key: cord-1036851-zy5gy1or authors: Hsu, Albert L; Johnson, Traci; Phillips, Lynelle; Nelson, Taylor B title: Sources of Vaccine Hesitancy: Pregnancy, Infertility, Minority Concerns, and General Skepticism date: 2021-08-18 journal: Open Forum Infect Dis DOI: 10.1093/ofid/ofab433 sha: 36baa6106d439e86fdb3cee3cea2edc739b1b7bb doc_id: 1036851 cord_uid: zy5gy1or The COVID-19 epidemic continues to evolve, with variants of concern and new surges of COVID-19 noted over the past months. The limited data and evolving recommendations regarding COVID-19 vaccination in pregnancy have led to some understandable hesitancy among pregnant individuals. On social media, misinformation and unfounded claims linking COVID-19 vaccines to infertility are widespread, leading to vaccine skepticism among many men and women of reproductive age. The disproportionate impact of COVID-19 on communities of color, coupled with the unfortunate and troubled history of abuses of African Americans by the biomedical research community in the US, has also led to hesitancy and skepticism about the COVID-19 vaccines among some of our most vulnerable. The complex nature of vaccine hesitancy is evidenced by further divides between different demographic, political, age, geographical, and socioeconomic groups. Better understanding of these concerns is important in the individualized approaches to each patient. M a n u s c r i p t There are many sources of vaccine hesitancy surrounding the vaccines. This is not a new phenomenon. We have seen misinformation 1 and debate surrounding influenza and other thimerosal-containing vaccinations for decades, regardless of an abundance of evidence showing their safety and lack of connection to autism or infertility, or other detrimental effects. Early on, there was some public concern 2 about the rapidity with which the COVID-19 vaccines were studied and manufactured under "Operation Warp Speed." As we have transitioned from a time of severe COVID-19 vaccine scarcity, to a time of more-abundant vaccines and public health concerns about vaccine skepticism, we wish to outline some specific sources of vaccine hesitancy, including evolving recommendations on the COVID-19 vaccination in pregnancy, misinformation about infertility and the COVID- 19 vaccines, concerns about American medicine in general (and the COVID-19 vaccine specifically) among Communities of Color, and general vaccine skepticism and hesitancy. The United States Centers for Disease Control and Prevention (CDC) has noted that there are minimal data on the safety of COVID-19 vaccines in pregnant women, that animal developmental and reproductive toxicity (DART) studies are ongoing, and that studies in humans are ongoing. 3 There was also concern about the novel mRNA technology 4 used to create the Pfizer BNT162b2 and Moderna mRNA 1273 vaccines. While mRNA vaccines have been studied for many years in both oncology and A c c e p t e d M a n u s c r i p t infectious disease, they have been implemented on a large scale for the first time to address this pandemic. The mRNA vaccines are not live vaccines, they do not enter the nucleus of the cell, and they are degraded quickly by normal cellular processes. 4, 5 Therefore, as with other inactivated vaccines, there is no credible, biologically plausible mechanism for interference with pregnancy or fertility. Data supporting the safety of COVID-19 vaccines in pregnancy continue to emerge. As of June 2021, there have been over 128,000 pregnant individuals who have received COVID-19 vaccines, as reported in the CDC's "V-safe after-vaccination health checker." 6 Based on available information, no specific safety signals have been observed in pregnant people who have received a COVID-19 vaccine and enrolled in Vsafe; however, longitudinal follow-up is still needed. Worldwide experience on the COVID-19 vaccines in pregnancy have also yet to identify any signals for concern, although data remains preliminary. Globally, many pregnant individuals report being receptive to COVID-19 vaccination; however, hesitancy is higher among pregnant persons in the US as compared to many other countries. 7 Given the concerns about severe COVID-19 disease in pregnancy [8] [9] [10] [11] and early reports of an increased risk of preterm birth in pregnant women who have COVID-19, 8 the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal Fetal Medicine (SMFM) have stated that COVID-19 vaccines "should not be withheld from pregnant individuals," and that "routine testing for pregnancy prior to receipt of a COVID-19 vaccine is not recommended." 12 While the World Health A c c e p t e d M a n u s c r i p t Organization had also initially recommended against one of the COVID-19 vaccines during pregnancy, the WHO revised their statement in late January: "While pregnancy puts women at higher risk of severe COVID-19, very little data are available to access vaccine safety in pregnancy. Nevertheless, based on what we know about this kind of vaccine, we don't have any specific reason to believe there will be specific risks that would outweigh the benefits of vaccination for pregnant women. For this reason, those pregnant women at high risk of exposure to SARS-CoV-2 (e.g. health workers) or who have comorbidities which add to their risk of severe disease, may be vaccinated in consultation with their healthcare provider." 13 In the absence of clear safety data or firm recommendations for vaccination, and with widespread misinformation on social media, many pregnant women have been understandably concerned about the unknown long-term effects of the COVID-19 vaccines in pregnancy. ACOG further stated that "pregnant women who decline the COVID-19 vaccine should be supported in their decision," that in the interest of patient autonomy, ACOG recommends that pregnant individuals be free to make their own decision regarding COVID-19 vaccination," and that "regardless of their decision to receive or not receive the vaccine, these conversations provide an opportunity to remind patients about the importance of other prevention measures such as hand-washing, physical distancing, and wearing a mask." 12 ACOG and SMFM recommend individual discussions and shared decision-making, with considerations for COVID-19 vaccination during pregnancy to include the level of COVID-19 transmission in the community, an individual's personal risk of contracting COVID-19, comorbidities associated with A c c e p t e d M a n u s c r i p t disease severity, the risks of COVID-19 to the pregnant person and the potential risks to the fetus, the efficacy and known side effects of the vaccine, and the lack of data about the vaccine during pregnancy. What to make of such conflicting and confusing recommendations? With each patient, we review misconceptions as well as new evidence regarding the vaccine and pregnancy, and we evaluate each patient's individual risk. In populations that have been heavily impacted by the pandemic (e.g. Native Americans), it is quite likely that the benefit of the COVID-19 vaccine outweighs the risk. Since many patients develop fevers after one or both doses of the mRNA vaccines, it had previously been considered reasonable to wait until after the first trimester to avoid prolonged fever during early fetal development. If fevers occur, acetaminophen is recommended and safe in pregnancy. 12 In summary, if a pregnant patient is very concerned about acquiring COVID-19 disease (or getting a re-infection), especially given the increased circulation of COVID-19 "variants of concern," it would be reasonable to get the COVID-19 vaccine. However, if a patient is nervous about the COVID-19 vaccine during pregnancy (given the lack of long-term safety data in pregnancy on the fetus or child), it was considered reasonable to defer the COVID-19 vaccine until after pregnancy. Regardless, both groups should be encouraged to remain vigilant about other mitigation strategies to prevent infection, especially while variant strains circulate widely. The Delta (B.1.617.2) variant of SARS-CoV-2 carries several new mutations, 14 appearing first 15 in India last December, and now continuing to evolve and move M a n u s c r i p t throughout the United States. Amid the skyrocketing number 16 of COVID-19 cases in the country, mostly due to Delta variant, the American College of Obstetricians and Gynecologists (ACOG) revised and updated 17, 18 its guidance on 30 July 2021 to state that:  ACOG strongly recommends that all eligible persons receive a COVID-19 vaccine or vaccine series. Obstetrician-gynecologists and other women's health care practitioners should lead by example by being vaccinated and encouraging eligible patients to be vaccinated as well.  ACOG recommends that pregnant individuals be vaccinated against COVID-19.  ACOG recommends that lactating individuals be vaccinated against COVID-19." ACOG and SMFM state that "unfounded claims linking COVID-19 vaccines to infertility have been scientifically disproven. ACOG recommends vaccination for all eligible people who may consider future pregnancy." The American Society for Reproductive Medicine (ASRM) also specifically states that the mRNA vaccines "are not thought to cause an increased risk of infertility, first or second trimester loss, stillbirth, or congenital anomalies." 19 But where did these unfounded claims linking COVID-19 vaccines to infertility emerge? In a recent manuscript, 20 two of us (ALH and TN) outlined some of the misinformation and disinformation that has resulted in significant vaccine hesitancy among women with infertility or presenting with preconception concerns. Misinformation is defined as "false or inaccurate information, especially that which is deliberately intended to deceive." In contrast, disinformation is defined as "false information which is intended to mislead, especially propaganda issued by a government organization to a rival power or the media." A c c e p t e d M a n u s c r i p t Upon a review of the relevant social media, a former Pfizer scientist was noted to have raised the concern that the COVID-19 vaccine may somehow result in female infertility by inducing an autoimmune reaction against the syncytin-1 protein, which is involved in placenta formation. This concern was raised because of the "apparent homology between this viral spike glycoprotein and syncytin-1, a cell-cell fusion protein which is critical for placental development; they further allege that antibodies against the COVID-19 spike glycoprotein could potentially cross-react with syncytin-1, potentially leading to anti-placental antibodies and female infertility." 20 However, there is no significant sequence homology between the SARS-CoV-2 spike protein and syncytin-1 protein, and the initial "claim was based on a tiny sequence of five amino acids, four of which are reportedly shared between syncytin-1 and the SARS-CoV-2 spike protein," a sequence too short to result in autoimmunity due to placental antibodies. 20, 21 Unfounded claims about the COVID-19 vaccines and both female and male infertility have been dismissed by multiple expert organizations, including CDC, 22 ASRM, 19, 21 and ACOG/SMFM. 12 Currently, there is no credible, biologically plausible mechanism by which either COVID-19 disease or the COVID-19 vaccines may negatively impact female fertility. [19] [20] [21] From the male perspective, there may be some potential concern about COVID-19 disease and male reproductive function; specifically, there may be a negative impact of A c c e p t e d M a n u s c r i p t COVID-19 disease on testicular function, sperm production, male sex hormone function, and male fertility. 20 Indeed, orchitis and testicular pain are among the many side effects of the COVID-19 diseaseand so for any male individual who is concerned about his fertility relative to COVID-19, the preponderance of evidence suggests that getting the COVID-19 vaccine would be better than getting COVID-19 itself. 20 Given that the COVID-19 pandemic in the U.S. is now being called "a pandemic of the unvaccinated," 21 mostly due to the Delta variant, the American Society for Reproductive Medicine (ASRM) also issued an update 21 on 23 July 2021 to state that:  "COVID19 vaccination does not impact male or female fertility or fertility treatment outcomes.  Existing data suggest COVID19 vaccination during pregnancy does not increase risk of miscarriage.  COVID19 vaccination does not induce antibodies against the placenta.  None of the currently available COVID-19 vaccines reach or cross the placenta. The intramuscularly administered vaccine mRNA remains in the deltoid muscle cell cytoplasm for just a few days before it is destroyed. However, protective antibodies to COVID19 have been shown to cross the placenta and confer protection to the baby after delivery.  Reproductive endocrinologists should discuss COVID-19 vaccination with all patients and encourage vaccination for all patients during evaluation and treatment for infertility. Vaccination either pre-conception or early during pregnancy is the best way to reduce maternal/fetal complications. Physician counseling has been shown to have significant positive impact on patient willingness to consider vaccination." American medicine in general) There are a variety of factors behind the underlying disparities in underrepresented communities of color. Independent of the pandemic, and compared with non-Hispanic Whites, we know that Blacks aged 18-49 are twice as likely to die from heart disease, 25 Blacks aged 35-64 are 50% more likely to have high blood pressure, 25 while Native Nations have a life expectancy that is 5.5 years less than all other races (with mortality often linked to diabetes, cirrhosis, and liver disease). 26 We know that there are also significant disparities in women's health. Black women have a 3-fold higher risk of A c c e p t e d M a n u s c r i p t maternal mortality than White women in Missouri. 27 Black women with ovarian, endometrial, and cervical cancer also had worse 5-year survival compared to other groups. To help understand the full impact of the pandemic on minority communities, the American Medical Association has encouraged HHS to make available all COVID-19 race and ethnicity data. 28 As a medical community, our emphasis has been on acknowledging inequities, ensuring access to care and testing, providing community resources, and data collection. However, pre-existing medical conditions are just one piece of the puzzle. The question that often arises is, "What could explain these disproportionate outcomes?" Quite plainly, "Why do Blacks seem to do so much worse?" Researchers in social sciences have attempted to answer this question for decades and many theories have been debunked, namely genotypic variance such as the "slavery hypertension hypothesis." 29 Meanwhile, shameful episodes in American biomedical research include the abusive Tuskegee syphilis study, the atrocities of J. Marion Sims' effort to advance his surgical techniques via medical experiments on enslaved Black women without anesthesia, 30 and research on Henrietta Lax and her children without their consent. In addition, research by Dr. Arline Geronimus and many others document that Blacks experience higher levels of allostatic stress over their lifetimes, leading dysregulated stress responses, chronic inflammation, and accelerated aging. 31 Allostatic load is a term coined by Dr. Bruce McEwen, referring to "the wear and tear on the body" which accumulates as an individual is exposed to repeated or chronic stress (such as A c c e p t e d M a n u s c r i p t microaggressions). 32 In the literature, a direct link has been made from allostatic load to morbidity and mortality for Blacks, and especially Black women; this is the principal theory for why this population fares poorly with a diversity of clinical syndromes including cardiovascular disease, malignancy, autoimmune disease, and sepsis. 32, 33 The health of black women begins to deteriorate in early adulthood as a physical consequence of socioeconomic disadvantage. This "impact of dealing with disadvantage throughout the life course wears down the body's organs and tissues, particularly the cardiovascular system, causing advanced health deterioration and early death," 33 vaccine scarcity this past winter. We applaud the efforts of our state and federal governments, in implementing a multi-pronged effort including mass vaccination events, hospital distribution, a big push for state vaccinators, and federal distribution through pharmacies and federally-qualified health centers. There has also been widespread concern about the ability and capacity of getting vaccine into underrepresented rural 37 and urban communities. In our state, the University of Missouri's Extension Service CARES program has been publishing "story maps" to help elucidate where the greatest need for COVID-19 vaccines exist; this dashboard provides a snapshot of COVID-19 cases in Missouri, as well as "vulnerability indicators" for counties within Missouri. 38 In recent weeks, we have unfortunately seen a substantial rise in case numbers in several of our rural communities, which has been echoed in areas with low vaccination rates across the US. A c c e p t e d M a n u s c r i p t Vaccine hesitancy is complex and multifactorial, 39 and we have seen a divide in attitudes towards the pandemic in general as well as vaccination efforts in many different groups. In a recent survey 40 that concern is higher about getting COVID among those who have been vaccinated than among those who haven't indicates how difficult it will be to get many of these remaining Missourians vaccinated." While hesitancy rates have decreased over time, some who have been staunchly against COVID vaccination have not changed their opinions. 39, 40 Conclusion: Hopefully, many of those who have opted not to get the vaccine are a "slow yes" rather than a "hard no." We are aware of many individuals who contracted COVID-19 over the past year, and who had opted to delay receiving the vaccine during a time of limited vaccine supply; indeed, the CDC also previously indicated that it would be reasonable to defer the COVID-19 vaccine within the first 90 days after being infected with SARS-CoV-2. With vaccines now widely available to willing recipients in the US, we Hospital Association states that "Ultimately, the more information residents have regarding the vaccine, the more likely they are to be vaccinated. This information is best communicated by providers, especially their primary care physicians." As case numbers due to emerging COVID-19 variants continue to rise globally, predominantly in unvaccinated populations here in the US, it will be incumbent upon all of us to address continued vaccine hesitancy and skepticism in the coming months and years. Increasing exposure to antibodystimulating proteins and polysaccharides in vaccines is not associated with risk of autism Attitudes Toward a Potential SARS-CoV-2 Vaccine : A Survey of U.S. Adults What Clinicians Need to Know about the Pfizer-BioNTech COVID-19 Vaccine Understanding mRNA COVID-19 Vaccines mRNA vaccines -a new era in vaccinology V-safe COVID-19 Vaccine Pregnancy Registry COVID-19 vaccine acceptance among pregnant women and mothers of young children: results of a survey in 16 countries Pregnant People -at increased risk for severe illness from COVID-19 COVID-NET Surveillance Team. Characteristics and Maternal and Birth Outcomes of Hospitalized Pregnant Women with Laboratory-Confirmed COVID-19 -COVID-NET, 13 States Characteristics of Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status -United States Meaney-Delman D; CDC COVID-19 Response Pregnancy and Infant Linked Outcomes Team Vaccinating Pregnant and Lactating Patients Against COVID-19 by the American College of Obstetricians and Gynecologists, at Vaccinating Pregnant and Lactating Patients Against COVID-19 | ACOG by the World Health Organization, at The Moderna COVID-19 (mRNA-1273) vaccine: what you need to know SARS-CoV-2 Variant Classifications and Definitions" by the US Centers for Disease Control and Prevention Variants of the Virus" by the US Centers for Disease Control and Prevention New COVID-19 Cases Worldwide Making a Strong Recommendation for COVID-19 Vaccination, by the American College of Obstetricians and Gynecologists (ACOG) ACOG and SMFM Recommend COVID-19 Vaccination for Pregnant Individuals" press release December 16, 2020 by the American Society for at: