A comprehensive review of the impact of COVID-19 on human reproductive biology, assisted reproduction care and pregnancy: a Canadian perspective

On December 29th, 2019, in Wuhan, the capital city of Hubei province of China, four cases of pneumonia of unknown etiology were reported. On Jan 12th, 2020, next generation sequencing analysis of the full-length genome from respiratory tract samples of the pneumonia cases indicated a novel coronavirus (CoV), previously not linked with infection in humans. On February 11th, 2020 the International Committee of Taxonomy of Viruses, recognized the etiology of this infection and named it ‘Severe acute respiratory syndrome coronavirus-2’ (SARS-CoV-2) and at the same time the World Health Organization (WHO) named the disease COVID-19 (https://​www.​who.​int/​emergencies/​diseases/​novel-coronavirus-2019/​technical-guidance/​naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it).

Epidemiologically, the first cases were linked to the wet seafood market in Wuhan, where the sale of animals that allowed transmission of the virus from the host bat reservoir through an, as yet not identified, animal host, facilitated the adaptation and capacity of this virus to jump species boundaries and infect humans (https://​www.​who.​int/​emergencies/​diseases/​novel-coronavirus-2019/​technical-guidance/​naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it, [1]). COVID-19 spread very quickly throughout the world, and on March 11th, 2020, the WHO declared it a pandemic. By September 29th, 2020, more than 33 million people have been infected worldwide, and 1,007,508 have died (https://​www.​worldometers.​info/​coronavirus/​country/​canada/​). In Canada, as of that date, 155,301 have been infected with SARS-CoV-2, 141,885 are ‘closed’ cases (132,607 (~ 93.5%) have recovered, and 9278 (6.5%) have died), and 13,416 are active cases (99% (13,306) with mild disease and 1% (110) with severe or critical disease) (https://​www.​worldometers.​info/​coronavirus/​country/​canada/​). The most severely affected provinces in Canada are Quebec and Ontario with 72,651 and 50,531 positive cases to date respectively, accounting for over 80% of the cases in Canada. In Quebec and Ontario there have been 5826 and 2840 deaths respectively, accounting for 93.4% of the all deaths in Canada (https://​www.​canada.​ca/​en/​public-health/​services/​diseases/​2019-novel-coronavirus-infection.​html). The majority of Canadian COVID-19 related deaths have been in patients over 70 years of age (8242/29,050) (mortality rate of ~ 28%), with ~ 90% of all deceased patients being older than 70 years: 80+ years accounting for 71.3% of COVID-19 related deaths (6567/9210) and 70–80 years old for 18.2% (1675/9210). The distribution of deaths in patients in younger age groups are: ~ 7.3% (668/9210) for 60-69y age group, 3% (274/9210) for 40-59y, 0.26% (24/9210) for 20–39 y and 0.02% (2/9210) for the youngest group of 0–19 years (https://​health-infobase.​canada.​ca/​covid-19/​epidemiological-summary-covid-19-cases.​html#fn3). The high mortality rate in older people has been due to the poor infection control management in long term care (LTC) facilities at the beginning of the pandemic, linking ~ 80% of deaths in Canada to LTC (https://​www.​cihi.​ca/​sites/​default/​files/​document/​covid-19-rapid-response-long-term-care-snapshot-en.​pdf). In contrast, woman in reproductive age from 20 to 49 years old has accounted for 24.6% (36,871/14,9851) of all COVID-19 infections in Canada, and from the same group 2.5% (914) were hospitalized, 0.5% (189) admitted to ICU, and the mortality rate has been 0.06% (23/36,871) (https://​health-infobase.​canada.​ca/​covid-19/​epidemiological-summary-covid-19-cases.​html#fn3).

Federal, provincial and local governments of all 10 provinces and 3 territories in Canada have cooperatively worked together in response to this pandemic. Measures imposed to fight the COVID-19 pandemic have affected the normal functioning of almost all aspects of daily and social life including closing of schools, universities, public offices and spaces, as well as cancellation of all non-essential activities including elective medical diagnostic and treatment procedures. At the beginning of the pandemic (mid March until mid May, 2020) many fertility clinics in Canada closed completely or provided only emergency care, as in many other countries. Implementation of mitigation strategies such as physical distancing, wearing masks, restriction of non urgent medical care, limiting social gatherings, minimization of non essential traveling, border closing, expanding the testing capacity and contact tracing had a positive effect on limiting the spread of COVID-19 and flattening the curve of infection incidence. Eventually this was followed by staggered and staged reopening of businesses in Canada. The ART (Assisted Reproductive Technologies) services in Canada were reopened during the first stage of easing the restrictions and returning back to normal functioning which included resumption of all non-essential medical treatment and diagnostic procedures [2], with adoption of changes in protocols to maximize the protection of patients and healthcare staff.

ACE2, the functional receptor for SARS-CoV-2, is a key component of the renin-angiotensin system (RAS), modulating the cleavage of angiotensin II (Ang II) and Ang (1–7) [27]. After cell invasion, COVID-19 disrupts the RAS system, by downregulating ACE2 expression in the host cells, leading to an increased proinflammatory response by Ang II [27, 28]. Ang II, ACE2 and Ang (1–7) regulate basic functions in the male and female reproductive systems. In the female, these include folliculogenesis, steroidogenesis, oocyte maturation, ovulation [29], and endometrial regeneration [30]. In the male, testicular ACE2 may regulate testicular function [31], plays a role in sperm function [32], and may be important for sperm’s contribution to embryo quality [33]. Since SARS-CoV-2 enters the cell by binding to the ACE2 receptor, reproductive cells and/or tissues expressing it are potentially vulnerable to the virus, and their functions may theoretically be disturbed.

ACE2 receptors are much more abundant in the male reproductive system than the female reproductive system. Low expression of ACE2 was demonstrated in the fallopian tube (ciliated and endothelial cells), ovary, vagina, cervix and endometrium [34‐36]. On the other hand, ACE2 expression in the testis is among the highest observed, with high expression in Leydig and Sertoli cells and medium expression in glandular cells of the seminal vesicle [34, 37, 38]. As a result, it is expected that the testes will be more vulnerable than the ovaries to the detrimental effects of a SARS-CoV-2 infection.

The male reproductive system may be contaminated by viruses during viremia, due to compromised blood–testes/vas deferens/epididymis barriers, especially in the presence of systemic or local inflammation. Salam et al. [63] reported the presence of 27 viruses, possibly resulting from viremia, in human semen. For many of them, data regarding sexual transmissibility is lacking [63]. Infectivity, which is a prerequisite for viral transmission, depends on the infectious dose and the exposure route. Nowadays, virus detection is largely achieved by means of molecular methods, which have replaced standard procedures of virus isolation. However, the only definitive way to prove infectivity is isolation of the virus. The fact that sexual transmission can rarely be confirmed for some viruses, despite the detection of RNA in the semen long after the acute infection, emphasizes the shortcomings of molecular detection alone in understanding transmissibility [64].

Should sexual contact be a matter of concern in the case of COVID-19? The need for cautious sexual behavior is clear, since salivary viral shedding has been reported in COVID-19 patients for up to 11 days after hospitalization [65]. Some may claim it is unnecessary to investigate genital secretions in the context of sexual transmission, as air droplets and human contact are the main routes of this virus spread, and both will most likely happen during sexual activity anyhow [66]. However, research shows that sexual transmission may possibly cause delayed outbreaks after the first wave of cases, and the absence of a virus in the genital secretions should not be assumed for traditionally non–sexually transmitted viruses [63, 64]. Furthermore, transmission via semen is especially relevant in infertile patients undergoing ART, due to the theoretic possibility of direct transmission via intracytoplasmic sperm injection (ICSI). It is possible that this virus could affect early embryogenesis, and this should be taken into consideration in future research [67].

COVID-19 infection has raised concerns for pregnant woman and their fetus due to physiological changes in immunity during pregnancy, maternal susceptibility to respiratory infections, increased oxygen requirements, and risks associated with treatment during pregnancy.

The fatality rate in pregnancy for previous pandemics, including: the 1918 Spanish influenza pandemic, the SARS-CoV pandemic, and the MERS pandemics were ~ 27–50%, 25–30%, and ~ 40% respectively [77]. Knowledge regarding the effects of COVID-19 on pregnancy, including vertical transmission and perinatal infection, is based on very limited data. A systematic review and meta-analysis of COVID-19 in pregnant women from 77 cohort studies by Allotey et al. [78], showed an overall 10% (95% CI [7–14%]; 28 studies, 11,432 women) COVID-19 positivity in pregnant and recently pregnant women attending or admitted to hospital for any reason. This relatively high incidence may partially reflect the increased vigilance and screening for COVID-19 in pregnant women admitted to hospitals, and is in line with admissions in regions that were mainly reporting data from the peak epidemiological curve of large outbreaks [78].

COVID-19 disease has a similar spectrum of symptoms in pregnant woman as in non-pregnant woman, such as: fever ~ 40%, cough 39%, shortness of breath 13.2%, malaise 13%, muscle pain 10%, diarrhea 3.7–7%, sore throat 3.4%, headache 40%, chills 28%, loss of taste and smell ~ 16%. However, most of the symptoms are less frequent during pregnancy [76, 78‐80]. Pregnant women with COVID-19 are less likely to report symptoms of fever (OR 0.43, 95% CI [0.22 to 0.85]; I2 = 74%; 5 studies; 80,521 women) and myalgia (0.48, [0.45–0.51]; I2 = 0%; 3 studies; 80,409 women), but they are more likely to need admission to an ICU (OR 1.62 [1.33–1.96]; I2 = 0%) and require invasive ventilation (1.88, [1.36–2.60]; I2 = 0%; 4 studies, 91,606 women), compared with non-pregnant women of reproductive age [78].

The overall data from 26 studies, that included 11,580 women, showed 73 deaths in COVID-19 positive pregnant women (0.1, 95% CI [0.0–0.7%]) [78]. The severe form of COVID-19 manifested in 13% of pregnant women with suspected or confirmed COVID-19 infection (6–21%; 21 studies, 2271 women); admission to an intensive care unit was required for 4% (2 to 7%; 17 studies, 10,901 women), 3% (1 to 5%; 13 studies, 10,713 women) required invasive ventilation, and 0.4% (0.1 to 0.9%; 9 studies, 1935 women) required extracorporeal membrane oxygenation [78]. Factors associated with severity were pre-existing maternal comorbidities, such as increased maternal age (1.78, 1.25 to 2.55; I2 = 9%; 4 studies; 1058 women), high body mass index (2.38, 1.67 to 3.39; I2 = 0%; 3 studies; 877 women), chronic hypertension (2.0, 1.14 to 3.48; I2 = 0%; 2 studies; 858 women), and pre-existing diabetes (2.51, 1.31 to 4.80; I2 = 12%; 2 studies; 858 women).

Vertical transmission happens if an infected pregnant woman transmits the infection to her fetus/infant during the fetal, intra-partum or post-partum period. The route of vertical transmission can occur through the placenta in-utero, maternal - neonatal contact during delivery, or during breastfeeding. ACE2 receptors necessary for viral infection are expressed in the placenta (syncytiotrophoblast, cytotrophoblast, endothelium and vascular smooth muscle from both secondary and primary villi), ovaries, uterus and vagina, and may be involved in vertical transmission [81, 82]. A transcriptomic study on single cell expression profiling has shown that ACE2 and TMPRSS2 positive cells are present in human trophectoderm and placenta throughout pregnancy, indicating susceptibility for SARS-CoV-2 infection of these tissues and the possibility of intrauterine fetal infection [83]. In addition, there are other potential SARS–CoV-2 receptors, such as BSG (CD147) and NRP1(enriched in trophoblast) receptors (expressed in the pre-gastrulation embryo), and proteases, such as CTLS (Cathepsine L-like cysteine protease), a key protease in embryos, suggesting there are other routes for infection of embryos that need further investigation [84‐87].

Kotlyar A et al. [88] in their systematic review and meta-analysis of 38 cohort/case series (total n = 936) reporting on neonatal infection immediately after or within 48 h after birth, in COVID-19 positive pregnant women, showed a pooled proportion of 3.2% (95% CI 2.2–4.3%) for vertical transmission of COVID-19 infection [88].

Allotey et al. [78] reported a spontaneous preterm birth rate of 6% (95% CI [3–9%]; I2 = 55%; 10 studies; 870 women) in women with COVID-19. The odds of any preterm birth were higher in pregnant women with COVID-19 compared with those without the disease (OR = 3.01, 95% CI [1.16–7.85]; I2 = 1%; 2 studies; 339 women). A quarter of all neonates born to mothers with COVID-19 were admitted to the neonatal ICU, revealing an increased risk of admission, compared to those born to mothers without COVID-19 (OR = 3.13, 95% CI [2.05–4.78], 1 study, 1121 neonates) [78].

The overall rate of caesarean section (CS) in COVID-19 mothers is high, ranging from 67.2 to 94%, and vaginal delivery from 6 to 32.8% of cases [80, 88‐91]. Most of these women were in their 3rd trimester when the infection occurred.

Outcomes of neonates born from SARS CoV-2 positive mothers during pregnancy was systematically summarized by Yoon et al. [90]. They included 16 case series and 12 case reports, reporting overall on 223 neonatal outcomes [90]. In total, 201 delivered live born infants before the end of the study, with gestational age at birth ranging from 30 wks + 6 days to 41 wks + 5 days, and birth weight ranging from 1880 to 4050 g. SARS CoV-2 detection within 36–48 h after birth showed positive results in 2.4% (4/167) of tested neonates. All four SARS CoV-2 positive neonates were delivered by CS due to maternal Covid-19 pneumonia and all manifested signs of pneumonia on chest imaging, all had a negative RT-PCR nasopharyngeal (NP) swab 1 week after birth, and all recovered well [90]. The authors reported a group of four neonates with false positive tests, one of them had a positive SARS-CoV-2 PCR test from NP swab, but it was negative when repeated, and other three neonates showed positive SARS CoV-2 IgM, but their NP samples were negative as well. In that systematic review the incidence of premature birth was 25.9% (48/185), small for gestational age (SGA) 8.3% (5/60), low birth weight (LBW) 15.6% (15/96) and neonatal asphyxia was reported in 1.8% (3/168). Overall, 93% (68/73) of the infants born to COVID-19 positive mothers were asymptomatic. Only one (1/177, 0.6%) newborn born at 34 wks + 5 days died due to gastric bleeding (disseminated intravascular coagulation) and multiple organ failure 9 days after birth. His nucleic test for SARS Cov-2 was negative before his death. That study reported a frequency of preterm rupture of membranes (PROM) of 12.7% (16/126) of cases, and fetal distress in 10.6% (15/141). Five mothers received mechanical ventilation in ICU and two (2/5) developed acute respiratory distress syndrome and delivered stillbirths [90, 92].

Pathohistological changes in placentas from COVID-19 positive pregnant women commonly showed vascular malperfusion with central and peripheral villous infarctions, fibrin deposition and chorionic villitis or intervillositis with inflammatory infiltrate of CD68+ macrophages and T cells [93‐95]. In a series of cases, RT-PCR testing of placentas from SARS CoV-2 positive pregnant women showed that 20% (4/20) were positive for SARS CoV-2 [88]. This is evidence that SARS CoV-2 can infect the placenta, however transmission to the fetus was not detected in 2/4 fetuses from SARS CoV-2 positive placentas. Both were diagnosed in the second trimester of pregnancy, 19 and 22 wks respectively, and both pregnancies ended with fetal demise [88, 94, 96]. There was an additional reported case, where a woman who delivered at 29 wks due to disease severity, had visible virions in the syncitiotrophoblast on electron microscopy, but the fetus was negative for SARS CoV-2 [97].

Some studies have shown a linkage of fetal vertical transmission with maternal disease severity. Penfield et al. [98] showed that 3 of 11 placental or amniotic membranes swabs of SARS CoV-2 positive mothers, after CS delivery were positive. The three positive placental cases were from mothers in severe/critical stage of the disease, whereas the other 7/8 placentas were negative with mild disease and delivered vaginally, and only one of the SARS CoV-2 negative patients (1/8) was in the critical phase of the disease and delivered by CS. All newborns 11/11 tested negative for SARS Cov-2 and did not have COVID-19 symptoms at the first or fifth day of life, which raises the question that swabs from the placenta and membranes might be mixed with maternal tissue, amniotic fluid and/or maternal blood [98]. Furthermore, Chen et al. [99] described nine pregnant women with mild symptoms and laboratory confirmed SARS CoV-2, who had a live birth by CS in the third trimester of pregnancy. None of the mothers had severe COVID-19 symptoms, pneumonia or died. All six, tested, cases of infant/mother pairs had negative SARS CoV-2 swabs/samples from multiple sites (amniotic fluid, cord blood, neonatal throat swab and breast milk) [99].

Yan J. et al. [89] analyzed 116 pregnant women (65 laboratory confirmed SARS CoV-2 and 51 clinically diagnosed with COVID-19 pneumonia) admitted to hospital. 23.3% (27/116) cases were asymptomatic of the disease, however after close evaluation due to positive epidemiological history and close contact with confirmed COVID-19 positive patients 21/27 were clinically diagnosed with pneumonia. The study showed that only 6.9% (8/116) of positive pneumonia maternal cases during pregnancy progressed to severe pneumonia and admitted to ICU without maternal death [89]. In this study, 8 patients presented with COVID-19 during the first and early second trimester, and 1/8 (12.5%) miscarried. The rate of preterm birth (< 37 GW) was 21.2% (21/99), 26.8% (6/21) of which involved PROM [89, 100]. The most common symptoms in COVID-19 positive mothers during the second and third trimester were fever (42.3%) and cough (31.8%). There were laboratory findings of leucocytosis in 31.5%, lymphocytopenia in 43%, increased C-reactive protein in 63%, and patchy shadowing or ground glass opacity in the lungs in 96% [89, 90]. The study reported that 47% (47/99) of the neonates were transferred in neonatal ICU, neonatal death in 1% (1/99), 76.7% (76/99) were discharged, 23.2% (23/99) were still in hospital. Importantly, all 86 neonates were negative for SARS-CoV-2 [89].

Juan J. et al. [76], in their systematic review analysed 24 studies (9 case series and 15 case reports), involving a total of 324 women diagnosed with SARS CoV-2. Gestational age at admission ranged from 5 to 41 weeks, and at delivery 28–41 wks. There were 4 women who miscarried [76].

Huntley et al. analyzed 13 studies, involving a total of 462 pregnant patients with a laboratory confirmed COVID-19 diagnosis. Maternal ICU admission rate was 3% (8/263), 1.4% (3/209) had critical disease, no (0/313) maternal deaths were reported, preterm birth rate was 20.1% (51/284) (iatrogenic and spontaneous), and the neonatal death rate was only 0.3% (1/313). There was no vertical transmission detected in all 310 neonates [101].

COVID-19 symptom progression during pregnancy compared to non-pregnant women was analyzed by Hsu at al., who showed that 8.3% (36/431) of the COVID-19 patients during pregnancy had severe disease, of whom 86% (31/36) progressed to a critical stage and were admitted to the ICU [102]. Another study by Blitz et al. [103], reported no significant difference between the rates of ICU admission in hospitalized COVID-19 pregnant woman (9.8%; 8/82), and non-pregnant COVID-19 positive patients (15.1%; 50/3320) (p = 0.22). These studies suggest that hospitalized pregnant SARS CoV-2 positive patients are not at an increased risk for severe disease progression compared with non-pregnant COVID-19 positive hospitalized woman [102, 103].

In contrast, Ellington et al. [79] reported that COVID-19 positive pregnant woman have higher chance to be hospitalized vs. non pregnant COVID-19 positive woman (31.5% vs. 5.8% respectively). However, they did not stratify for the underlying causes of hospitalization in this cohort (ie delivery, pregnancy related procedures, or Covid-19 related complications). The authors reported an adjusted risk ratio (aRR) of 1.5 (CI 1.2–2.4) for pregnant COVID-19 positive patients to be admitted to the ICU, and an aRR of 1.7 (CI = 1.2–2.4) to receive mechanical ventilation. The fatality rate was similar between pregnant COVID-19 patients and non-pregnant woman, 16/8207 (0.2%) and 208/83205 (0.25%) respectively (aRR = 0.9, 95% CI = 0.5–1.5). In this study, the pregnant woman cohort had more comorbidities overall vs. non-pregnant woman included: chronic lung disease, 21.8% vs 10.3%; diabetes mellitus, 15.3% vs. 6.4%; and cardiovascular disease, 14% vs 7.1%, respectively [79]. Collin et al. reported that the incidence of COVID-19 and admission to ICU for pregnant/post-partum woman in Sweden was 14.4 per 100,000 (CI 7.3–23.4) compared to 2.5 per 100,000 (CI 1.8–3.5) for non-pregnant COVID-19 positive woman, RR = 5.39 (CI 2.89–10.08); and a higher risk of requiring mechanical ventilation for admitted pregnant/post-partum woman, RR = 4 (CI 1.75–9.14) [104]. These results warrant careful and close follow up of all COVID-19 positive pregnant and postpartum women until more data is available. It should be noted that these studies potentially capture differences in health care systems and local management of epidemics.

In Ontario, Canada, the BORN (Better Outcomes Registry and Network) database, during the period from March, 1st to May, 29th, 2020 captured cases of COVID-19 pregnant woman from 57.4% (54/94) of the hospitals and 31.5% (29/92) of the midwifery practice groups in their network [105]. There were 36 reported pregnant COVID-19 patients in Ontario for this period; 75% (27/36) confirmed and 25% (9/36) suspected. The most common symptoms in confirmed cases were: cough (44.4%), fever (40.7%), anosmia (22.2%), myalgia (14.8%), malaise (14.8%), shortness of breath (14.8%), headache (11.1%), anorexia (11.1%), rhinitis (7.4%), sore throat, diarrhea, vomiting, loss of taste, and chest pain; 25.9% (7/27) of the cases were asymptomatic. Three of confirmed cases 11.1% (3/27) had complications (2 patients had pneumonia/abnormal X-ray finding, and 1 patient had coagulopathy). Infection was confirmed at different gestational ages; 4 cases at < 20 wks, 3 cases at 21–32 wks, 2 cases at 33–36 wks, 13 cases at 37–40 wks, and 5 cases at > 40 wks. Birth outcomes available to date are as follow: 21/ 27 live birth, 2/27 data is missing, and 4/27 were still pregnant. Four of 21 had preterm births, and 17 of 21 had term/post-term births. There was one (1/12) infant who tested positive for SARS CoV-2 after birth (https://​www.​bornontario.​ca/​en/​data/​resources/​Documents/​2020-06-04-BORN-Ontario%2D%2D-COVID-19-in-Pregnancy-in-Ontario-Report%2D%2DFinal.​pdf).

In response to the COVID-19 pandemic, scientific and professional fertility societies around the world, such as American Society of Reproductive Medicine (ASRM), Canadian Fertility and Andrology Society (CFAS), European Society for Human reproduction and embryology (ESHRE) and the International Federation for Fertility Societies (IFFS) issued guidelines for couples who are undergoing or will undergo treatments involving ART [106‐109]. All of them had in place COVID-19 working groups to monitor the evolution of this pandemic with updated scientific evidence on COVID-19 infection and current practice guidelines in line with local governmental and public health recommendations, as well as, provide continuous support for medical professionals and patients.

Implementation of restrictions in ART and fertility care worldwide at the beginning of the pandemic was to support the overwhelmed healthcare systems, and reduce over usage of personal protective equipment (PPE), which was in deficit worldwide. Although lacking scientific evidence on the risks associated with COVID-19 in pregnancy and patients undergoing ART, almost all guidelines issued by afore mentioned societies, shortly after WHO declared COVID-19 a global pandemic in mid March, 2020, recommended suspension of new fertility treatments – ovulation induction, intrauterine insemination and in-vitro fertilization, and all non-urgent gamete cryopreservation, as well as postponement of all embryo transfers and all elective surgeries and non-urgent diagnostic procedures. The reasons stated not to start new ART cycles were: 1) to avoid complications from ART and ART-pregnancies, 2) to avoid potential SARS-CoV-2 related complications during pregnancy, 3) to mitigate the potential, but unknown, risk of vertical transmission in SARS-CoV-2 positive patients, 4) to support the necessary re-allocation of healthcare resources, and 5) to observe the recommendations for social distancing. The recommendations directed couples using ART to discuss their treatment in detail with their treating physicians, and consider gamete cryopreservation or embryo preservation for those in-cycle to postpone embryo transfer. Only patients who required urgent stimulation and gamete preservation, such as oncology fertility preservation patients, were exempted from the restrictions and their medical care was not altered. All societies emphasized the importance of developing emergency preparedness plans for fertility clinics, monitoring of PPE supplies, active screening of patients and staff for COVID-19, increased utilization of telemedicine, and reduced clinic visits.

The eventual resumption of ART and fertility care worldwide was in line with the decline phase of local epidemiologic curves of incidence, as well as, a reduction of the impact of COVID-19 on healthcare resources [2, 110‐113]. In Canada, the guidance on reopening of fertility clinics was given by the local provincial reopening strategies and outlined in the CFAS COVID-19 Update # 5 from April 29th, 2020, which was supported by two guiding CFAS documents “Guiding Principles to assist Canadian ART clinics to resume services and care” [114] and “Recommendations related to IVF Laboratory shutdowns and start-up during a Pandemic” [115] to assist clinics in their preparations for resumption of care. General principles include: a) Reduced face to face interactions to support social/physical distancing by virtual consultations; b) Pre-screening of all patients within 48-h of their intended appointment; c) Mandatory screening of all people entering the clinic; d) Informing patients of potential risks of treatment and/or pregnancy related to COVID-19; e) Changes in clinic policies because of COVID-19 as well as providing patients with local Public Health contact information; f) Continue fertility treatment if patient and staff safety is maintained with the recommendation that “patients with positive COVID-19 testing may require discontinuation of treatment (if safe to do so) until they have completely recovered, or until 4 weeks after onset, whichever is longer”; g) Defer treatment when necessary, especially patients under investigation for COVID-19, or who have had exposure to SARS CoV-2; h) Mandatory daily screening of all staff for symptoms and risk factors for COVID-19; i) Prevent infection and have control measures in place, in addition to physical distancing, that includes wearing appropriate PPE for the procedure as well as enhanced cleaning and disinfection protocols, consistent with current Public Health recommendations [114]. Recommendations related to laboratory operations during the current pandemic guided safe laboratory shutdown by properly managing the supply of medical gases and liquid nitrogen with an accent on cryo-storage safety (https://​cfas.​ca/​_​Library/​_​documents/​CFAS-Guidance-Document-on-Cryo-Storage-June-2018.​pdf [116]), proper shut down of incubators and other laboratory equipment, and managing supplies and ongoing maintenance ensuring enough consumables (culture media and vit/warm kits) for 2 months of full operation at all times [115]. The guidance on safe restart of ART laboratories indicated implementation of the necessary steps for the restart of equipment by following operational QC and maintenance protocols, external QC validation and thorough cleaning before clinical use, re-stocking of supplies. It also included elaborate directions on mandatory staff screening, strategies to provide safe workplace for staff and patients by scheduling, shifts, staggered restart of clinical procedures, extending the working day, limiting contacts between ART lab staff and other staff in the clinic, reducing number of deliveries, decontamination protocols in place for items received, limiting contact with delivery personnel, reducing number of shipments of biopsied cells to reference labs, proper use of PPE, and measures for infection containment by all staff [115].

One Italian study evaluated the impact of the COVID-19 pandemic on the desire for parenthood in couples of reproductive ages. This study included 944 women and 538 men aged 18–46 years, in heterosexual stable relationships. Interestingly, more than a third (37.3%) of participants who were planning to have a child before the pandemic, decided to abandon their intention during the quarantine, due to worries regarding future economic difficulties (58%) and/or potential risks to a pregnancy (58%). Of those who did not intend to conceive before the pandemic, 11.5% revealed a new desire for parenthood during quarantine, related to wanting a life change (50%) and a need for positivity (40%). However, only 4.3% of them actually tried to conceive [122]. Another study assessed the willingness to go ahead with the desire for pregnancy in infertile women during the outbreak. Almost half of the women (44.6%, n = 45) replied they would consider postponing their pregnancy plan due to COVID-19 [123].

More than a third (36%) of infertile women, in general, will experience anxiety symptoms, affecting their quality of life [124]. Anxiety disorders are also prevalent in pregnant women. Some of them, such as panic disorder, have a higher prevalence during pregnancy than the lifetime prevalence rates for women in the general population [125]. During pandemics, the prevalence of psychological distress and symptoms of mental illness tends to be higher compared to routine periods [126]. A recent systematic review and meta-analysis reported that stress was the most common psychological after-effect among the general population during COVID-19 pandemic. It has been suggested that the reason for such a high burden is the prolonged quarantine [126]. Among the major stressors contributing to worldwide emotional distress and increased risk for psychiatric illness associated with the COVID-19 pandemic, are uncertainty, lack of resources, financial losses, violation of personal liberty, and conflicting messages from authorities [127]. Because they are coping with an additional burden, it would be expected that the infertile and pregnant subpopulations may be more prone to negative psychosocial effects. Several studies have assessed those aspects in these specific populations during the current pandemic.

The Government of Canada has been providing funding for developing and implementing measures for rapid testing, management and reduction of transmission of COVID-19 through the Canadian Institute of Health Research (CIHR) (165,663,556 CAD) and provincial partners, such as the International Development Research Centre (IDRC) (6,554,078 CAD), in partnership with Partnership with Alberta Innovates (AI) 100,000 CAD, Michael Smith Foundation for Health Research (MSHFR) 150,000 CAD, Research Manitoba (RMB) 100,000 CAD, Research Nova Scotia (RNS) 100,000 CAD, Saskatchewan Health Research Foundation (SHRF) 50,000 CAD, and New Brunswick Research Foundation (NBHRF) Alberta Innovates (AI), Michael Smith Foundation for Health Research (MSFHR), Research Manitoba (RM), Research Nova Scotia (RNS), Saskatchewan Health Research Foundation (SHRF), and the New Brunswick Health Research Foundation (NBHRF) (https://​www.​canada.​ca/​en/​institutes-health-research/​news/​2020/​06/​government-of-canada-and-provincial-partners-invest-more-than-109m-in-covid-19-research-details-of-the-funded-projects.​html).

Research findings and data produced as a result of the funding will be shared rapidly and openly (in line with the joint statement on sharing research data and findings relevant to the novel coronavirus outbreak) to inform the global public health response and to help save lives.

Based on the last update from September 1st,2020, CIHR currently funds 332 COVID-19-related projects in two major areas: 1) Medical countermeasures focusing on: diagnostics, vaccines, therapeutics, clinical management, transmission dynamics and animal host modeling; and 2) Social and policy countermeasure projects focused on: studying the public health response and its impact, social dynamic communication and trust, coordination governance, and logistic. There are 6 (1.8% of all CIHR Covid-19 funded studies) operating grants with total of 2.47 M (1.4% of CIHR COVID-19 related funds) funding for projects addressing COVID-19 during reproduction (Table 2). Three are funded under the mental health and psychosocial/health behavioural research program (“Assessing and addressing the psychosocial impact of COVID-19 among pregnant woman and health care providers in Anhui, China”, 317,176 CAD; “Acceptability and Impact of Prenatal Internet Intervention for Maternal Mental Health in the COVID-19 Context”, 177,960CAD; and “Online 1-Day Cognitive Behavioural Therapy-Based Workshops for Postpartum Depression”, 199,567CAD. One reproduction-related project is funded under ‘nutrition in health research’ (“Can COVID-19 and maternal antibodies to SARS-CoV-2 be transmitted through human milk? Implications for breastfeeding and human milk banking”, 154,245CAD). In the field of Reproduction/pregnancy, CIHR currently funds two projects: “The COVID-19 Ontario Pregnancy Event (COPE) Network: Assessing the impact of pregnancy on maternal, fetal and newborn health”, 795,559CAD; and “Canadian Surveillance of COVID-19 in Pregnancy: Epidemiology, Maternal and Infant Outcomes”, 825,367CAD.

The COVID-19 Ontario Pregnancy Event (COPE) Network as a multisite study that will be assessing the impact of COVID-19 during pregnancy on maternal, fetal and newborn health. This study aims to assess the mother to infant and potential, vertical transmission of SARS-CoV-2 infection in pregnant women by analysis of prospectively collected maternal and neonatal biological samples (vaginal mucosa, amniotic fluid, placenta, cord blood, breast milk and neonatal NP swabs). They will also examine the serology and viral load in neonates and placenta to quantify the impact of SARS-CoV-2 on neonates.

Canadian COVID-19 In Pregnancy Surveillance (CANCOVID-Preg) Study (CANCOVID-Preg) will track maternal and infant outcomes among pregnant women with COVID-19 [138] by teams working in almost all provinces and territories across Canada, and will aid to the understanding of the epidemiology of COVID-19 in pregnancy, and will provide critical data to inform recommendations for pregnant women and their infants. The goals of the project are to determine the burden of COVID-19 among pregnant women in Canada, as well as maternal and neonatal outcomes associated with infection, including the possibility for vertical transmission. The data captured regionally is to be combined for a national dataset of cases of COVID-19 in pregnancy. Researchers will also contribute data to international collaborations, allowing for a more comprehensive global understanding of COVID-19 in pregnancy [138].

In addition, united efforts from a Group of 15 Canadian Research Universities, Compute Ontario, the University of Toronto and Canada’s science advisors, established a new CanCOVID (cancovid.ca), Canada-wide network of health, science and policy researchers to facilitate COVID-19 research collaboration. The aim is to provide rapid response network to expedite transdisciplinary communication and collaboration.

A Canadian initiative to study COVID-19 impact on ART is still to be conceived. Canada has invested in infrastructure to facilitate collaboration and research in reproduction, especially in ART, as evident from the numbers above, and calls for immediate action from basic science, clinical and psychosocial researchers from the field. In the U.S.A., the ASPIRE (Assessing the Safety of Pregnancy In the Coronavirus Pandemic) Study is a nationwide prospective cohort study of pregnant women and their offspring during the COVID-19 pandemic, that will include patients in the care of a reproductive medicine specialist who conceive spontaneously vs with ART, between March 1st and December 31st, 2020.

COVID-19 pandemic has imposed unprecedented changes in all aspects of life and healthcare. Canada is currently at the beginning of the predicted second wave of COVID-19 infections. Active prevention with effective vaccine will likely be possible in early 2021, challenging the global response and management to be tailored and adjusted continuously and actively, as data becomes available.

Unlike previous pandemics, pregnant women do not appear to be at an increased risk for COVID-19 and are less likely to manifest COVID-19 related symptoms, compared to non-pregnant reproductive age women. Maternal outcomes are favourable, with severity of symptoms correlated to advanced maternal age and pre-existing comorbidities such as chronic cardio-pulmonary diseases, obesity and diabetes. Pregnant women have higher odds of needing ICU treatment for COVID-19, compared to non-pregnant women. Preterm birth rates (OR = 3.01, 95%CI 1.16–7.85) are higher in pregnant women with COVID-19 than in pregnant women without the disease, however this finding warrants caution, as there is no established causative relationship, and there is a possibility that the same risk factor predisposes to both COVID-19 and preterm birth. The high CS rate of 67–94% in COVID-19 infected pregnant women does not relate to obstetrical indication, but rather to infection control and management of the delivery and postnatal care. With respect to the impact of infection on maternal and fetal health in the first and second trimester, only a few reports are available, but preliminary data do not indicate an increased risk for miscarriage or fetal loss later on. Limited data on vertical transmission shows that it may be possible, occurring at a rate of ~ 3%, however, this finding must be interpreted with caution, since this data is for maternal infections occurring in the third trimester, and there are limitations of the methods used to detect SARS-CoV-2, that were not addressed in those studies. Future studies based on prospectively collected data and samples, analyzed with standardized protocols, during pregnancy and the neonatal period, including data on sequelae and long-term impact on health and development, will greatly add to current knowledge. This will allow for true risk estimation and provide guidance on epidemiologic and medical management of COVID-19 in this population. Observed shifts in the demographics of COVID-19 infections from predominantly over 60y at the beginning of pandemic to younger populations in the second wave, will likely provide the much-needed information on the reproductive age population.

The influence of COVID-19 on the female and male reproductive system needs further investigation. Future studies should include assessment of ovarian function in female patients during the acute and recovery phase. Furthermore, since there is no long term follow up, significant effects of this virus on reproductive function, cannot be excluded as yet. Since inflammation plays a significant role in the pathogenesis of some cases of premature ovarian insufficiency, it is currently unknown whether COVID-19 could induce a chronic systemic pro-inflammatory effect, which may impair ovarian reserve. Evidence so far suggests potential effects on the male reproductive system from COVID-19 infection. However, data regarding the effect on semen parameters needs further investigation. Future studies should focus on long-term effects on gonadal function in recovering patients. Fertility evaluation and follow-up in the months and years following recovery from COVID-19 infection should be considered for all COVID-19 male patients. Sperm cryopreservation could be considered for male patients at higher risk for infertility.

Given that the COVID-19 risk for reproductive age women appears to be low, in addition to reassuring initial evidence of low risk for pregnant patients and their fetuses, we feel that ART procedures and fertility treatments should not be delayed due to the pandemic. Adherence to practice guidance and preventative measures during COVID-19 pandemics should be strict. There is an immediate need for more research on ART during COVID-19 to address open questions on the impact of this virus on reproduction, and to allow for more informed patient care and counselling. The emotional impact of COVID-19 on infertile patients cannot be underestimated. Identifying patients at risk of psychological distress should be promoted by providing psychosocial education and training for health care professionals in the reproductive field. Future psychosocial research should focus on the possible long-term impact of COVID-19 on infertile patients in the coming years.

“Reproductive care is essential and reproductive medicine professionals are in a unique position to promote health and wellbeing. United efforts and collaboration are needed to gather together data and resources to enhance understanding of COVID-19 as it pertains to reproduction, pregnancy, and potential impact on the fetus and neonate. The lessons learned from current and future research in this area will be useful as humanity deals with future pandemics.” [110].