Should women undergoing in vitro fertilization treatment or who are in the first trimester of pregnancy be vaccinated immediately against COVID-19

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is far from over and, despite the rapid emergence of effective vaccines, shows no indication of coming to a quick conclusion. As of May 26, 2021, documented COVID-19 cases exceed 33 × 106 in the United States (US) and over 168 × 106 globally. Additionally, deaths attributed to COVID-19 have surpassed 590,000 in the US and approach 3.5 × 106 worldwide (1Johns Hopkins University and Medicine Coronavirus Resource Center website.https://coronavirus.jhu.edu/Date accessed: May 26, 2021Google Scholar). In the US, pregnant women are estimated to account for approximately 1% of the general population (2Jamieson D.J. Honein M.A. Rasmussen S.A. Williams J.L. Swerdlow D.L. Biggerstaff M.S. et al.H1N1 2009 influenza virus infection during pregnancy in the USA.Lancet. 2009; 374: 451-458Abstract Full Text Full Text PDF PubMed Scopus (1133) Google Scholar), whereas almost 8% of women of reproductive age are believed to be pregnant, seeking pregnancy, or up to 6 weeks postpartum at any given time (3Daniels K. Abma J.C. Current contraceptive status among women aged 15-49: United States, 2017-2019, NCHS Data Brief, No. 388. Hyattsville, MD: National Center for Health Statistics. 2020; Google Scholar). Although the overall risk of severe COVID-19 among pregnant women is relatively low for an individual patient, those who get infected and develop symptoms are at increased risk of more severe illness compared with their nonpregnant counterparts. Specifically, pregnant women with symptomatic COVID-19 demonstrate an increased risk of admission to an intensive care unit, need for mechanical ventilation, and death compared with that in symptomatic nonpregnant individuals (4Delahoy M.J. Whitaker M. O’Halloran A. Chai S.J. Kirley P.D. Alden N. Characteristics and maternal and birth outcomes of hospitalized pregnant women with laboratory-confirmed COVID-19 — COVID-NET, 13 States, March 1–August 22, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 1347-1354Crossref PubMed Google Scholar, 5Panagiotakopoulous L. Myers T.R. Gee J. Lipkind H. Kharbanda E.O. Ryan D.S. et al.SARS-CoV-2 infection among hospitalized pregnant women: reasons for admission and pregnancy characteristics—eight US health care centers, March 1–May 30, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 1355-1359Crossref PubMed Google Scholar, 6Zambrano L.D. Ellington S. Strid P. Galang R.R. Oduyebo T. Tong V.T. et al.Update: characteristics of symptomatic women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status—United States, January 22–October 3, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 1641-1647Crossref PubMed Google Scholar, 7Allotey J. Stallings E. Bonet M. Yap M. Chatterjee S. Kew T. et al.Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.Br Med J. 2020; 370: m3320Crossref PubMed Scopus (860) Google Scholar). Infection earlier in pregnancy may increase the risk of adverse fetal outcome (8Di Mascio D. Sen C. Saccone G. Galindo A. Grunebaum A. Yoshimatsu J. et al.Risk factors associated with adverse fetal outcomes in pregnancies affected by coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.J Perinat Med. 2020; 48: 950-958Crossref PubMed Scopus (82) Google Scholar). Furthermore, a recent systematic review and meta-analysis of 42 studies involving 438,548 pregnancies concluded that SARS-CoV-2 infection may be associated with increased risk of preeclampsia, preterm birth, and stillbirth (9Wei S.Q. Bilodeau-Bertrand M. Liu S. Auger N. The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis.CMAJ. 2021; 193: E540-E548Crossref PubMed Scopus (176) Google Scholar). As such, the US Centers for Disease Control & Prevention (CDC) considers pregnancy a risk factor for an increased risk of severe illness related to COVID-19 (10Centers for Disease Control and PreventionCoronavirus disease 2019 (COVID-19): people with certain medical conditions.https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.htmlDate accessed: March 27, 2021Google Scholar). Therefore, preventing disease in pregnancy, in major part through active vaccination against SARS-CoV-2, and specifically early vaccination either in the periconceptional period or first trimester, is of paramount importance to potentially reduce both maternal and fetal COVID-19–related morbidity and mortality. In general, non-live-attenuated vaccines are widely utilized and recommended in pregnancy. Maternal immunization through prenatal vaccination has improved maternal and neonatal health with regard to numerous infectious conditions (11Moniz M.H. Beigi R.H. Vaccination during pregnancy.Obstet Gynecol Surv. 2016; 71: 178-186Crossref PubMed Scopus (5) Google Scholar). Although the advantage of vaccination during pregnancy sometimes focuses on the potential fetal and infant benefit through passive immunization, the impact of severe maternal infectious disease prevention in pregnancy should not be minimized (12Swamy G.K. Beigi R.H. Maternal benefits of immunization during pregnancy.Vaccine. 2015; 33: 6436-6440Crossref PubMed Scopus (28) Google Scholar). This is especially important for respiratory disease prevention, including influenza and COVID-19, from which pregnant women are at heightened risk of adverse outcomes. Other than live-attenuated vaccines, which are relatively contraindicated in pregnancy, almost all vaccines are permissible in pregnancy (if not actively recommended, like influenza and Tdap) when the benefits are believed to outweigh the risks. The current vaccines developed and demonstrated to have significant potential for prevention of severe infection related to SARS-CoV-2 among the general population undoubtedly will in addition provide substantial benefit to pregnant individuals. This is the primary reason that the leading professional societies in women’s and reproductive health recommend that the vaccine should not be withheld from this population (13American College of Obstetricians and Gynecologists’ Immunization, Infectious Disease, and Public Health Preparedness Expert Work GroupACOG practice advisory: vaccinating pregnant and lactating patients against COVID-19.https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/12/vaccinating-pregnant-and-lactating-patients-against-covid-19Date accessed: May 23, 2021Google Scholar, 14American Society for Reproductive MedicineASRM, ACOG and SMFM issue joint statement: medical experts continue to assert that COVID vaccines do not impact fertility.https://www.asrm.org/news-and-publications/news-and-research/press-releases-and-bulletins/asrm-smfm-acog-issue-joint-statement-medical-experts-continue-to-assert-that-covid-vaccines-do-not-impact-fertility/Date accessed: March 28, 2021Google Scholar, 15Coronavirus/COVID-19 Task Force of the American Society for Reproductive MedicineASRM patient management and clinical recommendations during the coronavirus (COVID-19) pandemic: update no. 11—COVID-19 vaccination December 16.https://www.asrm.org/globalassets/asrm/asrm-content/news-and-publications/covid-19/covidtaskforceupdate11.pdfDate: 2020Date accessed: March 28, 2021Google Scholar). As of May 2021, there are currently three vaccines developed for the prevention of COVID-19 that have received Emergency Use Authorizations (EUA) by the US Food and Drug Administration (FDA). These include the messenger ribonucleic acid (mRNA) vaccines from Pfizer-BioNTech and Moderna that each requires two doses 21 and 28 days apart, respectively, along with the single-dose adenovirus-vector vaccine from Janssen BioTech Inc. (Johnson & Johnson). All have demonstrated high efficacy with regard to their clinical trial end points. In individuals with no prior evidence of SARS-CoV-2 infection, the mRNA vaccines appear to be 94%–95% effective at prevention of laboratory-confirmed COVID-19 illness (16Polack F.P. Thomas S.J. Kitchin N. Absalon J. Gurtman A. Lockart S. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine.N Engl J Med. 2020; 383: 2603-2615Crossref PubMed Scopus (6854) Google Scholar, 17Baden L.R. Sahly H.M. Essink B. Kotloff K. Frey S. Novak R. et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2021; 384: 403-416Crossref PubMed Scopus (4538) Google Scholar), meaning those who received two doses of these vaccines had a 94%–95% lower risk of contracting COVID-19 compared with a non-vaccinated control group. Similarly, the adenovirus-vector vaccine has demonstrated 66% efficacy for the prevention of all levels of disease and 85% efficacy against severe disease globally (18Centers for Disease Control and PreventionOverview of Janssen’s single-dose COVID-19 Vaccine, Ad26.COV2.S.https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-02/28-03-01/02-COVID-Douoguih.pdfDate accessed: March 28, 2021Google Scholar). These vaccines do not contain live virus; therefore, there is no real nor theoretical risk of infection related to the vaccine itself. Along these lines, the American Society of Reproductive Medicine (ASRM, formerly The American Fertility Society) Coronavirus/COVID Task Force states that “since the vaccine is not a live virus, there is no reason to delay pregnancy attempts because of vaccination administration or to defer [fertility] treatment until the second dose has been administered” (15Coronavirus/COVID-19 Task Force of the American Society for Reproductive MedicineASRM patient management and clinical recommendations during the coronavirus (COVID-19) pandemic: update no. 11—COVID-19 vaccination December 16.https://www.asrm.org/globalassets/asrm/asrm-content/news-and-publications/covid-19/covidtaskforceupdate11.pdfDate: 2020Date accessed: March 28, 2021Google Scholar). Data from the Development and Reproductive Toxicity (DART) studies regarding use of the approved vaccines are very encouraging. Animal studies demonstrated no increased adverse reproductive effects such as on female fertility or embryonic/fetal/postnatal development when these vaccines were delivered pre-mating or during early or late gestation (19United States Food and Drug AdministrationFact sheet for healthcare providers administering vaccine (vaccination providers). Emergency use authorization (EUA) of the Pfizer-BioNTech COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19).https://www.fda.gov/media/144413/downloadDate accessed: March 28, 2021Google Scholar, 20United States Food and Drug AdministrationVaccines and Related Biological Products Advisory Committee meeting December 17, 2020—FDA briefing document: Moderna COVID-19 vaccine.https://www.fda.gov/media/144434/downloadDate accessed: March 28, 2021Google Scholar, 21United States Food and Drug AdministrationFact sheet for healthcare providers administering vaccine (vaccination providers). Emergency use authorization (EUA) of the Janssen COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19).https://www.fda.gov/media/146304/downloadDate accessed: March 29, 2021Google Scholar). The theoretical concept that has grown from unclear sources about vaccines against COVID-19 being linked to infertility is wholly unfounded and has thus been discredited by leading societies in reproductive health (14American Society for Reproductive MedicineASRM, ACOG and SMFM issue joint statement: medical experts continue to assert that COVID vaccines do not impact fertility.https://www.asrm.org/news-and-publications/news-and-research/press-releases-and-bulletins/asrm-smfm-acog-issue-joint-statement-medical-experts-continue-to-assert-that-covid-vaccines-do-not-impact-fertility/Date accessed: March 28, 2021Google Scholar). It is acknowledged that there are relatively limited safety data regarding the use of COVID-19 vaccines in human pregnancy, because the vaccines currently available under the EUA have not yet been tested directly in pregnant women. However, vaccine trials have now commenced in this population. In addition, ongoing safety data that are being collected and reported from the CDC and FDA (i.e., through the Vaccine Adverse Event Reporting system [VAERS]) fail to demonstrate any adverse safety signals in regards to pregnancy outcomes or side effect profiles (22Centers for Disease Control and PreventionV-safe COVID-19 vaccine pregnancy registry.https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafepregnancyregistry.htmlDate accessed: May 26, 2021Google Scholar, 23Shimabukuro T.T. Kim S.Y. Myers T.R. Moro P.L. Oduyebo T. Panagiotakopoulous L. et al.Preliminary findings of mRNA COVID-19 vaccine safety in pregnant persons.https://www.nejm.org/doi/full/10.1056/NEJMoa2104983Date accessed: May 23, 2021Google Scholar). Specifically, the CDC has established v-safe, an active safety monitoring and surveillance smartphone-based tool for after vaccine follow-up. Participants can indicate pregnancy status and enroll in the v-safe COVID-19 vaccine registry, which provides ongoing information regarding the use of the vaccine in the periconceptional period and people who are pregnant. Pregnancy and neonatal outcomes of interest include miscarriage, stillbirth, and pregnancy complications such as preeclampsia, growth restriction, preterm birth, congenital anomalies, and neonatal death. As of May 24, 2021, almost 120,000 v-safe participants have indicated that they were pregnant at the time they received COVID-19 vaccination and over 5,000 are enrolled in the v-safe COVID-19 vaccine registry. To date, there have not been any observed safety concerns for those pregnant people enrolled in v-safe. Moreover, early data collected from over 1200 completed pregnancies in the v-safe pregnancy registry do not indicate any safety concerns with regard to pregnancy and neonatal outcomes following COVID-19 vaccination with mRNA vaccines (23Shimabukuro T.T. Kim S.Y. Myers T.R. Moro P.L. Oduyebo T. Panagiotakopoulous L. et al.Preliminary findings of mRNA COVID-19 vaccine safety in pregnant persons.https://www.nejm.org/doi/full/10.1056/NEJMoa2104983Date accessed: May 23, 2021Google Scholar) (CDC personal communication). For additional vaccine safety monitoring, the CDC and FDA comanage the VAERS, an early warning system for identifying possible safety concerns after vaccination including detection of rare adverse effects. Limited by reporting bias, VAERS is not designed to assess for causality nor is there an unvaccinated control group. Of those adverse events in pregnant women after receiving an mRNA COVID-19 vaccine that were reported to VAERS through February 28, 2021, most (70%) involved non-pregnancy-specific adverse events (local and systemic reactions) (23Shimabukuro T.T. Kim S.Y. Myers T.R. Moro P.L. Oduyebo T. Panagiotakopoulous L. et al.Preliminary findings of mRNA COVID-19 vaccine safety in pregnant persons.https://www.nejm.org/doi/full/10.1056/NEJMoa2104983Date accessed: May 23, 2021Google Scholar). Although miscarriage was the most frequently reported pregnancy-specific adverse event, the observed rate among women receiving one of the mRNA COVID-19 vaccines was 12.6% (104/827 completed pregnancies), falling well within published and expected background rates of miscarriage (23Shimabukuro T.T. Kim S.Y. Myers T.R. Moro P.L. Oduyebo T. Panagiotakopoulous L. et al.Preliminary findings of mRNA COVID-19 vaccine safety in pregnant persons.https://www.nejm.org/doi/full/10.1056/NEJMoa2104983Date accessed: May 23, 2021Google Scholar, 24American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—GynecologyACOG practice bulletin no. 200: early pregnancy loss.Obstet Gynecol. 2018; 132: e197-e207Crossref PubMed Scopus (132) Google Scholar). Despite the relatively limited data of COVID-19 vaccines in pregnant women, there are no data suggesting that the vaccines should be contraindicated in this population or in those individuals planning pregnancy. It is noted, however, that the Janssen adenovirus-vector COVID-19 vaccine has recently been associated with thrombosis with thrombocytopenia syndrome (TTS), a rare but serious condition of which most cases have occurred in nonpregnant women of reproductive age (25Shimabukuro T. Thrombosis with thrombocytopenia syndrome (TTS) following Janssen COVID-19 vaccine. Advisory Committee on Immunization Practices (ACIP). Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04-23/03-COVID-Shimabukuro-508.pdf. Accessed May 23, 2021.Google Scholar). A thorough review of these cases by the Advisory Committee on Immunization Practices was performed, after which recommendations for the use of the Janssen COVID-19 vaccine were reaffirmed (49Centers for Disease Control and PreventionInterim clinical considerations for use of COVID-19 vaccines currently authorized in the United States.https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.htmlDate accessed: April 30, 2021Google Scholar). Women of reproductive age and those who are pregnant can receive any available FDA-authorized COVID-19 vaccine with appropriate counseling regarding the rarity and risk of TTS following receipt of the Janssen COVID-19 vaccine (approximately seven out of every one million doses to females 18-49 years) (25Shimabukuro T. Thrombosis with thrombocytopenia syndrome (TTS) following Janssen COVID-19 vaccine. Advisory Committee on Immunization Practices (ACIP). Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04-23/03-COVID-Shimabukuro-508.pdf. Accessed May 23, 2021.Google Scholar), and should be aware of other COVID-19 vaccines available (13American College of Obstetricians and Gynecologists’ Immunization, Infectious Disease, and Public Health Preparedness Expert Work GroupACOG practice advisory: vaccinating pregnant and lactating patients against COVID-19.https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/12/vaccinating-pregnant-and-lactating-patients-against-covid-19Date accessed: May 23, 2021Google Scholar). In general, the available vaccines against COVID-19 appear to be relatively safe and highly effective in preventing severe illness, and there is no evidence to date that COVID-19 vaccination in the periconception or prenatal period is associated with increased reproductive, pregnancy, or neonatal adverse outcomes compared with background rates. In this vein, it is recommended that patients undergoing fertility treatment receive vaccination when eligible (15Coronavirus/COVID-19 Task Force of the American Society for Reproductive MedicineASRM patient management and clinical recommendations during the coronavirus (COVID-19) pandemic: update no. 11—COVID-19 vaccination December 16.https://www.asrm.org/globalassets/asrm/asrm-content/news-and-publications/covid-19/covidtaskforceupdate11.pdfDate: 2020Date accessed: March 28, 2021Google Scholar), either in the periconceptional period or early pregnancy, while adhering to guidance set forth by the ASRM Coronavirus/COVID-19 Task Force to avoid vaccination within three days before or after an elective surgical or fertility-related procedure such as oocyte retrieval, embryo transfer, or intrauterine insemination (26Coronavirus/COVID-19 Task Force of the American Society for Reproductive MedicineASRM patient management and clinical recommendations during the coronavirus (COVID-19) pandemic: upate no. 13—variants, vaccines, and vaccination February 22, 2021.https://www.asrm.org/globalassets/asrm/asrm-content/news-and-publications/covid-19/covidtaskforceupdate13.pdfDate accessed: March 28, 2021Google Scholar). This guideline regarding timing considerations is important because known common side effects of vaccines (fever, chills, myalgia, fatigue, etc.) could confuse possible perioperative evaluation for complications, and many facilities may not allow patients to enter or proceed with procedures if they have COVID-like symptoms, which can be similar to the side effects of vaccines. The decision to receive the vaccine while undergoing in vitro fertilization (IVF) treatment or early in pregnancy should not be weighed solely against the theoretical and “unknown” risk of the vaccine itself, but more so within the context of the real increased risk of adverse outcomes associated with severe COVID-19 illness while pregnant and the known ability of the vaccines to prevent disease. Any delay in taking the vaccine would facilitate pregnant women to incur the risks of contracting and experiencing severe illness and adverse outcomes related to COVID-19 infection, including maternal and fetal death. Delaying vaccination while undergoing fertility treatment could lead to an unknown period of delay as fertility and IVF treatments are often not successful on the first attempt and may require numerous attempts to achieve an ongoing pregnancy. Treatment success relies on numerous variables, and despite the clinical team’s best attempts, cannot always be predicted. Of those patients who conceive a successful pregnancy, time to pregnancy after initiation of fertility treatment could be 8–12 months (27Reindollar R.H. Regan M.M. Neumann P.J. Levine B.S. Thornton K.L. Alper M.M. et al.A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial.Fertil Steril. 2010; 94: 888-899Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 28Goldman M.B. Thornton K.L. Ryley D. Alper M.M. Fung J.L. Hornstein M.D. et al.A randomized clinical trial to determine optimal infertility treatment in older couples: the Forty and Over Treatment Trial (FORT-T).Fertil Steril. 2014; 101: 1574-1581.e1Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar) or longer. Some patients will not ever conceive. Therefore, given the uncertainty surrounding treatment success, it is reasonable to recommend vaccination once eligibility criteria are met and “at the soonest possible time, whether pre-conception or during pregnancy”, as supported by ASRM (26Coronavirus/COVID-19 Task Force of the American Society for Reproductive MedicineASRM patient management and clinical recommendations during the coronavirus (COVID-19) pandemic: upate no. 13—variants, vaccines, and vaccination February 22, 2021.https://www.asrm.org/globalassets/asrm/asrm-content/news-and-publications/covid-19/covidtaskforceupdate13.pdfDate accessed: March 28, 2021Google Scholar). In addition, there is likely some flexibility with regard to scheduling the vaccine if a patient is in an active treatment cycle, to avoid the 6-day window surrounding a possible procedure, or, there may be the luxury of scheduling the start of a fertility treatment cycle around first and, if needed, second vaccine doses. Additionally, as opposed to other vaccines, the vaccines against SARS-CoV-2 are still serving as a relatively scarce resource and may not always be readily available to specific populations at any given time. Electing to delay vaccination may mean it is not readily available in the future. Fever, a common side effect of any vaccine, is reported in up to 9% and 16% of individuals after the single dose of the Janssen vaccine (29United States Food and Drug AdministrationVaccines and Related Biological Products Advisory Committee meeting 26 February 2021: COVID-19 vaccine Ad26.COV2.S VAC31518 (JNJ-78436735) sponsor briefing document.https://www.fda.gov/media/146219/downloadDate accessed: March 28, 2021Google Scholar) or final dose of both mRNA vaccines, respectively (20United States Food and Drug AdministrationVaccines and Related Biological Products Advisory Committee meeting December 17, 2020—FDA briefing document: Moderna COVID-19 vaccine.https://www.fda.gov/media/144434/downloadDate accessed: March 28, 2021Google Scholar, 30United States Food and Drug AdministrationVaccines and Related Biological Products Advisory Committee meeting December 10, 2020—FDA briefing document: Pfizer-BioNTech COVID-19 vaccine.https://www.fda.gov/media/144245/downloadDate accessed: March 28, 2021Google Scholar). Fever may be of concern in early pregnancy because of an observed association with congenital anomalies (31Dreier J.W. Andersen A.M. Berg-Beckhoff G. Systematic review and meta-analyses: fever in pregnancy and health impacts in the offspring.Pediatrics. 2014; 133: e674-e688Crossref PubMed Scopus (100) Google Scholar), especially neural tube defects, but this association was not observed in a recent, large cohort study (32Sass L. Urhoj S.K. Kjaergaard J. Dreier J.W. Strandberg-Larsen K. Nybo Andersen A.M. Fever in pregnancy and risk of congenital malformations: a cohort study.BMC Pregnancy Childbirth. 2017; 17: 413Crossref PubMed Scopus (36) Google Scholar). In addition, a causal relationship is challenging to construct because of retrospective study designs, reporting bias, inconsistency of reported degree/duration of fever, and the fact that fever is typically caused by a response to an underlying infection, and therefore any association with congenital anomalies would need to distinguish the effects of fever itself from those related to an underlying infection. Furthermore, any association between hyperthermia and congenital anomalies appears to be mitigated in the setting of adequate folic acid intake (31Dreier J.W. Andersen A.M. Berg-Beckhoff G. Systematic review and meta-analyses: fever in pregnancy and health impacts in the offspring.Pediatrics. 2014; 133: e674-e688Crossref PubMed Scopus (100) Google Scholar, 33Kerr S.M. Parker S.E. Mitchell A.A. Tinker S.C. Werler M.M. Periconceptional maternal fever, folic acid intake, and the risk for neural tube defects.Ann Epidemiol. 2017; 27: 777-782.e1Crossref PubMed Scopus (24) Google Scholar) and single-agent acetaminophen use (34Feldkamp M.L. Meyer R.E. Krikov S. Botto L.D. Acetaminophen use in pregnancy and risk of birth defects: findings from the National Birth Defects Prevention Study.Obstet Gynecol. 2010; 115: 109-115Crossref PubMed Scopus (78) Google Scholar). The observed fevers after vaccination to COVID-19 are short-lived, and taking acetaminophen for alleviation is recommended (13American College of Obstetricians and Gynecologists’ Immunization, Infectious Disease, and Public Health Preparedness Expert Work GroupACOG practice advisory: vaccinating pregnant and lactating patients against COVID-19.https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/12/vaccinating-pregnant-and-lactating-patients-against-covid-19Date accessed: May 23, 2021Google Scholar) without any perceived risk, advice with which most pregnant women will comply. In conclusion, contraction of SARS-CoV-2 during pregnancy may have devastating maternal and fetal outcomes. Further, emerging data suggest vaccination may lead to maternal antibody transmission to the fetus providing potential protection against infant infection (35Gray K.J. Bordt E.A. Atyeo C. Deriso E. Akinwunmi B. Young N. et al.COVID-19 vaccine response in pregnant and lactating women: a cohort study.Am J Obstet Gynecol. 2021; (2021.03.07.21253094)Abstract Full Text Full Text PDF Scopus (283) Google Scholar). Current safety data surrounding the vaccines against COVID-19 are reassuring and do not indicate safety concerns for individuals who are planning pregnancy or are in the first trimester, while at the same time demonstrate high efficacy in the general population. For those patients undergoing IVF treatment or in early pregnancy, it is in their best interests to strongly consider vaccination once eligible, and sooner rather than later, as they may incur the risk of severe COVID-related illness and associated morbidity and mortality the longer they wait. In this past year, we have seen an unprecedented accomplishment of science—the rapid development, testing, and emergency use authorization (EUA) of highly effective COVID-19 vaccines, including those using novel mRNA and viral vector technologies. Concurrently, we have seen systemic social upheaval and heightened consciousness to provide equal rights and opportunities to all Americans regardless of race, gender, sexual orientation, socioeconomic status, etc. In this regard, we have not seen one woman who is pregnant enrolled in the initial clinical trials used to obtain EUA of COVID-19 vaccines by the US Food and Drug Administration (FDA), despite the propensity for more serious manifestations of COVID-19 in this population. This exclusion represents systemic discrimination against women unfairly stigmatized by the natural and physiologic condition of pregnancy and has led to an inability to gather key safety and efficacy data for COVID-19 vaccines in an at-risk population. Medical recommendations for vaccination of women who are pregnant ideally should be subject to the same rigid scrutiny and evidence as recommendations for vaccination in other adults. Thus far, this has not been the case for COVID-19 vaccines. A universal recommendation for COVID-19 vaccination in pregnancy cannot be made without acknowledging crucial gaps in scientific knowledge. The chief argument here is not for the systemic exclusion of women who are pregnant from COVID-19 vaccination but rather the systemic inclusion of women who are pregnant in the studies of pandemic vaccines, so that data-driven vaccine recommendations can be made in the future. The ethical conduct of human medical research in the US is guided by the Federal Policy for the Protection of Human Subjects or the “Common Rule”. The Common Rule, which was first issued in 1981, is part of the Code of Federal Regulations (CFR). The CFR is published by the executive branch of the government, specifically the Department of Health and Human Services, and then codified in separate regulations by 15 Federal departm