have been key influencing factors in patients’ decision to move forward with treatment.
In summary, our study suggests that the majority of infertility patients desire treatment amid the COVID-19 pandemic. At the time of this publication, the COVID-19 pandemic remains an ongoing threat and access to fertility treatment at our center has remained a safe option for patients. While at some point, this pandemic will become more controlled, we are certainly not immune to future pandemics. We hope that these data inform our readers about the patient desires for fertility treatment and helps us to create tools to operate safely and efficiently while also recognizing the conviction of infertility patients to seek treatment amid chaotic and uncertain circumstances.
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