There is no vaccine equity without gender equity

By Ilana Ambrogi, MD, PhD
Postdoc - PPGBIOS/Fiocruz - Epidemic EthicsSenior Research Analyst at Anis – Institute of Bioethics (Brazil)
ORCID: 0000-0003-2886-4284.
 
The well-founded plausibility and logical assumption that an emerging lethal respiratory infectious disease would likely, and now verifiably aggravate risks during pregnancy has somehow been insufficient to guarantee the inclusion of pregnant women (1) in vaccine clinical trials (2). Even after early alerts of the negative and deadly outcomes of COVID-19 during pregnancy, pregnant women continued to be excluded from ongoing vaccine trials. It was only after some COVID-19 vaccines were already available for the general population and almost a year after the pandemic started that their inclusion happened (3). It is relevant to mention that vaccination during pregnancy is not a novelty. It is a known and recommended practice linked to improved health outcomes as seen with influenza and Tdap vaccines (4). This raises the question of why unproven interventions with improbable effectiveness and known risks such as hydroxychloroquine / chloroquine or ivermectin have been considered for “compassionate use” (5), but the inclusion of pregnant women into vaccine trials has been perceived as an insurmountable barrier even in the face of the most tragic outcomes of an emerging disease?
 
By the time the COVID-19 pandemic was officially announced in early 2020, there was already extensive evidence demonstrating that pregnant women are disproportionally affected during public health emergencies. Zika, Ebola, H1N1 influenza are recent infectious disease outbreaks that significantly impacted pregnant women (6). It is also indisputable that vaccines and vaccination are essential ways to prepare and respond to an emerging lethal infectious disease. Yet, pregnant women continue to be persistently and categorically excluded from vaccine trials. During the pandemic, pregnant women were not initially included in clinical trials for COVID-19 vaccines, leading to several concerns and significant delays in their access to immunization against the new lethal threat (7). The exclusion from clinical trials led to lack of evidence and created further barriers to the care and protection of those who were or could get pregnant, further endangering them.
 
It is no novelty that respiratory infectious diseases such as the flu as well as inflammatory airway disease processes like asthma are important when considering pregnancy wellness. It is well established that they can lead to adverse outcomes including maternal mortality and risks to the newborn and fetus (8). Some early studies stating that COVID-19 was not associated with adverse pregnancy outcomes or that those who are pregnant were not at an increased risk for severe COVID-19 needed to be treated with caution, given their implausibility (9). Of course scientific knowledge is an ever evolving body of verifiable truths and new information can challenge and dismantle old knowledge. However, SARS-CoV-2 was identified after a cluster of pneumonia cases in late 2019, hence there was never a doubt that the emerging disease severely affected the respiratory system. Unsurprisingly, findings indicating the dangers of COVID-19 during pregnancy did not take long to appear and in August of 2020, The Pan American Health Organization/ World Health Organization sent out an alert given data showing the increased risks of COVID-19 during pregnancy (10). Nonetheless, pregnant women to this day still face barriers to obtain COVID-19 vaccines (11). 
 
The argument that pregnant women should be excluded from trials to protect them is insufficient for at least two main reasons. First, systematic and categorical exclusions of pregnant women become a discriminatory practice when they do not take into account the morbidity and mortality of the emerging disease in this population. Equating the interests of pregnant women to just the interests associated with the pregnancy itself, is a reductionist and gender biased way of treating women which has limited their access to the potential, and now proven, benefits of COVID-19 vaccine research. Even if the outcomes of early clinical research on COVID-19 vaccines were different and they were later found to cause some sort of harm, there are no grounds to argue that pregnancy should preclude someone from the potential benefits of scientific discovery in the setting of an unknown novel lethal emerging disease. To say so would be to argue for a limited autonomy given pregnancy which is an ethical as well as human rights violation.
 
Second, exclusion from trials places pregnant women in an even more vulnerable situation. They are a high-risk group where evidence-based interventions are historically very limited (12). A critical and known consequence of this “cycle of exclusion” is that it widens knowledge gaps regarding pregnancy care (13). In real life, leaving pregnant women gravely affected by COVID-19 leaves no other option but to rely on “off label use” or “compassionate use” of suggested interventions with similar potential risks and unknowns, in a situation where one’s sickness further deepens their context of vulnerability and jeopardizes their agency and choices. It is an ethical decision, therefore; and one that reduces the options offered to those who are knowingly pregnant. Consequently, given the predictable and known potentiation of vulnerabilities and risks, pregnant women should be a priority when conducting research into preventative measures, such as vaccines, and never categorically excluded.
 
Preprints and publications which contradict well-established evidence regarding the pathophysiology of respiratory infections during pregnancy should draw the urgent attention of scientists, health professionals and bioethicists, given the harm they can cause in contexts where there are significant knowledge gaps and urgency to develop solutions. The anguish-filled moments of trying to discover more about a pandemic pathogen demands careful ethical assessment. Desperation, the will to be (or not) true, or other unfounded beliefs, cannot trump scientific methodology, plausibility, and the guarantee of human rights. “Limited in-vitro and anecdotal clinical data” (14) does not constitute evidence-based medicine in the absence of judicious research, even in the face of an emerging disease that leads to a pandemic. The rush to skip indispensable scientific steps is likely multifactorial, ranging from political interests, that might involve notoriety or even financial gain, to duties of care (15). However, technical and ethical evaluation must also consider the effects improbable or implausible propositions can have by distracting and detracting form needed efforts to find adequate, scientifically based, valid and ethical solutions.
 
The proof of how unethical exclusion of pregnant women from trials comes with some of the initial aftermath findings: “Severe COVID-19 in pregnancy is almost exclusively limited to unvaccinated women “ (16). While severe COVID-19 during pregnancy might not be associated with high mortality rates in high income countries, it has had a devasting impact in the Latin America and Caribbean region where maternal mortality rates due to COVID-19 can be forty to over one hundred times higher than in the United States or Canada (17). Vaccine trials and vaccination of pregnant persons during the COVID-19 pandemic is evidence that vaccine equity, as an essential aspect of health equity, can only happen if gender inequity in the research and rollout of vaccines is addressed.
 
Categorical exclusion of pregnant women from vaccine trials of an emerging lethal disease culminates in making them even more vulnerable and prioritizes the pregnancy (or fetus), instead of the pregnant women (18). In addition, in times of intense anti-vaccine, anti-science rhetoric, exclusions also widens knowledge gaps that fuel dangerous narratives creating further barriers to health (19). In this case, as in all cases of clinical and vaccine trials, gender equity requires the “The Presumptive Inclusion of Pregnant Women” (20). This must be the default ethical position for inclusion of those who are pregnant through the understanding that “the burden of proof, both scientific and ethical, falls on those who want to argue for their exclusion” (21). This is fundamental to guarantee of the pregnant women’s autonomy, in the sense of substantiating their authority and agency regarding the decisions about their own bodies. It is an essential component of gender equity, a human right and ethical principle, and an urgent step towards de facto vaccine equity.
 
Ilana Ambrogi is a family and community medicine physician by training with a Ph.D. in bioethics, applied ethics, and public health from PPGBIOS/Fiocuz/ENSP. She has been researching public health emergencies, ethics, reproductive justice and health in the global south.
https://anis.org.br/https://ppgbios.nubea.ufrj.br/index.php/pt-BR/
 
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1. The term women is used throughout the text, although much of what is expressed also applies to all persons who can get pregnant. Yet, some of the barriers to research inclusion might be different to transgender and gender non-conforming persons.2. Smith DD, Pippen JL, Adesomo AA, Rood KM, Landon MB, Costantine MM. Exclusion of Pregnant Women from Clinical Trials during the Coronavirus Disease 2019 Pandemic: A Review of International Registries. Am J Perinatol [Internet]. 2020 Jun 19;37(08):792–9. Available from: www.slctr.lk/
Whitehead CL, Walker SP. Consider pregnancy in COVID-19 therapeutic drug and vaccine trials. Lancet [Internet]. 2020;395(10237):e92. Available from: http://dx.doi.org/10.1016/S0140-6736(20)31029-1. Shimabukuro (2021)
Pramanick A, Kanneganti A, Wong JLJ, Li SW, Dimri PS, Mahyuddin AP, et al. A reasoned approach towards administering COVID‐19 vaccines to pregnant women. Prenat Diagn [Internet]. 2021 Jul 30;41(8):1018–35. Available from: https://onlinelibrary.wiley.com/doi/10.1002/pd.5985
Shimabukuro, T. T., Kim, S. Y., Myers, T. R., Moro, P. L., Oduyebo, T., Panagiotakopoulos, L., Marquez, P. L., Olson, C. K., Liu, R., Chang, K. T., Ellington, S. R., Burkel, V. K., Smoots, A. N., Green, C. J., Licata, C., Zhang, B. C., Alimchandani, M., Mba-Jonas, A., Martin, S. W., … Meaney-Delman, D. M. (2021). Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons. New England Journal of Medicine, 384(24), 2273–2282. https://doi.org/10.1056/NEJMOA2104983/SUPPL_FILE/NEJMOA2104983_DATA-SHARING.PDF
3. Pan American Health Organization / World Health Organization. Epidemiological Update: COVID-19 in pregnant women. 13 August 2020, Washington, D.C.: PAHO/WHO; 2020. https://iris.paho.org/bitstream/handle/10665.2/52613/EpiUpdate13August2020_eng.pdf?sequence=1&isAllowed=y
Pfizer. Pfizer and Biontech Commence Global Clinical Trial to Evaluate COVID‐19 Vaccine in Pregnant Women; 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-commence-global-clinical-trial-evaluate
There is documentation of single COVID-19 vaccine trail starting late August of 2020 that did not purposely exclude pregnant women, yet it is unclear how many pregnant women were included. The published study does not make any inferences regarding pregnant women or pregnancy. See also Pramanick (2021) op cit note 2 and Falsey AR, Sobieszczyk ME, Hirsch I, Sproule S, Robb ML, Corey L, Neuzil KM, Hahn W, Hunt J, Mulligan MJ, McEvoy C, DeJesus E, Hassman M, Little SJ, Pahud BA, Durbin A, Pickrell P, Daar ES, Bush L, Solis J, Carr QO, Oyedele T, Buchbinder S, Cowden J, Vargas SL, Guerreros Benavides A, Call R, Keefer MC, Kirkpatrick BD, Pullman J, Tong T, Brewinski Isaacs M, Benkeser D, Janes HE, Nason MC, Green JA, Kelly EJ, Maaske J, Mueller N, Shoemaker K, Takas T, Marshall RP, Pangalos MN, Villafana T, Gonzalez-Lopez A; AstraZeneca AZD1222 Clinical Study Group. Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine. N Engl J Med. 2021 Dec 16;385(25):2348-2360. doi:10.1056/NEJMoa2105290. Epub 2021 Sep 29. PMID: 34587382;
PMCID: PMC8522798. And ClinicalTrials.gov. Phase III Double‐Blind, Placebo‐Controlled Study of AZD1222 for the Prevention of COVID‐19 in Adults; 2020. https://clinicaltrials.gov/ct2/show/NCT04516746.
4. Adhikari EH, Spong CY. COVID-19 Vaccination in Pregnant and Lactating Women. JAMA [Internet]. 2021 Mar 16;325(11):1039. Available from: https://jamanetwork.com/journals/jama/fullarticle/2776449;
Dawood FS, Kittikraisak W, Patel A, Rentz Hunt D, Suntarattiwong P, Wesley MG, et al. Incidence of influenza during pregnancy and association with pregnancy and perinatal outcomes in three middle-income countries: a multisite prospective longitudinal cohort study. Lancet Infect Dis [Internet]. 2021;21(1):97–106. Available from: http://dx.doi.org/10.1016/S1473-3099(20)30592-2
Pramanick (2021) op cit note 2 Table 1 summarizes the vaccines and recommendations for use during pregnancy.
5. Whitehead (2020) op cit note 2
Dashraath P, Wong JLJ, Lim MXK, Lim LM, Li S, Biswas A, et al. Coronavirus disease 2019 (COVID-19) pandemic and pregnancy. Am J Obstet Gynecol [Internet]. 2020;222(6):521–31. Available from: https://doi.org/10.1016/j.ajog.2020.03.021
6. Krubiner CB, Faden RR, Karron RA, Little MO, Lyerly AD, Abramson JS, et al. Pregnant women & vaccines against emerging epidemic threats: Ethics guidance for preparedness, research, and response. Vaccine [Internet]. 2019 May 3 [cited 2019 Jul 13]; Available from: https://www.sciencedirect.com/science/article/pii/S0264410X19300453?via%3Dihub
7. Shimabukuro (2021) op cit note 2 ; Adhikari (2021) op cit note 4; Smith (2020) Op cit note 2; Pramanick (2021) op cit note 2.
8. Dombrowski MP. Asthma and Pregnancy. Obstet Gynecol [Internet]. 2006 Sep;108(3, Part 1):667–81. Available from: http://journals.lww.com/00006250-200609000-00028:
Dawood (2021) op cit note 4
9. https://www.ox.ac.uk/news/2020-05-12-pregnant-women-are-not-greater-risk-severe-covid-19-other-women;
Adhikari EH, Moreno W, Zofkie AC, et al. Pregnancy Outcomes Among Women With and Without Severe Acute Respiratory Syndrome Coronavirus 2 Infection. JAMA Netw Open. 2020;3(11):e2029256. doi:10.1001/jamanetworkopen.2020.29256. Available from: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2773105
10. PAHO (2020) op cit note 3
11. Beigi RH, Krubiner C, Jamieson DJ, Lyerly AD, Hughes B, Riley L, et al. The need for inclusion of pregnant women in COVID-19 vaccine trials. Vaccine [Internet]. 2021;39(6):868–70. Available from: https://doi.org/10.1016/j.vaccine.2020.12.074
Zavala E, Krubiner CB, Jaffe EF, Nicklin A, Gur-Arie R, Wonodi C, et al. Global disparities in public health guidance for the use of COVID-19 vaccines in pregnancy. BMJ Glob Heal [Internet]. 2022 Feb 24 [cited 2022 Apr 11];7(2):e007730. Available from: https://gh.bmj.com/lookup/doi/10.1136/bmjgh-2021-007730
PAHO. A third of pregnant women with COVID-19 unable to access life-saving critical care on time. 2 Mar 2022. https://www.paho.org/en/news/2-3-2022-third-pregnant-women-covid-19-unable-access-life-saving-critical-care-time
12. Krubiner CB, Faden RR, Karron RA, Little MO, Lyerly AD, Abramson JS, et al. Pregnant women & vaccines against emerging epidemic threats: Ethics guidance for preparedness, research, and response. Vaccine [Internet]. 2021 Jan [cited 2021 Nov 5];39(1):85–120. Available from: https://doi.org/10.1016/j.vaccine.2019.01.011
13. Beigi (2021) Op cit note 11
14. Hinton DM. Request for emergency use authorization for use of chloroquine phosphate or hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of 2019 coronavirus disease. March 28, 2020. https://www.fda.gov/media/136534/download
15. Furlan L, Caramelli B. The regrettable story of the “Covid Kit” and the “Early Treatment of Covid-19” in Brazil. Lancet Reg Heal - Am [Internet]. 2021 Dec 1 [cited 2022 Apr 19];4:100089. Available from: http://www.thelancet.com/article/S2667193X21000855/fulltext
16. Engjom H, van den Akker T, Aabakke A, Ayras O, Bloemenkamp K, Donati S, et al. Severe COVID-19 in pregnancy is almost exclusively limited to unvaccinated women – time for policies to change. Lancet Reg Heal - Eur [Internet]. 2022 Feb 1 [cited 2022 Mar 3];13. Available from: http://www.thelancet.com/article/S2666776222000060/fulltext
17. Pan American Health Organization / World Health Organization. Epidemiological Update: Coronavirus disease (COVID-19). 2 December 2021, Washington, D.C.: PAHO/WHO; 2021. https://iris.paho.org/bitstream/handle/10665.2/55322/EpiUpdate2Dec2021_eng.pdf?sequence=1&isAllowed=y
18. Diniz D, Brito L, Rondon G. Maternal mortality and the lack of women-centered care in Brazil during COVID-19: Preliminary findings of a qualitative study. Lancet Reg Heal - Am [Internet]. 2022;10:100239. Available from: https://doi.org/10.1016/j.lana.2022.100239
19. Zavala (2022) Op cit note11 and PAHO (2022) Op cit note 11
20. Krubiner (2021) Opt cit note 12
21. Krubiner (2021) Opt cit note 12
 
Ilana Ambrogi is a family and community medicine physician by training with a Ph.D. in bioethics, applied ethics, and public health from PPGBIOS/Fiocuz/ENSP. She has been researching public health emergencies, ethics, reproductive justice and health in the global south.
https://anis.org.br/
https://ppgbios.nubea.ufrj.br/index.php/pt-BR/

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