Universal screening of SARS-CoV-2 in asymptomatic patients starting fertility treatment in New York City

The incidence of SARS-Cov-2 infection among asymptomatic fertility patients is low. Fertility care can be provided safely in a way to limit risk to our patients, staff, and physicians.

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Authors:

Alex Robles, M.D.a, Brittany N. Robles, M.D.,b Laura C. Gemmell, M.D.,a Paula C. Brady, M.D.,a Eric J. Forman, M.D., H.C.L.D.,a Zev Williams, M.D., Ph.D.a

a Columbia University Fertility Center
Department of Obstetrics & Gynecology

b Wyckoff Heights Medical Center
Department of Obstetrics, Gynecology and Reproductive Sciences

Abstract:

Objective(s): To evaluate a protocol of universal symptom and viral screening for SARS-CoV-2 prior to the initiation of controlled ovarian stimulation (COS) among asymptomatic patients receiving care in New York City, and to determine the incidence of SARS-CoV-2 infection among this patient population.

Design:  This was a single center, retrospective cohort study conducted in New York City from April 21, 2020 – May 21, 2020. Prior to the initiation of COS for oocyte cryopreservation or in vitro fertilization (IVF), patients were screened by phone for symptoms of fever, cough, sore throat, recent travel or contact with confirmed COVID-19 cases. If screening was negative, patients were scheduled for nasopharyngeal swabs at our center the following day. Nasopharyngeal swabs were collected in accordance with the Centers for Disease Control and Prevention (CDC) guidelines, and delivered to the university clinical microbiology laboratory. The swabs were tested using the Roche Cobas SARS-CoV-2 test.y. A negative test result was required prior to patients’ baseline ultrasound and bloodwork the following morning. At our center, critical staff were divided into teams working in rotating shifts to minimize exposure and in-person monitoring visits were spaced out to further minimized in-person contact. All patients and staff were screened daily for COVID-19 symptoms and temperature checks. Procedures were also spaced out to allow for adequate disinfection of our procedure room, and to minimize the number of patients in our recovery room. All procedures were performed with the use of personal protective equipment.

Setting: New York City academic fertility practice at the epicenter of the COVID-19 pandemic

Patients: Asymptomatic patients seeking fertility treatment at our institution

Interventions: Controlled ovarian stimulation (COS) and transvaginal oocyte retrieval

Main Outcome Measured: Incidence of SARS-CoV-2 infection among asymptomatic patients prior to and during controlled ovarian stimulation, and feasibility of resuming fertility care in the epicenter of infection.

Results: The study sample included 151 asymptomatic patients who were tested for SARS-CoV-2 via nasopharyngeal swab between April 21 and May 21 2020. Overall 150 (99.3%) tested negative, 1 (0.7%) tested indeterminate, and 0 (0%) tested positive for SARS-Cov-2. Of the 150 patients who have tested negative, 127 have successfully undergone oocyte retrieval with no complication. One patient screened positive for COVID-19 symptoms at the time of swab presentation and was instructed to return for testing at least 2 weeks after symptoms resolved.

Conclusion(s): The incidence of SARS-Cov-2 infection among asymptomatic patients seeking fertility treatment in NYC during the COVID-19 pandemic is low. We have demonstrated that fertility care can safely resume in a way to limit risk to patients, staff, and physicians working in the epicenter of infection. 

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Introduction

The coronavirus disease (COVID-19) pandemic has led to dramatic changes in healthcare policy, resulting in the suspension of any elective or non-emergent procedures. The American Society for Reproductive Medicine (ASRM) COVID-19 task force issued its first guidance statement on March 17, 2020 which advised against the initiation of new treatment cycles including ovulation induction (OI), intrauterine inseminations (IUI), in vitro fertilization (IVF), and frozen embryo transfer cycles (FET).1 This led to widespread cycle cancellations across the nation, particularly in areas most affected by COVID-19. At that time, New York City was the global epicenter of the pandemic, experiencing over 2,500 new cases daily, up to 500 deaths daily and represented 3.5% of total global cases as of March 29, 2020.2,3 Yet, the emotional impact of the cancellations was severe, as 22% of patients surveyed rated their cycle cancellations as the equivalent of losing a child.4

As the curve of new cases in New York City and the U.S. flattened, the ASRM COVID-19 task force updated its guidance to allow treatments to resume, with measures in place to reduce the risk of infection.5 In accordance with the task force’s recommendations, our New York City-based practice has enacted numerous measures to limit risk to patients, staff, and physicians, including utilizing telemedicine whenever possible, providing all staff with personal protective equipment, sterilizing clinical spaces after each patient, and redistributing patient volume to avoid crowding. In addition to those measures, we also instituted universal diagnostic testing for SARS-CoV-2 prior to initiation of treatment cycles. The rationale behind this policy was to minimize the risk of asymptomatic carriers exposing patients and staff to the virus, as well as to minimize the risk of cycle cancelation should symptoms appear during treatment.

. As a result, finding a means of safely resuming care has been our priority during the pandemic. The purpose of this study is to determine the feasibility of resuming fertility care during the COVID-19 pandemic with universal screening for SARS-Cov-2 along with determining the incidence of infection among asymptomatic patients prior to undergoing fertility treatment.

Materials and Methods

This was a retrospective cohort study of all adult patients who were planning to start COS with oocyte or embryo cryopreservation at our academic institution in New York City from April 21, 2020 to May 21, 2020. This study was approved by the Institutional Review Board at New York Presbyterian Columbia.

Prior to the initiation of a treatment cycle, patients were instructed to call our office to be screened for symptoms of fever, cough, sore throat, recent travel or contact with confirmed COVID-19 cases. If the patient screened positive for any signs or symptoms of COVID-19, the patient was encouraged to stay home for at least 2 weeks from symptom resolution. If the patient screened negative, they were scheduled for nasopharyngeal swabs at our center the following day, with visits spaced at 15-minute intervals. Upon presentation, patients were again screened for symptoms and fever. The nasopharyngeal swab was then performed by a member of the research team at our institution according to the Centers for Disease Control and Prevention (CDC) guidelines.6 Personal protective equipment was used including an N95 facemask, eye protection, gloves, and a gown.

The nasopharyngeal swab was introduced through the nostril until resistance was encountered or until the depth was equivalent to the distance of the ear to the nostril of the patient. The swab was left in place for several seconds with a gentle rub and roll to absorb the secretions. If this was unable to be achieved in one nostril, the second nostril was then swabbed. Specimens were then immediately transported to our central laboratory at Columbia University, a facility accredited by the College of American Pathologists (CAP) and New York State Department of Health.

The results were available within 3-4 hours using Roche’s Cobas SARS-CoV-2 Test, a qualitative assay used under the Emergency Use Authorization (EUA) that allows the detection of nucleic acids in the samples. The test uses polymerase chain reaction (PCR) technology, which is considered the gold standard for detecting the virus. Roche’s Cobas SARS-CoV-2 test has a reported 95% certainty and can detect very low levels of the virus. Factors leading to false positives or false negatives include: persons tested too early with low concentration of the virus present, persons tested too late after the disease has progressed, sample contamination, or if the sample has been stored for too long.7

If the patient was negative for SARS-Cov-2, they were allowed to continue with their scheduled ultrasound and bloodwork appointment the following day for possible initiation of COS. Patients who tested indeterminate or positive were instructed to visit their primary care physician, quarantine and return in two weeks for repeat testing. If a test was invalid, it could be repeated the following day.

Patient demographics were collected from the medical chart and included name, age, race, ethnicity, body mass index, zip code, comorbid conditions, infertility diagnosis, and result of SARS-Cov-2 testing.

At our center, critical staff were divided into teams working in rotating shifts to minimize exposure. Staff wore disposable surgical cloth masks on a daily basis. Additionally, telemedicine consultations and spacing out in-person monitoring visits during stimulations further minimized in-person contact. No in-person consultations were done during this time. Procedures were also spaced out to allow for adequate disinfection of our procedure room, and to minimize the number of patients in our recovery room. All procedures were performed with the use of personal protective equipment, including an N95 mask and a disposable procedural gown. In accordance with a consensus document published by the American Society for Assisted Reproductive Technology (SART), the College of Reproductive Biology (CRB), and the Society for Reproductive Biologists and Technologists (SRBT), our laboratory practices have also changed with heightened focused on personal protective equipment and interventions that minimize risk of cross-contamination.8 Lastly, all patients and staff were also screened for symptoms of SARS-CoV-2 or contact with confirmed COVID-19 cases, along with temperature checks upon arrival to the office. 

Results

The study sample included 152 patients aged 23 to 48 years who were scheduled to initiate treatment for oocyte or embryo cryopreservation. Patient demographics are listed in Table 1. The majority of patients included in our study were non-Hispanic whites (53.6%), followed by Asians (18.5%), non-Hispanic Blacks (11.3%), and Hispanics (11.3%). The average age was 38 years. The average body mass index (BMI) was 24.3. Among patients with infertility undergoing IVF, the most common diagnosis was diminished ovarian reserve (51.7%), followed by unexplained infertility (18.5%). The most common comorbidity was asthma, followed by breast cancer. Patients also came from a wide range of zip codes in the tristate area. In total patients presented from 106 different zip codes (Figure 1). The location where the highest proportion of patients resided was noted to be Manhattan, accounting for 35% of patients.



No patients screened positive at the initial phone call. At the time of presentation for nasopharyngeal swab, one patient had reported symptoms of anosmia, ageusia, and cough. The patient was instructed contact her primary care doctor and to resume treatment when symptoms were resolved for at least two weeks. The remaining 151 asymptomatic patients presented for nasopharyngeal swab testing for SARS-CoV-2. Of the 151 patients who had testing performed, 148 tested negative for SARS-CoV-2, 1 tested indeterminate, 2 tested invalid, and 0 tested positive for SARS-CoV-2 (Table 2).

The patient who tested indeterminate was a healthcare worker who already tested positive for SARS-CoV-2 and had recovered several weeks earlier. She returned for repeat testing in two weeks which was negative. The two patients who tested invalid were noted to have excessive mucus by the laboratory.  A repeat test was performed the following day after nasal clearing which resulted as negative in both patients. As such, they were counted as negative results and allowed to initiate treatment.

Of the 151 negative patients, 135 patients started a COS cycle, and 127 made it to oocyte retrieval without complications. 7 patients were cancelled due to poor response, and 10 patients did not begin treatment for either spontaneous pregnancy (n=2), or elevated day 3 follicle stimulating hormone > 18 mIU/mL (n = 8). Lastly, 6 patients underwent diagnostic or operative hysteroscopy in our center in anticipation of COS start. (Table 3)

Discussion

New York was the epicenter of the COVID-19 pandemic in the United States, reporting over 340,000 confirmed cases and 22,000 fatalities by May 15, 2020.9  Over the time period of this study, the number of daily cases in New York City ranged from 59 to 3,455.2  Ninety-nine percent of those tested at our center were negative for the SARS-CoV-2, while one patient who had previously tested positive six weeks prior was “indeterminate” on our swab testing.

Whether the indeterminate result represented a true risk of infection or reflected persistent noninfectious shedding of viral RNA is unclear. This patient also had positive SARS CoV-2 IgG titers. Preliminary analyses indicate neutralizing antibodies may protect from re-infection;10 however, the scientific community’s knowledge regarding the immune response to SARS CoV-2, duration of immunity, and validity of serologic tests is limited.11

The very low rate of asymptomatic carriers is in contrast to the experience at our hospital’s labor floor where universal screening found that 15.4% of patients were positive, and of those, 87.9% were asymptomatic.12 There are several potential explanations for the discrepancy between these findings. Obstetric patients require frequent clinic visits for prenatal care, which could increase risk of exposure SARS-CoV-2 infection. Differences in race, ethnicity, and socioeconomic status between these populations may be reflected in their rates of SARS-CoV-2 infection, as higher rates of SARS-CoV-2 have been documented in Hispanic and non-Hispanic Blacks than non-Hispanic whites in the United States.13 In addition, pregnancy is thought to be a risk factor for the development of influenza and other respiratory tract infections increasing the likelihood of acquiring a viral ilnness.14 Lastly, a different SARS-CoV-2 assay was often performed for patients presenting to the labor floor at our institution. The Cepheid Xpert Xpress SARS-CoV-2 assay was used when results were needed urgently. However, one study did find a 98.9% positive agreement and 92% negative agreement with the Cobas Roche assay.15

Our study population included patients from diverse ethnicities and backgrounds with a variety of infertility diagnoses. Although we are in the infancy of understanding this virus, studies suggest hypertension, diabetes, and coronary heart disease are common comorbidities for patients with laboratory-confirmed SARS CoV-2.16 Additionally, older age and obesity are significant risk factors, with disease severity increasing with increasing body mass index (BMI).17 Currently, there is a paucity of data on COVID-19 in early pregnancy, though initial data appears that pregnancy does not necessarily confer increased risk.19 All patients undergoing COS were counseled on the theoretical risk of increased pregnancy morbidity if SARS-CoV-2 infection developed. ur study included only women, which also may have influenced our results as research suggests a skewed sex ratio towards males.18 At this time, our patient population appears to be low risk and the safe resumption of fertility care even in the epicenter of COVID-19 infection is possible following a protocol to minimize risk and patient/staff exposure. At this time, we no longer require patients to have a negative COVID-19 swab prior to the initiation of treatment. Rather, all patients must have a negative NP swab for SARS-CoV-2 within 72 hours of a scheduled procedure requiring anesthesia.

Strengths and Limitations

            The strengths of this study include our diverse patient population presenting from numerous zip codes in New York and other states.  Strengths also include the strict adherence to the protocol, swab performance by a consistent small group of trained providers, and utilization of the Roche Cobas 6800, a reliable, validated, RT-PCR-based assay performed at a single academic clinical laboratory.

Limitations include the possibility of false negative tests, with evidence suggesting up to 29% of patients suspicious for SARS CoV-2 may have initial false negative tests with subsequent positive tests.20  Further studies investigating the incidence of false negative tests in asymptomatic or low suspicion patients are urgently needed. Additionally, this study does not capture the entirety of our infertility population. Many patients left New York City at the beginning of the pandemic and may still be fearful of returning to the clinic. Future studies on the effectiveness of our COVID-19 mitigation strategies, once clinical volume returns to baseline, are necessary.

Conclusion

            The incidence of SARS-Cov-2 infections among asymptomatic patients seeking fertility treatment in New York City at the height of the pandemic is low.  We have demonstrated that fertility care can be resumed in a way to limit risk to our patients, staff, and our physicians working in the epicenter of infection.   

References:

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  2. Statista. Number of new COVID-19 cases in New York City from March 8 to May 31, 2020, by diagnosis date. Updated June 2, 2020. Available at: https://www.statista.com/statistics/1109711/coronavirus-cases-by-date-new-york-city/. Accessed on June 4, 2020.
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  6. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19). Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons for Coronavirus Disease 2019 (COVID-19). Updated May 22, 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/lab/guidelines-clinical-specimens.html. Accessed on May 4, 2020.
  7. Roche Diagnostics. COVID-19 testing: What you need to know about test accuracy Updated April 20, 2020. Available at: https://diagnostics.roche.com/us/en/roche-blog/COVID-19-testing-what-you-need-to-know-about-test-accuracy.html. Accessed May 4, 2020.
  8. Society for Assisted Reproductive Technology. Laboratory Guidance For Commencing Or Continuing ART Operations During The Ongoing COVID-19 Pandemic. Available at: https://www.sart.org/professionals-and-providers/covid-19-resources/laboratory-guidance-for-commencing-or-continuing-art-operations-during-the-ongoing-covid-19-pandemic/. Accessed on May 9, 2020.
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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.

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