Obstetrical and gynecologic implications of COVID-19: what have we learned over the first two years of the pandemic
   Since the first case of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was diagnosed in December 2019, there has been an increasing amount of research completed regarding the implications of the illness in obstetrics and gynecology. While the original disease-causing virus has mutated repeatedly since 2019, and will likely continue to do so, we felt it important to update our initial review article published in June of 2020. The principles of transmission and symptomatology remain true to what we initially described. In contrast, the duration of the illness, hospitalization rates, and ICU admission rates seem to vary according to the dominant strain and population vaccination rate and even the type of vaccine administered at any point in time. Despite the rapidly changing nature of the pandemic, we hope to review the ideas brought forward in recent studies. The following is designed to provide a broad understanding of the global impact of the pandemic within the field of obstetrics and fertility. Clinical presentation Transmission occurs primarily through breathing-in aerosol contaminated air . Exposure to contaminated fluids encountering the eyes, nose, or mouth, and rarely via contaminated surfaces, have fallen out of favour as a means of contamination, in most cases . Droplets spread through means of coughing, sneezing, singing, and talking (particularly loudly) is the primary mechanism of contamination. It should be noted that most infected individuals have mild cases, and the rate of symptomatology varies based on the variant. However, a small but significant group of those infected will get quite ill. It is important to recognize that at least one third of infected individuals will not present with any noticeable symptoms . Unfortunately, these asymptomatic carriers tend to be untested and act as vehicles for further spread. Indeed, this is also true of those who are minimally symptomatic or develop symptoms later in the disease course, deemed “pre-symptomatic” . Through time we have come to recognize three common clusters of symptoms in those with COVID-19: (1) a respiratory symptom cluster including cough, sputum, shortness of breath, and fever; (2) a musculoskeletal symptom cluster involving myalgias and arthralgias, headache, and fatigue; and (3) a digestive symptom cluster such as abdominal pain, vomiting and diarrhea . Additional rare presentations include pericarditis, myocarditis, atrial fibrillation, congestive heart failure, encephalopathy, diabetic ketoacidosis, dehydration possibly resulting in renal failure, liver failure, as well as disseminated hypercoagulability and Kawasaki’s disease . Long-term symptoms of COVID-19 have been noted in approximately one third of infected individuals irrelevant of severity of initial presentation in one study . The World Health Organization (WHO) defines post-COVID conditions as occurring in individuals with probable or confirmed SARS-CoV-2 infection 3 months from the onset of COVID-19 symptoms, lasting for a minimum of 2 months, unexplained by another diagnosis . Alternatively, the Centre for Disease Control (CDC) definition includes symptom onset as early as 4 weeks following infection . There are clear differences in these two definitions. The WHO has included 12 domains necessary for clinical diagnosis, including: history of infection, laboratory confirmed infection, a minimum of 3 months from date of infection, greater than 2 month of symptom duration, no minimum number of symptoms, clustering of symptoms that may change in time course and nature (fluctuate, relapse, persist, be new in onset), unexplained by alternative diagnosis, impact everyday function, involve sequalae of described complications of COVID-19, and acknowledgement that different populations may require separate definitions (ex. children, pregnancy, elderly). A systematic review revealed that after 1 month 54% (IQR 45–69%) of individuals experienced a minimum of one post-COVID symptom, by 2–5 months 55% (IQR 34.8%-65.5%) experienced a minimum of one symptom, and following 6 months, that number remained stable at 54% (IQR 31–67%) . Clearly, the rate of post COVID-19 conditions varies based on the study. In the same systematic review, the most common neurocognitive symptoms included difficulty concentrating (IQR, 23.8% [20.4–25.9%]), memory deficits (IQR, 18.6% [17.3–22.9%]), and cognitive impairment (IQR, 17.1% [14.1–30.5%]). The most common mental health disorders included anxiety (IQR, 29.6% [14–44%]), sleep disorder (IQR, 27% [19.2–30.3%]), depression (IQR, 20.4% [19.2–21.5%]), and post-traumatic stress (IQR, 13.3% [7.3–25.1%]). Other commonly reported symptoms included: joint pain (IQR, 10% [6.1–19%]), fatigue or muscle weakness (IQR, 37.5% [25.4–54.5%]), and flu-like symptoms (IQR, 10.3% [4.5–19.2%]). An investigation of 309 COVID-19 patients identified 4 risk factors for developing post-acute sequelae including pre-existing type 2 diabetes, SARS-CoV-2 RNAemia (presence of circulating mRNA fragments of SARS-Co-V-2), pre-existing Epstein Barr viremia, and the creation of specific autoantibodies in response to SARS-Co-V-2 . How post COVID-19 conditions affect women differently than men in addition to how reproductive age status, menstrual cyclicity, and potential reproductive tract symptomatology alter chronic COVID-19 presentations, requires further study. COVID-19 and pregnancy Whether symptomatic or asymptomatic COVID-19 alters spontaneous abortion (SAB) rates is not well studied. When examining miscarriage rates amongst asymptomatic women undergoing first trimester viability scans during the early months of the pandemic versus the year prior, the viable clinical pregnancy rate did not differ (76.1% vs. 80.2% in the pandemic and pre-pandemic groups p = 0.41) . No difference was seen in the total number of arrested pregnancies (defined as the sum of biochemical, 1st trimester miscarriages, and blighted ova) (22.1 vs. 16.9% p = 0.32). A national cohort study examining administrative claims from 78,283 pregnancies also did not find an association with SAB and SARS-CoV-2 infection . Theoretical models purport a potential mechanism of implantation failure and SAB in the setting of SARS-CoV-2 infection. Sills and Woods proposed that systemic inflammation and interference with trophectoderm-endometrium molecular signalling could occur . In addition, the hypercoagulable state induced by the COVID-19 “cytokine storm” could result in a toxic endometrial environment and microthrombus formation resulting in hypoperfusion. Although research on severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) suggest an association with SAB, this has not been borne out in the literature surrounding SARS-CoV-2 infection. A meta-analysis of 27 studies of COVID-19 revealed a miscarriage rate of 15.3% (95% CI 10.94–20.59) using fixed models and 23.1% (95% CI 13.17–34.95) random effect models . Authors concluded this was within the normal population range. However, further large studies addressing rates of first trimester miscarriage in symptomatic and asymptomatic women infected with SARS-CoV-2 are needed. While literature published from data collected during the initial wave of the B.1.1.7 variant, also deemed the alpha variant, was reassuring regarding obstetrical outcomes , emerging data from subsequent waves of infection have been more concerning. Amongst women who gave birth within 28 days of a COVID-19 diagnosis, the extended perinatal mortality rate was significantly elevated at 22.6 per 1000 births (95% CI 12.9 − 38.5), as compared to the background pandemic rate of 5.6 per 1000 births (95% CI 5.1 − 6.2) . Those who were unvaccinated at the time of COVID-19 diagnosis disproportionately accounted for 77.4% (95% CI 76.2 − 78.6) of infections, 90.9% (95% CI 88.7 − 92.7) of SARS-CoV-2 associated hospital admissions and 98% (95% CI 92.5 − 99.7) of SARS-CoV-2 associated critical care admissions. While the authors could not conclude causality, there appears to be a strong correlation between COVID-19 and significant morbidity within the pregnant population. A systematic review published in the British Medical Journal revealed that pregnant women are more likely to experience severe undesirable outcomes associated with SARS-CoV-2 infection such as admission to an intensive care unit (odds ratio 2.13, 1.53 to 2.95; I 2 = 71.2%), need invasive ventilation (2.59, 2.28 to 2.94; I 2 = 0%) and need for extra corporeal membrane oxygenation (2.02, 1.22 to 3.34; I 2 = 0%) as compared to their non-pregnant counter parts . These outcomes have been replicated . Risk factors identified for severe disease included advanced maternal age, high body mass index, non-white ethnicity, vaccination status or pre-existing comorbidities. One of the leading causes of neonatal morbidity and mortality is preterm birth (PTB). Unfortunately, there appears to be a strong correlation between SARS-CoV-2 infection and PTB. In a study previously mentioned, the PTB rate increased to 16.6% (95% CI 13.7–19.8) amongst babies born within 4 weeks of maternal COVID-19 infection, as compared to the baseline rate of 7.9% (95% CI 7.7–8.1) . An association was further seen in the previously mentioned national cohort study by Regan et al. . They were able to identify a 2–threefold increased risk of induced abortion, as defined separately from spontaneous miscarriage, (adjusted hazard ratio [aHR] 2.60, 95% CI 1.17–5.78), caesarean section (aHR 1.99, 95% CI 1.71–2.31), clinician-initiated PTB (2.88; 95% CI 1.93–4.30), spontaneous PTB (aHR 1.79, 95% CI 1.37–2.34), fetal growth restriction (aHR 2.04, 95% CI 1.72–2.43), and postpartum hemorrhage (aHR 2.03, 95% CI 1.6–2.63). Maternal obstetrical disease in pregnancy also appears to be affected. A meta-analysis involving a total of 28 studies accounting for 790,954 pregnant women, of whom 15,524 were diagnosis with COVID-19, revealed an increased adjusted odds ratio (OR) of developing preeclampsia (OR 1.58; 95% CI, 1.39–1.80; P < 0.0001; I 2 = 0%) in the setting of SARS-CoV-2 infection . Additionally, there appeared to be an increased odds ratio for developing preeclampsia with severe features (OR, 1.76; 95% CI 1.18–2.63; I 2 = 58%; 7 studies), eclampsia (OR, 1.97; 95% CI 1.01–3.84; I 2 = 0%, 3 studies), and HELLP syndrome (OR, 2.10; 95% CI 1.48–2.97; 1 study). Vaccination and obstetrical outcomes Large population studies have not been able to show an increased risk of adverse obstetrical outcomes when women are vaccinated during pregnancy . Furthermore, the negative impact of SARS-CoV-2 on obstetrical outcomes may be assuaged by administration of mRNA COVID-19 vaccines. A previously cited article by Stock et al. examined the differences in obstetrical outcomes between vaccinated and unvaccinated populations. A greater proportion of infections during pregnancy was reported amongst the unvaccinated population accounting for 77.4% (3833 out of 4950; 95% CI 76.2 − 78.6) versus 11.5% (567 out of 4950; 95% CI 10.6 − 12.4) were in the partially vaccinated population and 11.1% (550 out of 4950; 95% CI 10.3 − 12.0) were fully-vaccinated . Unvaccinated individuals were more likely to require hospital admission 19.5% (748 out of 3833; 95% CI 18.3 − 20.8) versus 8.3% (47 out of 567; 95% CI 6.2 − 10.9) of partially vaccinated women and only 5.1% (28 out of 550; 95% CI 3.5 − 7.4) of the fully vaccinated population. The numbers for critical care admission were 2.7% (102 out of 3833; 95% CI 2.2 − 3.2), 0.2% (1 out of 567; 95% CI 0.01 − 1.1), and 0.2% (1 out of 550 cases; 95% CI 0.01 − 1.2), respectively. Ultimately 98.1% (102 out of 104; 95% CI 92.5 − 99.7) of critical care admissions during pregnancy occurred in those who were unvaccinated. The background rate of preterm birth during the study period was 8.0% (6381 out of 80,183 live births; 95% CI 7.8 − 8.1) and 7.9% (6083 out of 77,209 live births; 95% CI 7.7 − 8.1) amongst women without a documented SARS-CoV-2 infection. In unvaccinated women with documented infection, the PTB rate was 10.2%; 95% CI 9.1 − 11.6). This figure decreased amongst the vaccinated population to 8.6% (495 out of 5752; 95% CI 7.9 − 9.4). Similar trends were seen in the extended perinatal mortality rate. The background rate was 5.6 per 1,000 births (452 out of 80,456 total births; 95% CI 5.1 − 6.2). The extended perinatal mortality rate amongst vaccinated women was 4.3 per 1000 births (25 out of 5766 total births in women who received COVID-19 vaccination in pregnancy; 95% CI 2.9 − 6.4). Unfortunately, the extended perinatal mortality rate was 8.0 per 1,000 births following SARS-CoV-2 infection at any point in pregnancy (19 out of 2364; 95% CI 5.0 − 12.8). Of the 11 stillbirths that occurred within the study duration, all were amongst unvaccinated mothers. A recently published meta-analysis from Prasad et al. had similar findings with a 15% reduction in stillbirth . Vaccination and spontaneous abortion Many patients are concerned regarding vaccination and their risk of miscarriage. Literature has increasingly been released providing reassurance that there is no significant effect of vaccination on miscarriage rate. Among 2456 pregnant persons who received an mRNA COVID-19 vaccine preconception or prior to 20 weeks’ gestation, the cumulative risk of SAB from 6–19 weeks’ gestation was 14.1% (95% CI 12.1–16.1%) . Using direct age standardization to the selected reference population, the age-standardized cumulative risk of SAB was 12.8% (95% CI 10.8–14.8%). Authors concluded when compared to the expected range of SABs in recognized pregnancies, these data suggest receipt of an mRNA COVID-19 vaccine preconception or during pregnancy is not associated with an increased risk of SAB . Additional literature from Norway revealed that there was no statistical difference in SAB between 13,184 unvaccinated pregnancies as compared to 772 vaccinated pregnancies. The results remained non-significant once the OR was adjusted for age, country of birth, marital status, education level, household income, number of children, employment status, as well as underlying risk for COVID-19 (OR 0.91 CI 95% [0.75–1.10]) . International societies have recommended provision of COVID-19 vaccination when pregnant women are at risk of acquiring a SARS-CoV-2 infection or have suggested that vaccines should not be withheld from pregnant women where no other contraindications to vaccination exist . It is important to recognize that several existing vaccines, including those against influenza, tetanus and pertussis, have been shown to reduce both maternal and infant morbidity and mortality when used antenatally. Maternal vaccination against COVID-19 may reduce neonatal morbidity and mortality via transfer of SARS-CoV-2-specific antibodies resulting in passive immunization of the fetus . Reassuringly, preliminary research of 35,691 vaccinated pregnant patients revealed no increased incidence of preterm birth, small for gestational age, or pregnancy loss . Vaccination and fertility Despite evidence that support the safety of vaccination in pregnancy, there has been a significant hesitancy of uptake among reproductive age females, with some citing potential impacts on future fertility. This concern is so prevalent that queries in the Google Search Engine relating to the COVID-19 vaccine and fertility increased by as much as 2943.7% following the Emergency Use Authorization (EUA) approval on December 11, 2020 . Subsequent studies have explored relationships between vaccination and outcomes in assisted reproductive technology (ART). In 36 couples resuming in-vitro fertilization 7 to 85 days after receiving a mRNA SARS-CoV-2 vaccine, no between cycles differences pre and post vaccine were observed in ovarian stimulation or embryological variables . In a longitudinal study of 2126 couples living in the United States, COVID-19 vaccination was not associated with a statistical change in fecundity for either males or females . Anecdotally, patients have described menstrual irregularity coinciding with mRNA COVID-19 vaccination or SARS-CoV-2 infection. In a cohort study of 3959 individuals (vaccinated 2403; unvaccinated 1556) menstrual cycles were prospectively tracked . They collected data from the 3 cycles prior to vaccination and the 3 cycles following as compared to 6 cycles of unvaccinated individuals. They were unable to show a change in menstrual length according to vaccination status. COVID-19 vaccination did, however, result in a less than one day difference in cycle length between groups in both the first and second dose populations (first dose 0.71 day-increase, 98.75% CI 0.47–0.94; second dose 0.91, 98.75% CI 0.63–1.19). The proportion of individuals experiencing a clinically significant cycle change of 8 days (4.3% for unvaccinated vs. 5.2% for vaccinated, P = 0.181) did not differ. Looking at the data closely revealed the difference was driven by a subgroup of 358 individuals who received both vaccinations within the same cycle. They were found to have a 2.38-day cycle length increase (98.75%, CI 1.52–3.24) and the proportion of those with a clinically significant change in cycle length became statistically significant (10.6% versus 4.2%, p < 0.001). When these individuals were excluded, those receiving one dose within one menstrual cycle no longer had a statistically significant difference in cycle length. Alternatively, SARS-CoV-2 infection itself has been associated with significant differences in menstrual cycle length, typically prolongation, in 19% of women . Studies examining the effect of vaccination on sperm parameters have been reassuring, although small in participant numbers. In 45 male volunteers follow-up samples were obtained at a median of 75 days (IQR, 70–86) after the second dose of an mRNA vaccine. Of these men, 21 (46.7%) received BNT162b2 (Pfizer) and 24 (53.3%) received mRNA-1273 (Moderna). The baseline median sperm concentration and total motile sperm count (TMSC) were 26 million/mL (IQR, 19.5–34) and 36 million/mL (IQR, 18–51), respectively. After the second-vaccine dose, the median sperm concentration significantly increased to 30 million/mL (IQR, 21.5–40.5; P = 0.02) and the median TMSC to 44 million (IQR, 27.5–98; P = 0.001). Semen volume and sperm motility also significantly increased , . In another study, male semen volume count and motility were the same pre and post vaccine at the time of fertility care . Large studies are needed. COVID-19 infection and sperm parameters Due to the high concentrations of ACE-II receptors in testicular cells such as the seminiferous duct cells, spermatogonia, Leydig and Sertoli cells it has been hypothesized that an immunologic response to the virus could damage the testicle in the setting of severe infections. Specifically, through oxidative stress, DNA methylation and fragmentation. The resulting injured blood testes barrier could allow entry to the virus. Emerging research is revealing this may be true, at least in the short term. Among 2,126 couples followed longitudinally, males with self-reported COVID-19 infections had a transient reduction in fecundability within the following 60 days . The effect of the COVID- 19 pandemic on gynecological care Reproductive care was delayed in clinics globally because of the pandemic. A survey of 299 international fertility clinics, representing 228,500 IVF cycles was completed . Responses were received from clinics in Europe (34.8%), Asia (25.1%), South America (18.1%), North America (15.4%), Africa (5.3%), and Australia/New Zealand (1.3%). It was found 86.6% of respondents reported their reproductive medicine society released pandemic-specific recommendations for a complete (53.8%) or partial shutdown (23.7%). Which was higher than mandates imposed by local health authorities (32.5% and 19.7%, respectively). With respect to changes in IVF case volume: 76.6% of clinics reported a ≥ 75% reduction in fresh cycles, 80% reported a ≥ 75% reduction in frozen cycles, 73.6% reported a ≥ 75% reduction in IUI cases and 3.7% of clinics did not report any reduction in case volume. Among clinics that stopped or reduced services: 69.5% of respondents cited government-mandate as a reason for closing, 31.1% due to employer concern for the health and safety of staff, 35.4% due to patient concerns, 34% due to concerns regarding the possible effects of COVID-19 on early pregnancy and 5.3% lack of personal protective equipment. Due to the impact of COVID-19 shutdowns on the field, the POSEIDON group released recommendations that should shutdown be considered again, patients should be triaged, particularly those more vulnerable infertility cases (ex. those with advanced age and decreased ovarian reserve), patients should be stimulated, as should patients who need to undergo fertility preservation prior to medical treatments . These principles would allow for a progressive restart of fertility treatment in a field that contributes to 0.3% of the global population yearly. Historically, previous pandemics have resulted in a fertility decline. Initial research has revealed that in 7 out of 22 countries included, there was a significant decrease in birth rate due to the COVID-19 pandemic . The figures revealed a strong relationship in the countries of southern Europe such as Spain (− 8.4%), Italy (− 9.1%) and Portugal (− 6.6%). Otherwise there appeared to be heterogeneity amongst countries globally. Notably, none of the 22 countries included was seen to have a statistically significant increase in birth rates. Meanwhile, the number of gynecologic and breast cancer diagnosis decreased in the early days of the pandemic related lock-downs. Routine screening examinations and check-ups were restricted. A multi-centre trial in Austria collected data on the number of individuals diagnosed with gynecologic and breast cancer prior to the COVID-19 pandemic (January to May 2019) and after the pandemic began (January to May 2020) . When comparing March of both years, diagnosis were down by 24%, by April and May, diagnosis were down by 49%. Decreased access to routine testing resulting in postponed diagnosis of gynecologic and breast cancers. Women diagnosed during the pandemic were also found to have more advanced disease, and as such were less likely to be able to be treated surgically and more likely to require chemotherapy. Data from more regions are required.   Transmission occurs primarily through breathing-in aerosol contaminated air . Exposure to contaminated fluids encountering the eyes, nose, or mouth, and rarely via contaminated surfaces, have fallen out of favour as a means of contamination, in most cases . Droplets spread through means of coughing, sneezing, singing, and talking (particularly loudly) is the primary mechanism of contamination. It should be noted that most infected individuals have mild cases, and the rate of symptomatology varies based on the variant. However, a small but significant group of those infected will get quite ill. It is important to recognize that at least one third of infected individuals will not present with any noticeable symptoms . Unfortunately, these asymptomatic carriers tend to be untested and act as vehicles for further spread. Indeed, this is also true of those who are minimally symptomatic or develop symptoms later in the disease course, deemed “pre-symptomatic” . Through time we have come to recognize three common clusters of symptoms in those with COVID-19: (1) a respiratory symptom cluster including cough, sputum, shortness of breath, and fever; (2) a musculoskeletal symptom cluster involving myalgias and arthralgias, headache, and fatigue; and (3) a digestive symptom cluster such as abdominal pain, vomiting and diarrhea . Additional rare presentations include pericarditis, myocarditis, atrial fibrillation, congestive heart failure, encephalopathy, diabetic ketoacidosis, dehydration possibly resulting in renal failure, liver failure, as well as disseminated hypercoagulability and Kawasaki’s disease . Long-term symptoms of COVID-19 have been noted in approximately one third of infected individuals irrelevant of severity of initial presentation in one study . The World Health Organization (WHO) defines post-COVID conditions as occurring in individuals with probable or confirmed SARS-CoV-2 infection 3 months from the onset of COVID-19 symptoms, lasting for a minimum of 2 months, unexplained by another diagnosis . Alternatively, the Centre for Disease Control (CDC) definition includes symptom onset as early as 4 weeks following infection . There are clear differences in these two definitions. The WHO has included 12 domains necessary for clinical diagnosis, including: history of infection, laboratory confirmed infection, a minimum of 3 months from date of infection, greater than 2 month of symptom duration, no minimum number of symptoms, clustering of symptoms that may change in time course and nature (fluctuate, relapse, persist, be new in onset), unexplained by alternative diagnosis, impact everyday function, involve sequalae of described complications of COVID-19, and acknowledgement that different populations may require separate definitions (ex. children, pregnancy, elderly). A systematic review revealed that after 1 month 54% (IQR 45–69%) of individuals experienced a minimum of one post-COVID symptom, by 2–5 months 55% (IQR 34.8%-65.5%) experienced a minimum of one symptom, and following 6 months, that number remained stable at 54% (IQR 31–67%) . Clearly, the rate of post COVID-19 conditions varies based on the study. In the same systematic review, the most common neurocognitive symptoms included difficulty concentrating (IQR, 23.8% [20.4–25.9%]), memory deficits (IQR, 18.6% [17.3–22.9%]), and cognitive impairment (IQR, 17.1% [14.1–30.5%]). The most common mental health disorders included anxiety (IQR, 29.6% [14–44%]), sleep disorder (IQR, 27% [19.2–30.3%]), depression (IQR, 20.4% [19.2–21.5%]), and post-traumatic stress (IQR, 13.3% [7.3–25.1%]). Other commonly reported symptoms included: joint pain (IQR, 10% [6.1–19%]), fatigue or muscle weakness (IQR, 37.5% [25.4–54.5%]), and flu-like symptoms (IQR, 10.3% [4.5–19.2%]). An investigation of 309 COVID-19 patients identified 4 risk factors for developing post-acute sequelae including pre-existing type 2 diabetes, SARS-CoV-2 RNAemia (presence of circulating mRNA fragments of SARS-Co-V-2), pre-existing Epstein Barr viremia, and the creation of specific autoantibodies in response to SARS-Co-V-2 . How post COVID-19 conditions affect women differently than men in addition to how reproductive age status, menstrual cyclicity, and potential reproductive tract symptomatology alter chronic COVID-19 presentations, requires further study.   Whether symptomatic or asymptomatic COVID-19 alters spontaneous abortion (SAB) rates is not well studied. When examining miscarriage rates amongst asymptomatic women undergoing first trimester viability scans during the early months of the pandemic versus the year prior, the viable clinical pregnancy rate did not differ (76.1% vs. 80.2% in the pandemic and pre-pandemic groups p = 0.41) . No difference was seen in the total number of arrested pregnancies (defined as the sum of biochemical, 1st trimester miscarriages, and blighted ova) (22.1 vs. 16.9% p = 0.32). A national cohort study examining administrative claims from 78,283 pregnancies also did not find an association with SAB and SARS-CoV-2 infection . Theoretical models purport a potential mechanism of implantation failure and SAB in the setting of SARS-CoV-2 infection. Sills and Woods proposed that systemic inflammation and interference with trophectoderm-endometrium molecular signalling could occur . In addition, the hypercoagulable state induced by the COVID-19 “cytokine storm” could result in a toxic endometrial environment and microthrombus formation resulting in hypoperfusion. Although research on severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) suggest an association with SAB, this has not been borne out in the literature surrounding SARS-CoV-2 infection. A meta-analysis of 27 studies of COVID-19 revealed a miscarriage rate of 15.3% (95% CI 10.94–20.59) using fixed models and 23.1% (95% CI 13.17–34.95) random effect models . Authors concluded this was within the normal population range. However, further large studies addressing rates of first trimester miscarriage in symptomatic and asymptomatic women infected with SARS-CoV-2 are needed. While literature published from data collected during the initial wave of the B.1.1.7 variant, also deemed the alpha variant, was reassuring regarding obstetrical outcomes , emerging data from subsequent waves of infection have been more concerning. Amongst women who gave birth within 28 days of a COVID-19 diagnosis, the extended perinatal mortality rate was significantly elevated at 22.6 per 1000 births (95% CI 12.9 − 38.5), as compared to the background pandemic rate of 5.6 per 1000 births (95% CI 5.1 − 6.2) . Those who were unvaccinated at the time of COVID-19 diagnosis disproportionately accounted for 77.4% (95% CI 76.2 − 78.6) of infections, 90.9% (95% CI 88.7 − 92.7) of SARS-CoV-2 associated hospital admissions and 98% (95% CI 92.5 − 99.7) of SARS-CoV-2 associated critical care admissions. While the authors could not conclude causality, there appears to be a strong correlation between COVID-19 and significant morbidity within the pregnant population. A systematic review published in the British Medical Journal revealed that pregnant women are more likely to experience severe undesirable outcomes associated with SARS-CoV-2 infection such as admission to an intensive care unit (odds ratio 2.13, 1.53 to 2.95; I 2 = 71.2%), need invasive ventilation (2.59, 2.28 to 2.94; I 2 = 0%) and need for extra corporeal membrane oxygenation (2.02, 1.22 to 3.34; I 2 = 0%) as compared to their non-pregnant counter parts . These outcomes have been replicated . Risk factors identified for severe disease included advanced maternal age, high body mass index, non-white ethnicity, vaccination status or pre-existing comorbidities. One of the leading causes of neonatal morbidity and mortality is preterm birth (PTB). Unfortunately, there appears to be a strong correlation between SARS-CoV-2 infection and PTB. In a study previously mentioned, the PTB rate increased to 16.6% (95% CI 13.7–19.8) amongst babies born within 4 weeks of maternal COVID-19 infection, as compared to the baseline rate of 7.9% (95% CI 7.7–8.1) . An association was further seen in the previously mentioned national cohort study by Regan et al. . They were able to identify a 2–threefold increased risk of induced abortion, as defined separately from spontaneous miscarriage, (adjusted hazard ratio [aHR] 2.60, 95% CI 1.17–5.78), caesarean section (aHR 1.99, 95% CI 1.71–2.31), clinician-initiated PTB (2.88; 95% CI 1.93–4.30), spontaneous PTB (aHR 1.79, 95% CI 1.37–2.34), fetal growth restriction (aHR 2.04, 95% CI 1.72–2.43), and postpartum hemorrhage (aHR 2.03, 95% CI 1.6–2.63). Maternal obstetrical disease in pregnancy also appears to be affected. A meta-analysis involving a total of 28 studies accounting for 790,954 pregnant women, of whom 15,524 were diagnosis with COVID-19, revealed an increased adjusted odds ratio (OR) of developing preeclampsia (OR 1.58; 95% CI, 1.39–1.80; P < 0.0001; I 2 = 0%) in the setting of SARS-CoV-2 infection . Additionally, there appeared to be an increased odds ratio for developing preeclampsia with severe features (OR, 1.76; 95% CI 1.18–2.63; I 2 = 58%; 7 studies), eclampsia (OR, 1.97; 95% CI 1.01–3.84; I 2 = 0%, 3 studies), and HELLP syndrome (OR, 2.10; 95% CI 1.48–2.97; 1 study).   Large population studies have not been able to show an increased risk of adverse obstetrical outcomes when women are vaccinated during pregnancy . Furthermore, the negative impact of SARS-CoV-2 on obstetrical outcomes may be assuaged by administration of mRNA COVID-19 vaccines. A previously cited article by Stock et al. examined the differences in obstetrical outcomes between vaccinated and unvaccinated populations. A greater proportion of infections during pregnancy was reported amongst the unvaccinated population accounting for 77.4% (3833 out of 4950; 95% CI 76.2 − 78.6) versus 11.5% (567 out of 4950; 95% CI 10.6 − 12.4) were in the partially vaccinated population and 11.1% (550 out of 4950; 95% CI 10.3 − 12.0) were fully-vaccinated . Unvaccinated individuals were more likely to require hospital admission 19.5% (748 out of 3833; 95% CI 18.3 − 20.8) versus 8.3% (47 out of 567; 95% CI 6.2 − 10.9) of partially vaccinated women and only 5.1% (28 out of 550; 95% CI 3.5 − 7.4) of the fully vaccinated population. The numbers for critical care admission were 2.7% (102 out of 3833; 95% CI 2.2 − 3.2), 0.2% (1 out of 567; 95% CI 0.01 − 1.1), and 0.2% (1 out of 550 cases; 95% CI 0.01 − 1.2), respectively. Ultimately 98.1% (102 out of 104; 95% CI 92.5 − 99.7) of critical care admissions during pregnancy occurred in those who were unvaccinated. The background rate of preterm birth during the study period was 8.0% (6381 out of 80,183 live births; 95% CI 7.8 − 8.1) and 7.9% (6083 out of 77,209 live births; 95% CI 7.7 − 8.1) amongst women without a documented SARS-CoV-2 infection. In unvaccinated women with documented infection, the PTB rate was 10.2%; 95% CI 9.1 − 11.6). This figure decreased amongst the vaccinated population to 8.6% (495 out of 5752; 95% CI 7.9 − 9.4). Similar trends were seen in the extended perinatal mortality rate. The background rate was 5.6 per 1,000 births (452 out of 80,456 total births; 95% CI 5.1 − 6.2). The extended perinatal mortality rate amongst vaccinated women was 4.3 per 1000 births (25 out of 5766 total births in women who received COVID-19 vaccination in pregnancy; 95% CI 2.9 − 6.4). Unfortunately, the extended perinatal mortality rate was 8.0 per 1,000 births following SARS-CoV-2 infection at any point in pregnancy (19 out of 2364; 95% CI 5.0 − 12.8). Of the 11 stillbirths that occurred within the study duration, all were amongst unvaccinated mothers. A recently published meta-analysis from Prasad et al. had similar findings with a 15% reduction in stillbirth .   Many patients are concerned regarding vaccination and their risk of miscarriage. Literature has increasingly been released providing reassurance that there is no significant effect of vaccination on miscarriage rate. Among 2456 pregnant persons who received an mRNA COVID-19 vaccine preconception or prior to 20 weeks’ gestation, the cumulative risk of SAB from 6–19 weeks’ gestation was 14.1% (95% CI 12.1–16.1%) . Using direct age standardization to the selected reference population, the age-standardized cumulative risk of SAB was 12.8% (95% CI 10.8–14.8%). Authors concluded when compared to the expected range of SABs in recognized pregnancies, these data suggest receipt of an mRNA COVID-19 vaccine preconception or during pregnancy is not associated with an increased risk of SAB . Additional literature from Norway revealed that there was no statistical difference in SAB between 13,184 unvaccinated pregnancies as compared to 772 vaccinated pregnancies. The results remained non-significant once the OR was adjusted for age, country of birth, marital status, education level, household income, number of children, employment status, as well as underlying risk for COVID-19 (OR 0.91 CI 95% [0.75–1.10]) . International societies have recommended provision of COVID-19 vaccination when pregnant women are at risk of acquiring a SARS-CoV-2 infection or have suggested that vaccines should not be withheld from pregnant women where no other contraindications to vaccination exist . It is important to recognize that several existing vaccines, including those against influenza, tetanus and pertussis, have been shown to reduce both maternal and infant morbidity and mortality when used antenatally. Maternal vaccination against COVID-19 may reduce neonatal morbidity and mortality via transfer of SARS-CoV-2-specific antibodies resulting in passive immunization of the fetus . Reassuringly, preliminary research of 35,691 vaccinated pregnant patients revealed no increased incidence of preterm birth, small for gestational age, or pregnancy loss .   Despite evidence that support the safety of vaccination in pregnancy, there has been a significant hesitancy of uptake among reproductive age females, with some citing potential impacts on future fertility. This concern is so prevalent that queries in the Google Search Engine relating to the COVID-19 vaccine and fertility increased by as much as 2943.7% following the Emergency Use Authorization (EUA) approval on December 11, 2020 . Subsequent studies have explored relationships between vaccination and outcomes in assisted reproductive technology (ART). In 36 couples resuming in-vitro fertilization 7 to 85 days after receiving a mRNA SARS-CoV-2 vaccine, no between cycles differences pre and post vaccine were observed in ovarian stimulation or embryological variables . In a longitudinal study of 2126 couples living in the United States, COVID-19 vaccination was not associated with a statistical change in fecundity for either males or females . Anecdotally, patients have described menstrual irregularity coinciding with mRNA COVID-19 vaccination or SARS-CoV-2 infection. In a cohort study of 3959 individuals (vaccinated 2403; unvaccinated 1556) menstrual cycles were prospectively tracked . They collected data from the 3 cycles prior to vaccination and the 3 cycles following as compared to 6 cycles of unvaccinated individuals. They were unable to show a change in menstrual length according to vaccination status. COVID-19 vaccination did, however, result in a less than one day difference in cycle length between groups in both the first and second dose populations (first dose 0.71 day-increase, 98.75% CI 0.47–0.94; second dose 0.91, 98.75% CI 0.63–1.19). The proportion of individuals experiencing a clinically significant cycle change of 8 days (4.3% for unvaccinated vs. 5.2% for vaccinated, P = 0.181) did not differ. Looking at the data closely revealed the difference was driven by a subgroup of 358 individuals who received both vaccinations within the same cycle. They were found to have a 2.38-day cycle length increase (98.75%, CI 1.52–3.24) and the proportion of those with a clinically significant change in cycle length became statistically significant (10.6% versus 4.2%, p < 0.001). When these individuals were excluded, those receiving one dose within one menstrual cycle no longer had a statistically significant difference in cycle length. Alternatively, SARS-CoV-2 infection itself has been associated with significant differences in menstrual cycle length, typically prolongation, in 19% of women . Studies examining the effect of vaccination on sperm parameters have been reassuring, although small in participant numbers. In 45 male volunteers follow-up samples were obtained at a median of 75 days (IQR, 70–86) after the second dose of an mRNA vaccine. Of these men, 21 (46.7%) received BNT162b2 (Pfizer) and 24 (53.3%) received mRNA-1273 (Moderna). The baseline median sperm concentration and total motile sperm count (TMSC) were 26 million/mL (IQR, 19.5–34) and 36 million/mL (IQR, 18–51), respectively. After the second-vaccine dose, the median sperm concentration significantly increased to 30 million/mL (IQR, 21.5–40.5; P = 0.02) and the median TMSC to 44 million (IQR, 27.5–98; P = 0.001). Semen volume and sperm motility also significantly increased , . In another study, male semen volume count and motility were the same pre and post vaccine at the time of fertility care . Large studies are needed.   Due to the high concentrations of ACE-II receptors in testicular cells such as the seminiferous duct cells, spermatogonia, Leydig and Sertoli cells it has been hypothesized that an immunologic response to the virus could damage the testicle in the setting of severe infections. Specifically, through oxidative stress, DNA methylation and fragmentation. The resulting injured blood testes barrier could allow entry to the virus. Emerging research is revealing this may be true, at least in the short term. Among 2,126 couples followed longitudinally, males with self-reported COVID-19 infections had a transient reduction in fecundability within the following 60 days .   Reproductive care was delayed in clinics globally because of the pandemic. A survey of 299 international fertility clinics, representing 228,500 IVF cycles was completed . Responses were received from clinics in Europe (34.8%), Asia (25.1%), South America (18.1%), North America (15.4%), Africa (5.3%), and Australia/New Zealand (1.3%). It was found 86.6% of respondents reported their reproductive medicine society released pandemic-specific recommendations for a complete (53.8%) or partial shutdown (23.7%). Which was higher than mandates imposed by local health authorities (32.5% and 19.7%, respectively). With respect to changes in IVF case volume: 76.6% of clinics reported a ≥ 75% reduction in fresh cycles, 80% reported a ≥ 75% reduction in frozen cycles, 73.6% reported a ≥ 75% reduction in IUI cases and 3.7% of clinics did not report any reduction in case volume. Among clinics that stopped or reduced services: 69.5% of respondents cited government-mandate as a reason for closing, 31.1% due to employer concern for the health and safety of staff, 35.4% due to patient concerns, 34% due to concerns regarding the possible effects of COVID-19 on early pregnancy and 5.3% lack of personal protective equipment. Due to the impact of COVID-19 shutdowns on the field, the POSEIDON group released recommendations that should shutdown be considered again, patients should be triaged, particularly those more vulnerable infertility cases (ex. those with advanced age and decreased ovarian reserve), patients should be stimulated, as should patients who need to undergo fertility preservation prior to medical treatments . These principles would allow for a progressive restart of fertility treatment in a field that contributes to 0.3% of the global population yearly. Historically, previous pandemics have resulted in a fertility decline. Initial research has revealed that in 7 out of 22 countries included, there was a significant decrease in birth rate due to the COVID-19 pandemic . The figures revealed a strong relationship in the countries of southern Europe such as Spain (− 8.4%), Italy (− 9.1%) and Portugal (− 6.6%). Otherwise there appeared to be heterogeneity amongst countries globally. Notably, none of the 22 countries included was seen to have a statistically significant increase in birth rates. Meanwhile, the number of gynecologic and breast cancer diagnosis decreased in the early days of the pandemic related lock-downs. Routine screening examinations and check-ups were restricted. A multi-centre trial in Austria collected data on the number of individuals diagnosed with gynecologic and breast cancer prior to the COVID-19 pandemic (January to May 2019) and after the pandemic began (January to May 2020) . When comparing March of both years, diagnosis were down by 24%, by April and May, diagnosis were down by 49%. Decreased access to routine testing resulting in postponed diagnosis of gynecologic and breast cancers. Women diagnosed during the pandemic were also found to have more advanced disease, and as such were less likely to be able to be treated surgically and more likely to require chemotherapy. Data from more regions are required.   The literature published surrounding SARS-CoV-2 infections during pregnancy is no doubt concerning. Showing increased severity of maternal COVID-19, PTB, Preeclampsia, and neonatal morbidity and mortality. Reassuringly, the mRNA vaccines available appear to be safe for administration in pregnancy and may provide passive immunity to the neonate. Vaccine hesitancy fears amongst patients may be assuaged, with literature showing no effect on ART outcomes or SAB. Indeed, COVID-19 itself may be associated with decreased fecundity among males, at least in the short term.   