Kuo-Chung Lan, M.D., Ph.D.,1,2,
1 Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
2 Center for Menopause and Reproductive Medicine Research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
Objective: Currently the novel coronavirus (COVID-19) the epidemic is spreading globally. We conducted an investigation before and after a nosocomial outbreak of severe acute respiratory syndrome to clarify the impact of the outbreak on the hospital in vitro fertilization unit.
Design: A retrospective single-center cohort observational study.
Patients: A dataset including 603 IVF/ICSI cycles during the SARS outbreak and one year before and after between January 1, 2002 and December 31, 2004
Main Outcome Measure(s): Fresh cycle numbers and pregnancy rate
Results: A total of 150 patients received IVF treatment in 2003, a significant decrease from the previous year's 221 patients, but in 2005, the number of treatments (n=236) returned to the level of the year before the SARS outbreak. Except for the difference in the number of cycles and implantation rate (21.8% vs. 27.7%), there were no significant differences in patient age, pregnancy rate, or abortion rate in 2003 compared with those in 2002. There were also similar general characteristics between 2003 and 2004, except that there was a significant difference between the abortion rate (16.7% vs 9.1%) and estradiol levels on the hCG day (1498.5±1034.9 vs 1774.1±1316.4 pg/ml).
Conclusion: SARS outbreak did not adversely affect IVF outcomes despite the drop in treatment cycles
Currently the novel coronavirus (COVID-19) outbreak has been contained mostly to the Wuhan region of China, although there is growing evidence that the epidemic is spreading globally(1).
The establishment of an emergency plan is a long-term issue relating to infections during IVF practice and to the proposal of guidelines that may contribute to infection control and laboratory safety(2). Emergencies caused by epidemic infectious diseases, especially designated legal infectious diseases or new infection outbreaks, are rarely discussed in the literature.
An international outbreak of severe acute respiratory syndrome (SARS), a recognized syndrome caused by coronavirus, began in November 2002 and ended in July 2003(3). In late April 2003, a large nosocomial outbreak of SARS occurred in Chang Gung Memorial Hospital (CGMH) in Kaohsiung after the admission of a patient with unrecognized SARS(4). Kaohsiung CGMH is a primary care and tertiary care referral medical center in the city of Kaohsiung. The rapid development of the SARS outbreak in this large and densely populated facility posed a substantial threat to other hospitalized patients, to staff and to the community. Kaohsiung CGMH closed its outpatient clinics, and the IVF unit also stopped all treatment procedures on May 16 and rapidly closed the affected wards to minimize the impact on hospital operations(4).
This paper retrospectively analyzes the short-, medium- and long-term effects of the outbreak of SARS on the hospital IVF unit of the Kaohsiung CGMH. We share a reproductive center perspective on the incidents and lessons learned from the containment of the nosocomial SARS outbreak. This study was approved by the Ethics Committee of CGMH (CGMH202000161B0). The main study period was during 2003 and one year before and after the SARS outbreak (2002-2004). The validation period (2007) used the IVF fresh case number change curve similar to that used for the SARS outbreak period (Figure 1A).
Figure 1. Annual IVF/ICSI outcome from 1999-2019 in KCGMH (A). Annual case numbers (B). Annual fresh and thaw pregnancy rate, live birth rate per transfer and patient age curve.
The period of the hospital outbreak of Severe Acute Respiratory Syndrome
(April 26 ~ May 25, 2003) (Figure2)
On April 26, 2003, a patient with unrecognized SARS was admitted to Kaohsiung CGMH. The last SARS case that was epidemiologically linked to this outbreak and occurred outside the hospital was documented on May 25, whereas the last SARS case that developed in the hospital was documented on May 17, indicating the successful containment of this nosocomial outbreak of SARS.
Figure 2. Pregnancy rate and case number trends of women who received in vitro fertilization-embryo transfer (IVF-ET) before and after the SARS outbreak of KCGMH.
The number of IVF patients decreased immediately after the outbreak compared with the number in the previous one month. However, the levels returned to the pre-outbreak level 1 month after the outbreak (Figure 2). During the outbreak period, 11 patients (age=34.2±4.0; 26-37) finished oocyte retrieval and embryo transfer procedures (including 5 patients who were referred to other reproductive centers for continued treatment), and the pregnancy rate was 54.5%, and 0% spontaneous abortion rate.
During the SARS outbreak period of three to four weeks, patients usually had two choices: (i) postpone or cancel treatment or (ii) discontinue gonadotropin treatment or continue treatment and be transferred to another center to finish treatment. The ASRM and SART guidelines proposed that emergency arises and if time permits subsequent to oocyte retrieval and prior to embryo transfer, options regarding the transfer of embryos; cryopreservation of oocytes, zygotes, or embryos; or abandonment of the cycle altogether should be discussed with the patient and her partner(5). The most prudent course of action in the event of a catastrophic disaster may be to discontinue treatment for that cycle(6). If the patient wishes to continue treatment and the treating facility is not able to safely do so, patients can be given the option of completing their IVF at another center. We had 5 patients who were referred to another clinical center approved by the Taiwan National Institute of Health to continue treatment and seemed to have acceptable results. When the epidemic broke out that year, there was no comprehensive emergency plan in advance, but the epidemic situation changed rapidly. The treatment team and patient faced with the need to terminate the treatment, but the doctors took the initiative to contact other centers to continue treatment. Patients carried all original necessary medical supplies and copies of their cycle and clinic records with them when they evacuated to another clinic and doctor. Based on time and space, our practice met the ASRM and SART guidelines(5).
Since 2003, the IVF treatment process and method have greatly improved and changed(7, 8), such as the cryopreservation technology for gametes or embryos, elective freezing all policy, and the use of antagonist treatment, etc., so that the flexibility of treatment nowadays can be more significant. At that time, our frozen technology use was a relatively low (Figure 1B), and agonist protocol for all patients (9-11), and the fresh transfer was a primary goal. Therefore, patients who have encountered an epidemic outbreak can limit choose different treatment options. In the month of the epidemic, if we decide to continue treatment, the choice is conversion to IUI versus continuance with IVF(12).
The vast majority of IVF cycles are carried out without any problems. However, the SART and ASRM published guidelines for the development of an emergency plan for IVF programs(5). The primary objective of an emergency action plan should be to ensure the safety of program personnel and patients, fresh and cryopreserved human tissues, and critical equipment and records. Specific policies and procedures should be developed as part of a clinic's emergency plan, which addresses both natural disasters (e.g., earthquakes, snowstorms, tornadoes, etc.) and emergencies, such as fires, floods, power outages, terrorist attacks, etc.(5). A unique example is the damage faced by the Japanese IVF clinics as a result of the 311 Great Eastern earthquakes of 2011 in Japan (6, 13)
Our IVF unit with our hospital infection control committee was the establishment of IVF emergency response plans after containment of a nosocomial outbreak SARS in our hospital. Plan including the healthcare-associated infection prevention, for medical staff hand hygiene, antibiotic management, clinical staff and space sterile field line planning and so on non-sterile area, provide a standardized implementation of the principles and the annual education and training and auditing.
General characteristics related to maternal age, assisted reproduction technique (IVF or ICSI), and outcome from 2002-2004 were noted and are presented in Table 1 and Figure 1. Except for the difference in the number of cycles and implantation rate (21.8% vs. 27.7%), there were no significant differences in the patients’ age, pregnancy rate, or abortion rate in 2003 compared with the same parameters in 2002. There were also similar general characteristics between 2003 and 2004, except that there was a significant difference between the spontaneous abortion rate (16.7% vs 9.1%) and estradiol levels on the hCG day (1498.5±1034.9 vs 1774.1±1316.4 pg/ml). In 2003, compared with 2004, abortion women's husbands were older (40.5±0.7 vs 35.6±0.6). No other risk factors found(14).
Taiwan was hit hard by this SARS epidemic, and within a few months, it had a major impact on the country's economy, social order, and medical system. The results of the present study demonstrate that the IVF-ET case number significantly decreased in SARS years compared with the case numbers one year before and after the SARS outbreak. The analysis by year, except for the number of cases, most clinical indicators of IVF did not differ significantly.
Based on the annual analysis, there were two reductions in the number of treatment cycles in the hospital IVF unit: one from 2002 to 2003 (a decrease of 32.1%) and one from 2006 to 2007 (a decrease of 39.4%) (Figure 1A). Laboratory equipment; staffing and the main treatment guidelines had not changed; the reduction in 2003 was because of the SARS outbreak, but the main incident in 2007 was that the main medical professor director resigned (Figure 1A). Unlike the impact of SARS on the number of patients treated, it took three years for the number to return to its original level and continue to grow after the resignation (Figure 1A). We found that as long as infection outbreaks are well controlled, many indicators will soon return to the previous levels, but when the center's main medical director resigned, it took a long time to return to the past level. This seems to reflect the importance of the main medical director and/or laboratory director of reproductive centers with fewer than 500 cycles per year (15). In some countries, ART is offered under government health insurance programs, but in Taiwan, IVF treatment is performed at the patient’s own expense. Therefore, patients have the right to choose their own physicians and institutions(16, 17). From the perspective of Taiwanese society, the reputation of individual physicians seems to deeply affect the choice of patients(18, 19). Therefore, the departure of the leading physician may lead to medium-term effects that were similarly seen with the s rare SARS outbreaks in our center. If there is no suitable successor, the number of treatments will take a long time to recover, and even the whole development could be negatively affected.
Long-term effects: 2004-now
In April 2000, the World Health Organization (WHO) led the world to create a global outbreak alert and response network for the surveillance and prevention of emerging epidemics. Taiwan's Infectious Disease Prevention and Treatment Medical Network has also been established for many years. In addition to policy and medical endeavors and the response needs to start at the individual level in the form of developing good hygiene habits, obeying cough etiquette, correctly selecting and using masks, implementing correct hand washing timings and procedures, and monitoring body temperature. It was strongly implemented in the daily operations of the reproductive center after the 2003 SARS epidemic in Taiwan. This also echoes the spirit of good practice in IVF laboratories and emphasizes the effects of infectious substances and protective measures(15).
Based on the 2003 SARS epidemic situation, it is obvious that transmission is mostly related to hospitals, especially medical institutions that have acute, chronic, inpatient and outpatients operating at the same time, making infectious diseases particularly easy to spread from person to person. The epidemic of SARS in Taiwan made us attach importance to the role of the emergency department in the epidemic status of emerging infectious diseases. The emergency department became the first line of defense during the SARS outbreak, and it is also the place where the new cases are most accessible.
Therefore, hospital IVF units and other private reproductive clinics are often not the front line of the epidemic effects, but it is still possible that unrecognized SARS or new infectious disease cases visit a reproductive center directly for treatment. This also warns us that hand washing is important and the simplest preventive measure in hospitals and public places (such as elevator buttons, escalator handrails, etc. being disinfected to reduce human-to-human transmission). In addition, medical personnel must use masks if they have respiratory problems and be aware of changes in the epidemic situation of global or regional infectious diseases, and to continuously monitor fever patients.
Admittedly, the small and not generalizable retrospective results cannot completely rule out all adverse effects of the SARS outbreak. However, the SARS outbreak incident soon subsided and the psychological impact gradually subsided(20). The Dutch Famine and the 1918 Flu Pandemic have provided organic data about the epigenetic changes that can result from famine, infection, and stress(21). Although the 2003 SARS outbreak seemed to be associated with a slightly higher abortion rate, in our paper writing and retrospective follow-up of our IVF neonatal database, we had no definitive evidence to substantiate a specific effect.
Response to COVID-19 in Taiwan
ASRM is carefully monitoring the ongoing situation concerning the novel Corona virus (SARS-COV-2) and COVID-19 disease(1). Taiwan has been on constant alert and ready to act on epidemics arising from China ever since the SARS epidemic in 2003.
Government had established a public health response mechanism for enabling rapid actions for the next crisis and protect the interests of its citizens. Through early recognition of the COVID-19 crisis, daily briefings to the public, and simple health messaging, the government was able to reassure the public by delivering timely, accurate, and transparent information regarding the evolving epidemic(22).
Compared to the government level, Kaohsiung CGMH also immediately showed that early identification of suspected COVID-19 cases and rapid implementation of measures is critical to preventing or containing outbreaks in hospitals. We provide valuable strategies in healthcare settings(23), including immediately strengthen the information about personal travel history and helps close the loophole that people do not disclose their travel histories because of fear of being forcibly isolated. Infrared thermal camera scanning was introduced at hospital entrances and reduce the density of patients in outpatient departments, all inpatients carefully assessed, and any travel history to China or Hong Kong / Macau, or history of close contact with laboratory-confirmed COVID-19 in the preceding 14 days, is ascertained.
At the same time as the dissertation writing, in addition to previewing the emergency operation plan, our IVF unit pays attention to epidemic changes on the one hand. It cooperates with hospital prevent infection control measures. Staff started to work in different groups. Faced with patients must have surgical masks, hand washing habits establish again and again. Protective face masks, goggles, surgical masks ,and gloves are necessary for invasive treatment and handling of body fluids (all depending on potential infections). Patients with a history of travel exposure or upper respiratory symptoms and other suspicious risks advised to start treatment for at least 14 days and almost always use standard(24) or, if necessary, random start antagonist protocol(25). Cryopreservation protocols are well prepared to target immature or mature oocytes, zygotes, cleavage embryos to blastocysts(26), and even reassure regional IVF centers referral networks. However, so far, the treatment of infertility in most patients is still operating as usual, and the number of cases has not fluctuated.
Compare SARS in 2003, it is important to note that at this point we are still learning about COVID-19 virus and, for now, little is known about its impact on reproduction and pregnancy(1). We agree the points that “Patients, including prospective oocyte and sperm donors, as well as gestational carriers, who meet the diagnostic criteria for COVID-19 infection should avoid becoming pregnant. If they are undergoing active infertility treatment, we suggest that these patients consider freezing all oocytes or embryos and avoiding an embryo transfer until they are disease-free” (1).
In conclusion, our findings suggest that there was a minimal influence of the SARS outbreak on women who conceived using ART procedures. The short-term impact of the SARS outbreak included a reduction in the number of treatment cycles, and the long-term impact is built a culture of personal protective equipment, handwashing, environmental decontamination, education, and training becoming implemented in daily life.
This study was supported by CMRPG8G0071-73 and CMRPG8J0061 from Chang Gung Memorial Hospital.
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