Benefits and potential harms of <scp>COVID</scp>‐19 vaccination during pregnancy: evidence summary for patient counseling

Abstract

Historically, pregnant women have been excluded from the majority of drug and vaccine trials, a practice that has been criticized widely by the scientific community1-3. As a result, pregnant women are routinely denied beneficial, and sometimes potentially life-saving, therapeutic and preventive measures or receive them well after their non-pregnant peers. Data about safety and efficacy in pregnancy subsequently accumulate adventitiously as women receive the drug or vaccine before finding out that they are pregnant or become pregnant soon after receiving the therapy. In the absence of any significant adverse effects, eventually sufficient confidence is established (either as ‘evidence of no harm’ or, more frequently, as ‘no evidence of harm’) for a formal trial to be considered or, alternatively, the use of the intervention in pregnancy simply slips into routine practice. This practice was repeated with the coronavirus disease 2019 (COVID-19) vaccines, with pregnant women being excluded from the initial trials. Only a small number of women who were unknowingly pregnant or became pregnant soon after vaccination were included and this cohort is currently being followed up as part of the original trials4, 5. Due to lack of evidence around the safety of the COVID-19 vaccines in pregnancy, international societies have tended to take a cautious approach, recommending that vaccination of pregnant women should be evaluated on a case-by-case basis. The Society of Obstetricians and Gynaecologists of Canada and the International Federation of Gynecology and Obstetrics are notable exceptions as early endorsers of unrestricted COVID-19 vaccination in pregnancy6, 7. In the UK, the Royal College of Obstetricians and Gynaecologists (RCOG) recommends that pregnant women at high risk for contracting COVID-19 and/or developing severe illness should be considered eligible for vaccination8, 9; the criteria are under constant review and were recently updated on 24 February. The proposed risk factors are derived from literature relating specifically to pregnant women with COVID-19 or extrapolated from data on non-pregnant women with COVID-19, and consist primarily of chronic diseases or immunosuppressive conditions, as well as high risk of exposure to the virus (Table 1). It should be acknowledged that women may experience severe COVID-19 even in the absence of any of these risk factors10. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists has taken a stance similar to that of RCOG11. The American College of Obstetricians and Gynecologists recommends that COVID-19 vaccines should not be withheld from pregnant women who meet the criteria for vaccination based on the Advisory Committee on Immunization Practices recommended priority groups12. Here, we summarize the available evidence to support counseling of women contemplating COVID-19 vaccination during pregnancy. Most pregnant women with COVID-19 will remain asymptomatic or have mild illness. Fortunately, severe disease and death are rare outcomes. In the UK, for example, the maternal mortality rate associated with COVID-19 is 2.2 per 100 000 maternities13-16. However, pregnant women hospitalized with COVID-19 are more likely to be admitted to the intensive care unit (ICU) compared to non-pregnant women with the infection, although it is unclear whether this represents more serious illness or a lower threshold for ICU admission14. According to a large systematic review14, pregnant women with COVID-19 do not appear to be at higher risk of death compared to non-pregnant women with the disease. However, some studies from both high- and low-income settings have reported increased maternal mortality in pregnancies with COVID-1915, 17. Summary findings should be contextualized if used during patient counseling. Compared with pregnant women without COVID-19, those with symptomatic COVID-19 are at increased risk of adverse pregnancy outcomes, including admission to the ICU, iatrogenic preterm birth, pre-eclampsia-like symptoms, Cesarean section and death13-15. Existing data on the effect of COVID-19 on stillbirth are inconsistent, but it seems that stillbirth rates increased during the pandemic in low- to middle-income countries while there was no significant increase in high-income countries18, 19. COVID-19 has additional indirect effects on maternal and fetal outcomes, such as increased maternal mental distress and intimate partner violence19, 20. The risk of severe adverse outcomes (e.g. ICU admission, maternal death or stillbirth) in pregnant women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is affected by individual and societal risk factors, and the availability and performance of healthcare in their setting19. Nevertheless, it seems reasonable to counsel pregnant women with obesity, advanced age or significant chronic conditions (Table 1) that they are at increased risk of severe COVID-19 and, therefore, more likely to benefit from vaccination in terms of protection from life-threatening disease (Table 2). Observational studies indicate that postnatal transmission of SARS-CoV-2 from the mother to her baby is rare, and continued breastfeeding appears to be safe21-23; still, the postnatal transmission risk will probably be even lower in vaccinated mothers. Other secondary adverse effects of COVID-19 include mother–infant separation in some settings and increased incidence of Cesarean section and iatrogenic preterm birth. The prevalence of these adverse effects is also likely to be reduced by vaccination, therefore, women should be counseled about the probable additional benefits of vaccination over and above protection from severe disease (Table 2). The presence of anti-SARS-CoV-2 IgG was reported in the neonate of a vaccinated mother24, however, it is not yet possible to say what impact maternal vaccination will have on neonatal protection against infection after birth. Four different types of COVID-19 vaccine are currently available (Table 3): mRNA, viral vector, inactivated virus and recombinant antigen. As yet, only three COVID-19 vaccines (two mRNA and one adenovirus vector-based) have been approved for emergency use by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Medicines and Healthcare Products Regulatory Agency (MHRA), namely the mRNA-1273 (Moderna Therapeutics, Cambridge, MA, USA), BNT162b2 (BioNTech, Fosun Pharma, Pfizer, Mainz, Germany) and Ad26.COV2.S (Janssen Pharmaceutica, Beerse, Belgium) vaccines. The Oxford–AstraZeneca (AZD1222) viral vector vaccine has been approved by the EMA and is commonly used in the UK. The two FDA-approved mRNA vaccines were shown to elicit a very strong immune response and protection against severe COVID-194, 25. Unpublished data from a study of the mRNA-1273 vaccine in pregnant rats identified no safety concerns regarding malformations or embryotoxicity26. The trials of both mRNA vaccines excluded pregnant women. Yet, initial reports from regulatory bodies, such as the EMA, show that a small number of women in these trials were pregnant at the time of vaccination; safety data from these pregnancies are still pending but, as yet, no significant adverse effects have been observed27, 28. More recently, Dr Anthony Fauci, Chief Medical Advisor to the USA President, stated that more than 20 000 pregnant women have received the mRNA vaccine in the USA and to date there have been no concerning ‘red flags’29, 30. These as yet unpublished data illustrate that many pregnant women are willing to be vaccinated when their autonomy is respected and they have the opportunity to weigh their own personal risks and benefits. These preliminary safety data are reassuring and their publication is eagerly awaited. mRNA-based Zika virus vaccine used in pregnant mice showed no safety concerns Adenovirus vector-based Zika virus vaccine used in pregnant mice showed no safety concerns Although mRNA vaccines have not previously been deployed on such a scale, they are not new. mRNA vaccines do not contain a live virus and do not use an adjuvant to increase vaccine efficacy. The mRNA in vaccines does not enter the cell nucleus and cannot alter the human genome. Animal studies have demonstrated the safety, efficacy and potential benefit of mRNA vaccines in pregnant women, benefits which may extend beyond simply protecting the mother from pathogens. Zika virus is a zoonotic pathogen, like coronavirus, and is capable of intrauterine infection. In 2017, Richner et al. reported on the efficacy of an mRNA vaccine against Zika virus in pregnant mice31. Following vaccination, pregnant mice were infected with live Zika virus; pups born to vaccinated dams showed no viral load in their brain tissue. Furthermore, the viral load was at or below the detection threshold in placental samples. The authors concluded that the mRNA vaccine was safe in pregnant mice and that it prevented vertical transmission of Zika virus. The principles of this vaccination technology should also apply to COVID-19 vaccines and provides generic reassurance around the use of mRNA vaccines in pregnancy. Furthermore, vaccination is likely to protect not only the pregnant woman but also the fetus/neonate. With regards to SARS-CoV-2 vaccines, a recent case report demonstrated transplacental transmission of antibodies against the spike protein following vaccination of the mother24. Efficient transplacental transfer of SARS-CoV-2 IgG antibodies was also shown in the majority of seropositive pregnant women after natural infection32. The presence of neutralizing antibodies in the fetal/neonatal circulation is potentially an added benefit of vaccination for the protection of the baby, in both fetal and neonatal life, against COVID-19. Three adenovirus vector-based SARS-CoV-2 vaccines, AZD1222, Ad26.COV2.S and Gam-COVID-Vac (the latter also known as Sputnik V; Gamaleya Research Institute of Epidemiology and Microbiology, Moscow, Russia) have recently reported Phase-3 trial data showing high levels of efficacy against COVID-19, especially against severe disease and hospitalization5, 33, 34. As with the mRNA vaccines, there are limited data on the safety of adenovirus vector-based vaccines in pregnancy, though adenovirus vector-based Zika virus vaccines have been tested in pregnant mice without safety concerns35. These vaccines do not contain live virus and neither the SARS-CoV-2 spike protein nor the adenovirus vector replicates in humans and are eliminated from the tissues following injection. Two inactivated virus vaccines from China (BBIBP-CorV (Beijing Institute of Biological Products, Beijing, China) and CoronaVac (Sinovac Life Sciences, Beijing, China)) and one from India (COVAXIN, Bharat Biotech, Hyderabad, India) are also commercially available, with varying efficacy rates for preventing symptomatic infection reported36-40. They have similarly high protection against severe COVID-19 and death as the mRNA vaccines. Inactivated virus vaccines are considered safe in pregnancy, though the aluminium hydroxide adjuvants used in these vaccines do not have a designated FDA safety category due to the lack of data41, 42. However, alum adjuvants are used in many vaccines, including those for hepatitis B, DTaP (diphtheria, tetanus and pertussis) and human papillomavirus (HPV). Inadvertent vaccination with HPV vaccines during pregnancy has not been associated with any safety concerns43. A similar safety profile was observed with the respiratory syncytial virus vaccine, which also uses alum adjuvant44. One recombinant antigen vaccine (Novavax, Novavax, Inc., Gaithersburg, MD, USA) has shown high efficacy against symptomatic SARS-CoV-2 infection45. The antigens produced by recombinant technology are coupled with a saponin-based proprietary adjuvant in order to elicit an immune response. Recombinant vaccines are considered safe in pregnancy due to their non-replicating nature. However, the saponin-based proprietary adjuvant used in this vaccine lacks safety data in pregnant women. Pregnancy trials of the BNT162b2 and Ad26.COV2.S vaccines are due to start soon. However, enrolment to prospective trials is threatened by the current global demand for vaccines, which will only increase with time. Worldwide, pregnant women are already choosing to be vaccinated against SARS-CoV-2 and safety data accumulating in official registries are likely to play a key role for expectant mothers considering vaccination. It is essential that countries establish national registries of pregnant women receiving the different types of SARS-CoV-2 vaccine as a matter of urgency; where possible, international registries should be developed46, 47. Monitoring pregnancy, fetal and neonatal outcomes in vaccinated women and comparing them with those in unvaccinated pregnant women should be a priority. Moreover, the ethics of enrolling pregnant women into placebo-controlled trials is increasingly questionable, at a time when more and more pregnant women, particularly those with risk factors for severe COVID-19, are already receiving the vaccine. SARS-CoV-2 vaccines are likely to deliver similar benefits to pregnant women as to non-pregnant individuals, and are likely to be safe. Withholding such a vaccine from prospective mothers who understand and accept the uncertainty of available preventive measures, while offering them enrolment into a placebo-controlled trial, might prove ethically challenging. Nevertheless, there are a number of advantages in recruiting pregnant women into trials in which they receive a licensed SARS-CoV-2 vaccine. This includes addressing questions around optimal timing of vaccination, number of doses, dose intervals and need for boosters in future pregnancies. In the meantime, animal studies should be rapidly undertaken to provide safety information about the current unknowns of SARS-CoV-2 vaccines, such as transplacental passage of mRNA-containing lipids or the safety of adjuvants and adenovirus vectors. There is an urgent need to focus and allocate more resources to research on SARS-CoV-2 vaccination in pregnancy while awaiting safety data from official registries. Pregnant women should be provided with a balanced and clear assessment of their risk of COVID-19 in pregnancy, taking into account their individual circumstances, local practices and available evidence from similar healthcare settings. In addition, they should be counseled with a balanced summary of the potential direct and indirect benefits of SARS-CoV-2 vaccines, while acknowledging the limited safety data. Whilst these vaccines have not yet been trialled in pregnancy, they are being offered to pregnant women with risk factors for severe COVID-19 during the national rollout of vaccine programs in the UK. These vaccines are also currently offered to pregnant women with a high risk of exposure to SARS-CoV-2, including health and care workers. In the UK, the MHRA is receiving regular feedback from the vaccination program and any concerns are met with appropriate action. So far, no safety concerns in vaccinated pregnant women have been reported in either the UK or the USA. We believe that COVID-19 vaccination should not be withheld from pregnant women who have received adequate counseling and understand the uncertainties, minimal potential harms and likely benefits of these vaccines. We also encourage further research to address current and future issues around SARS-CoV-2 vaccines in pregnancy.

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