key: cord-0719329-c2z8nl1s
authors: Malinowski, Ann Kinga; Whittle, Wendy; Murphy, Kellie; Kingdom, John
title: Expecto Patronum! Leveraging the positive force of COVID-19 Vaccines for Pregnant and Lactating Individuals
date: 2021-05-14
journal: J Obstet Gynaecol Can
DOI: 10.1016/j.jogc.2021.04.015
sha: afec3b544dd0c768342aa7ade84fafa85c1df0e8
doc_id: 719329
cord_uid: c2z8nl1s

For over a year, the world has been gripped by the coronavirus disease 2019 (COVID-19) pandemic, which has had far-reaching effects on society. The integrity of national health care systems has also been challenged, owing to shifts in guidance and misinformation. While initial reports suggested that pregnant people were not at increased risk of severe COVID-19 disease, current data arising from the “third wave” paint a much more concerning picture. Additionally, pregnant and lactating people were excluded from vaccine trials, which has hindered the ability of health care professionals to provide evidence-based counselling regarding the safety and efficacy of the available vaccines in these populations. This commentary reviews the current data on the safety of COVID-19 vaccines in pregnancy. The evidence is clear that the risks of hospitalization and severe maternal and potentially fetal morbidity from COVID-19 in pregnancy far outweigh the very minimal risks of COVID-19 vaccination in pregnancy.

Disclosures: Dr. Malinowski reports consulting fees from Pfizer unrelated to this work and has served in an advisory capacity for and received honoraria from Alexion, also unrelated to this work. The other authors declare they have nothing to disclose.

All authors have indicated that they meet the journal's requirements for authorship.

For over a year, the world has been gripped by the coronavirus disease 2019 (COVID-19) pandemic, which has had far-reaching effects on society. The integrity of national health care systems has also been challenged, owing to shifts in guidance and misinformation. While initial reports suggested that pregnant people were not at increased risk of severe COVID-19 disease, current data arising from the "third wave" paint a much more concerning picture. Additionally, pregnant and lactating people were excluded from vaccine trials, which has hindered the ability of health care professionals to provide evidence-based counselling regarding the safety and efficacy of the available vaccines in these populations. This commentary reviews the current data on the safety of COVID-19 vaccines in pregnancy. The evidence is clear that the risks of hospitalization and severe maternal and potentially fetal morbidity from COVID-19 in pregnancy far outweigh the very minimal risks of COVID-19 vaccination in pregnancy.

For over a year, world attention has been gripped by the impact of the Coronavirus Disease 2019 (COVID-19) pandemic, with far-reaching effects on society at large, as well as the integrity of national health care systems. The speed and severity of this disease, induced by the Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) virus, has disrupted every dimension of our lives. The scientific community has responded swiftly, by shifting its focus to address the nuances of every aspect of the pandemic, producing new insights and effective care pathways at an unprecedented pace. While this prolific output has been invaluable, its speed and scale has meant an ever-changing series of advisory statements, and clinical practice recommendations.

The frequent shifts in guidance in response to our evolving understanding of the effects of COVID-19 have created levels of dissonance and distrust within some segments of the population, notably in vulnerable and racialized communities. Such conditions have been ripe for the propagation of misleading narratives, unsupported by credible data. This development has in turn led to some unintended consequences, for instance, fuelling vaccine hesitancy, and nowhere more so than within the pregnant population.

Daily life involves choices, each with a series of intended and unintended consequences. These decisions commonly extend to various facets of our health. At this juncture, it is imperative to consider the fears that accumulate on both sides of the vaccination equation, and in particular to use current best evidence to re-frame risk perceptions around susceptibility to SARS-CoV-2; especially the consequences of infection vs. the possible vaccine-related side-effects and the potential unknowns that presently remain.

While initial reports suggested that pregnant women are not at increased risk of severe COVID-19 disease, current data arising from the "third wave" paint a much more concerning picture; in retrospect this new concern is not surprising, given the known increased pregnancy-related morbidity attributed to other respiratory viruses, including influenza, Severe Acute Respiratory Syndrome (SARS), and Middle East Respiratory Syndrome. 1 The most recent report from the Canadian Surveillance of COVID-19 in Pregnancy (CanCOVID Preg), based on data obtained from the first and second waves, had already demonstrated a five-fold increased risk of hospitalization and Intensive Care Unit (ICU) admissions for pregnant women with COVID-19, as compared to the equivalent non-pregnant female population; a risk that also included higher rates of preterm birth (12%) , small for gestational age size (9%), and a 4-fold (1.2%) excess risk of stillbirth. 2 At the time of writing, Canada currently finds itself in the epicentre of the third wave of this pandemic, in which variants of concern (VOC) are not only more prevalent, they now dominate the burden of disease. In contrast to the previous waves, pregnant women are now clearly disproportionately more affected, with a higher incidence of respiratory compromise, hospitalization, and ICU admission. 3 Estimates suggest that 1:10 pregnant persons with COVID-19 infection will be hospitalized and 1:100 will be admitted to the ICU. 3 This increased propensity for severe illness mirrors the second wave experience from the United Kingdom, where the numbers of pregnant women with severe or critical COVID-19 were noted to escalate, with many requiring ICU-admission. A very disturbing trend is that of referrals for extra-corporeal membrane oxygenation (ECMO) treatment doubling in some units. 4 Unfortunately, this is now commensurate with our institutional experience in the current third wave.

The dire global impact of this pandemic spurred robust international scientific efforts, which with unprecedented speed have culminated in the development of a number of COVID-19 vaccines. In Canada, two messenger-RNA (mRNA) vaccines (Pfizer/BioNTech and Moderna) and a non-replicating viral vector-based vaccine (AstraZeneca-Oxford) have received emergency Health Canada authorization.

The mRNA vaccines do not contain live virus and therefore cannot induce infection in the host. These vaccines are comprised of modified nucleotides encoding the SARS-CoV-2 spike protein, with intra-cellular delivery achieved by a lipid nanoparticle structure. The mRNA does not gain entry to the nucleus and is incapable of interaction with or alterations of human DNA. Once inside the cell cytoplasm, the mRNA supplies directions to generate the trans-membrane spike protein antigen -within the deltoid muscle -which in turn induces both humoral and cellular immune responses. The mRNA, spike protein, and lipid nanoparticle are thereafter degraded and excreted within days to weeks. 5

The non-replicating viral vector vaccine uses a modified form of chimpanzee adenovirus (ChAd, incapable of replication) to transport genes that code for the SARS-CoV-2 spike protein into the cells, where these genes are transcribed into mRNA within the nucleus and translated into proteins within the cytosol. 5

The Pfizer/BioNTech, Moderna, and AstraZeneca-Oxford Trials have enrolled 45,000, 30,000, and 20,000 participants respectively, with 95%, 94.5%, and 70.4% efficacy. 6 Importantly, all three vaccines are now known to be extremely effective with respect to prevention of severe disease, as represented by mortality, hospitalization, and ICU-admission rates. 7 Regrettably, none of these trials included pregnant or lactating people. 6 This exclusion is disappointing, but sadly it is not surprising, since yet again a paternalistic approach, driven by a misguided desire to somehow protect a vulnerable pregnant population, has overridden the opportunity of such individuals to provide informed consent for trail participation, with total disregard for the violation of the right of pregnant and lactating persons to their autonomy and selfdetermination. 8 Thus, despite pleas of pregnant and lactating people to participate in trials, they were once again excluded from vaccine trials, which has hugely impacted upon the ability of healthcare practitioners to provide evidence-based counseling regarding safety and efficacy of the available vaccines.

Reassuringly, to date no animal nor human studies have raised any specific concerns about COVID-19 vaccines during pregnancy or lactation. Ongoing surveillance of pregnant people through the Center for Disease Control and Prevention's v-safe COVID-19 vaccine pregnancy registry has received registration from 35,691 individuals reporting pregnancy at the time of vaccination. Of 3,598 participants enrolled in the ongoing v-safe pregnancy registry, 827 have completed their pregnancies and no concerning safety signals have been identified thus far. 9 Furthermore, evidence of passive antibody transfer to infants, through placenta and breastmilk has been demonstrated. 3 Side-effects following vaccination in pregnancy are similar to those experienced by nonpregnant individuals; the most common include local tenderness at the injection site, transient fatigue, myalgias and low-grade fever, 9 all of which can be treated safely with acetaminophen.

Worthy of discussion are the recent reports of cerebral venous sinus thrombosis (CVST) following vaccination with AstraZeneca-Oxford in non-pregnant individuals. Close examination of these very rare events has resulted in the recognition of what was originally termed Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) now renamed as Vaccine Induced Thrombosis with Thrombocytopenia (VITT). 10 Thus far VITT has not been reported following administration of either of the available mRNA vaccines. Similarities with heparin induced thrombocytopenia (HIT) have been made, a disease characterized by an immune-mediated adverse reaction to heparin. In HIT, antibodies to platelet factor (PF4) emerge and bind to platelets resulting in their activation, which then leads to thrombosis and "paradoxical" thrombocytopenia. 11 As in HIT, but without the heparin exposure, high-levels of antibodies to PF4 have been discovered in individuals with VITT. 10 VITT-related thromboses may occur at atypical sites, including the cerebral venous sinus, the portal, splanchnic or hepatic venous circulations, alongside the more typical presentations of pulmonary embolism, deep vein thrombosis, and arterial thrombosis. 10 Potential risk factors include younger age and the female sex has thus far predominated. The associated thrombocytopenia, significantly elevated Ddimers, and hypofibrinogenemia intimate activation of the coagulation system. However, the syndrome is thought to be the result of an atypical autoimmune antibody-mediated reaction. At present the occurrence of VITT is estimated at around 1:100,000. 10 Symptoms typically present 4-28 days following vaccination. 12 Awareness of symptoms is critical to allow for early assessment and treatment, which consists of intravenous immunoglobulin and non-heparin anticoagulants (in pregnancy these include danaparoid sodium or fondaparinux). 12

Currently, there is no indication that the risk of VITT is increased in the presence of prior thrombosis or thrombophilia, and guidance from various thrombosis organizations, including the International Society on Thrombosis and Haemostasis (ISTH) 12 suggests that these are not contraindications to vaccination with AstraZeneca-Oxford. Thus, given the autoimmune as opposed to hypercoagulable state origins of VITT, pregnancy is not considered to be a contraindication to the administration of the AstraZeneca-Oxford vaccine. In comparison, a recent systematic review demonstrated a strikingly high risk of thrombo-embolic events mediated by COVID-19 (21%), which in one study rose to 31% amongst those admitted to the ICU. 13 In a recent statement, the Society of Obstetricians and Gynaecologists of Canada (SOGC) concurs in favor of vaccination in pregnancy. 3 Consideration of the balance of these risks may be aided by the relative comparisons of the risk of potential other events (Table 1 ).

In summary, the evidence is clear that the risk of hospitalization and of severe maternal and potentially fetal morbidity secondary to COVID-19 in pregnancy far outweighs the very minimal risks of COVID-19 vaccination in pregnancy. The SOGC agrees that current data support the safety of all COVID-19 vaccines available in Canada, and encourages their utilization in any trimester of pregnancy and during lactation. 3 Thus, it is incumbent upon all obstetric providers to strongly encourage every pregnant person to get their COVID-19 vaccine. And when they do so, to encourage them to participate in the Canadian COVID-19 Vaccine Registry for Pregnant and Lactating Individuals, a web-based, longitudinal survey aiming to record the outcomes and opinions regarding the COVID-19 vaccines experiences and can be found at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafepregnancyregistry.html.

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Report #3 of the canadian surveillacne of covid-19 in pregnancy: Epidemiology, maternal and infant outcomes

Sogc statement on the covid-19 vaccines and rare adverse outcomes of thrombosis associated with low platelets

Were pregnant women more affected by covid-19 in the second wave of the pandemic?

Coronavirus disease 2019 (covid-19) vaccines and pregnancy: What obstetricians need to know

Covid-19 real-world vaccine effectiveness -what we know so far

Excluding pregnancy from covid-19 trials: Protection from harm or the harm of protection?

Preliminary findings of mrna covid-19 vaccine safety in pregnant persons

Sars-cov-2 vaccine-induced immune thrombotic thrombocytopenia

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Thromboembolism risk of covid-19 is high and associated with a higher risk of mortality: A systematic review and meta-analysis

American society of hematology 2018 guidelines for management of venous thromboembolism: Venous thromboembolism in the context of pregnancy

Cuffe R. AstraZeneca vaccine: How do you weigh up the risks and benefits? Available at

risk in pregnancy is secondary to hypercoagulability; while VITT risk is secondary to an auto-immune reaction