key: cord-0897354-gbl54s0a
authors: Pramanick, Angsumita; Kanneganti, Abhiram; Wong, Jing Lin Jeslyn; Li, Sarah Weiling; Dimri, Pooja Sharma; Mahyuddin, Aniza Puteri; Kumar, Sailesh; Illanes, Sebastian Enrique; Chan, Jerry Kok Yen; Su, Lin Lin; Biswas, Arijit; Tambyah, Paul Anantharajah; Huang, Ruby Yun‐Ju; Mattar, Citra Nurfarah Zaini; Choolani, Mahesh
title: A reasoned approach towards administering COVID‐19 vaccines to pregnant women
date: 2021-06-30
journal: Prenat Diagn
DOI: 10.1002/pd.5985
sha: 92b4539c1aaa5bf5907ef48529dcccca20427320
doc_id: 897354
cord_uid: gbl54s0a

There are over 50 SARS‐CoV‐2 candidate vaccines undergoing Phase II and III clinical trials. Several vaccines have been approved by regulatory authorities and rolled out for use in different countries. Due to concerns of potential teratogenicity or adverse effect on maternal physiology, pregnancy has been a specific exclusion criterion for most vaccine trials with only two trials not excluding pregnant women. Thus, other than limited animal studies, gradually emerging development and reproductive toxicity data, and observational data from vaccine registries, there is a paucity of reliable information to guide recommendations for the safe vaccination of pregnant women. Pregnancy is a risk factor for severe COVID‐19, especially in women with comorbidities, resulting in increased rates of preterm birth and maternal morbidity. We discuss the major SARS‐CoV‐2 vaccines, their mechanisms of action, efficacy, safety profile and possible benefits to the maternal‐fetal dyad to create a rational approach towards maternal vaccination while anticipating and mitigating vaccine‐related complications. Pregnant women with high exposure risks or co‐morbidities predisposing to severe COVID‐19 infection should be prioritised for vaccination. Those with risk factors for adverse effects should be counselled accordingly. It is essential to support patient autonomy by shared decision‐making involving a risk‐benefit discussion with the pregnant woman.

� Provides an overview of the available SARS-CoV-2 vaccines, their mechanisms of action and feasibility of use in pregnancy. subunit of the S protein contains the receptor-binding domain (RBD) responsible for binding to host cell angiotensin converting enzyme-2 (ACE2), after being primed by the serine protease TMPRSS. [3] [4] [5] High levels of neutralising antibody response against RBD-located epitopes 6, 7 have been observed in convalescent individuals, correlating with CD4+ T cell response. 8 Convalescent plasma has, thus, been used for treatment 9 with variable results. Additionally, earlier work on SARS-CoV demonstrated the suitability of the spike protein as a target for vaccine development. 10 Like other vaccines, it is postulated that SARS-CoV-2 vaccine needs to elicit both antibody-mediated and T cell-mediated immunity for effective protection. 5, 10 The second trimester of pregnancy is characterised by an antiinflammatory, T H 2-biased microenvironment with increased immunoglobulin synthesis and decreased cell-mediated response to infection. This switches to a pro-inflammatory T H 1-type response in the third trimester. 11 While the relationship between these immunological shifts in pregnancy and SARS-CoV-2 remains unclear, it may potentially exaggerate the 'cytokine storm' due to the strong T H 1-polarised response to virus-linked programmed lytic cell death of infected cells that characterises severe SARS-CoV-2 infection. 5 This may explain the increased rates of intensive care admission, mechanical ventilation, and death among pregnant women with symptomatic COVID-19 infection, 12, 13 especially during the third trimester. Pro-inflammatory cytokines IL-1β, IL-2, IL-6, TNF and IFNγ are released by cell-mediated pathways and the Toll-like receptors activation 14, 15 at the maternalfetal interface. These disrupt the protective anti-inflammatory milieu maintained at the maternal-fetal interface by decidual natural killer cells and T reg cells 11, 16, 17 and may contribute to the observed increased stillbirth and preterm delivery rates. [18] [19] [20] [21] Vertical transmission of SARS-CoV-2 has been extensively discussed. [22] [23] [24] [25] While large observational studies report that 2.6%-5% of infants born to mothers with SARS-CoV-2 test positive, 19, 26, 27 only a few case reports [28] [29] [30] [31] have provided evidence of congenital infection through isolating viral particles in fetal tissue not exposed to maternal fluids or tissue. 32 Both the ACE-2 receptor and TMPRSS2 serine protease are required for infection but placental expression of these is highly variable with few placental cells consistently coexpressing both throughout pregnancy. [33] [34] [35] [36] [37] Thus, it is biologically not surprising that vertical transmission rates are low.

Finally, SARS-CoV-2 IgG has been identified in offspring of serology positive mothers 38, 39 and, together with IgM and IgA, has been found in breastmilk of mothers in active or convalescent phase of SARS-CoV-2 infection [40] [41] [42] [43] with proof of specificity against the RBD. 43, 44 However, the efficacy and duration of this protection remains to be assessed by longitudinal cohort studies.

Vaccination in pregnancy has dual-fold benefit, protecting the mother through the induction of cell-mediated and humoral immunity, and passive protection of the offspring via transplacental transfer of maternal IgG. Recommendations regarding vaccines in pregnancy are summarised in Table 1 . Most of the information regarding safety of inactivated vaccines in pregnancy comes from observational studies and historical data. 45 While live attenuated vaccines (LAV) are generally more immunogenic than inactivated vaccines, 46 -1019 pandemic, the USA's Food and Drug Administration (FDA) grants EUA following evaluation of Phase 3 safety data for at least 3000 vaccine recipients followed up for 2 months. 55 Table 3 summarises the characteristics of the five most widely used vaccines that have been approved in at least two or more countries.

The use of DNA-or RNA-based technology has contributed to the speed of vaccine production by being both quick to design and easy to manufacture. 56, 57 Moderna and Pfizer-BioNTech mRNAbased vaccines were the first two COVID-19 vaccines to attain FDA EUA for administration in the USA and represent the first ever mRNA-based vaccines provisionally approved for clinical use. These novel vaccines with efficacies of almost 95% in Phase 3 trials 58,59 and above 85% in real-world cohort studies [60] [61] [62] and work by injecting mRNAs nucleosides coding for S Protein peptides, encased in transfection reagents such as lipid nanoparticles, that induce host production of spike proteins peptides using the native cellular translation machinery. These spike proteins are expressed on the cellular surface, triggering the activation of cell-mediated and humoral immune systems and the creation of B memory cells which produce SARS-CoV-2-spike protein specific antibodies. The vaccine mRNA does not enter the nucleus or change host DNA, 63 are replication-deficient and have short lifespan characteristics, thus the likelihood of transplacental transfer of mRNA vaccine active compounds is low. 57, 64, 65 Pfizer-BioNTech's BNT162b2's Phase 3 clinical trial data reports side-effects such as local injection-site reactions (66%-88%), and mild to moderate systemic events including fever, fatigue, headache, and musculoskeletal pain (less than 60%). Two deaths were reported in the intervention arm but were deemed unrelated. 58 The CDC has determined that anaphylaxis with the first dose of BNT162b2 and term data spanning the entire gestational length of pregnancy and beyond is required.

Two prospective cohort studies 73,74 of mRNA-1273 or BNT162b2 vaccine recipients comparing non-pregnant and pregnant or lactating women did not reveal serious adverse effects. Comparable vaccine-induced neutralising antibody titres, functional antibody responses and cell-mediated immune responses were seen, and these were higher than in the infected and unvaccinated. Neutralising

IgG antibodies titres were present in the umbilical cord and breastmilk but were lower compared to maternal sera. 73, 74 Breastmilk IgG, but not IgA, was boosted by a second vaccine dose. 73 University of Oxford and AstraZeneca's AZD1222 is a doubledose replication-deficient chimpanzee adenoviral vector vaccine. 75 Interim analysis reports an overall vaccine efficacy of 70.4%. 76 This vaccine is comparatively more affordable than mRNA vaccines 75 and does not require ultra-low temperature storage. 77 The AZD1222

vaccine trial is one of the few which did not exclude pregnant women. 78 (Table 2) . Almost all the trials exclude pregnancy except for AZD1222 78 and BNT162b2. 108 As vaccination campaigns progress, the herculean tasks of largescale manufacture, cold-chain transportation, and equitable distribution of vaccines requires prioritisation of high-risk and vulnerable groups such as the elderly and healthcare workers. 75 

United States of America In the absence of conclusive evidence of harm, there are reasonable ethical arguments to support vaccinating pregnant women (Table 5) .

Following the debacle surrounding thalidomide and diethylstilbestrol, various research-related legislations and guidelines protect pregnant women and their fetuses from unintended harm. 127 This unfortunately, has also led to pregnant women being frequently excluded from trials to avoid exposure to 'greater than minimal harm'. 128, 129 This exclusion may be a result of anticipated socio-cultural complications if the vaccination program reports adverse pregnancy outcomes which could potentially jeopardise the entire program.

However, during a pandemic, the balance between 'benefit' and 'minimal harm' might vary significantly when compared to a nonpandemic situation. 130 pregnancy-specific and 52% excluded pregnancy. 133 Towards the goal of harmonising safety data collection in clinical trials, the Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA project) has formulated guidance on data collection and reporting in vaccine trials involving pregnant women allowing applicability in diverse settings. 134 With no precedent for mRNA vaccines and accelerated vaccinedevelopment programs lacking long-term Phase 3 safety data, it is right for investigators, funding bodies and the public to be concerned about the risk of harm in pregnancy. However, as with any new drug category, the potential for teratogenicity must be balanced against the potential for significant benefit, especially given that COVID-19 has significantly higher morbidity during pregnancy. 19, 117 To address non-maleficence, the pharmacokinetics of mRNA vaccines (i.e., short-lived and having very local effect), DART studies, 65, 71 cohort studies 73, 74 and post-vaccination registry reviews 72 vaccines in pregnant women, however, remains an unanswered concern given the predisposition of young women for TTS and reports of cerebral venous thrombosis. More data from prospective cohort studies and passive registries are needed.

The classification of pregnant women as vulnerable individuals has been challenged by various bodies arguing that pregnant women routinely exercise autonomy in complex clinical decisions to protect both their own and fetuses' interests. 135, 136 It is unreasonable to expect a pregnant woman not to have capacity to weigh the risks and benefits of vaccination even in the face of limited evidence and provide informed consent for or against vaccination.

A personalised risk-benefit analysis-based discussion is required for each pregnant woman to balance the paucity of pregnancy specific and long term data with the risks of non-vaccination and potentially severe SARS-CoV-2 infection, 137 with an aim of supporting her de- 117 These groups could also be considered for preconception vaccination.

Studies determining vaccine acceptability and factors influencing decisions in pregnant women are required. 145 As concerns surface regarding vaccine-related anaphylaxis 66, 146 clinicians need to be cognizant that severe anaphylaxis in pregnancy poses additional risks of preterm labour, fetal hypoxic brain injury or intrauterine fetal death. [147] [148] [149] [150] [151] [152] [153] The CDC reports an anaphylaxis rate 

The risks of mRNA vaccine in pregnancy are unknown with little precedent amongst the non-pregnant population. As with any new drug class, the potential for teratogenicity should be balanced with the untapped potential for benefit to the mother, fetus and neonate. Limited animal Developmental and reproductive toxicity studies and observations in Phase 3 participants with inadvertent pregnancy suggest no harm.

Beneficence COVID-19 in pregnancy has a greater risk of severe complications and there exists a potential to reduce morbidity and mortality amongst pregnant women by including them in vaccination. There is also a possibility of passive immunisation of the fetus or neonates through transplacental IgG transfer or through breastfeeding.

Adult pregnant women regularly exercise autonomy by providing informed consent for clinical decision-making. Similarly, they have the capacity to weigh the risks and benefits of vaccination and provide informed consent.

week gap is recommended between COVID-19 and influenza or pertussis vaccination. However, with availability of more safety data, currently COVID-19 vaccines may be co-administered along with other vaccines. 119 As Phase 3 mRNA vaccines trials 58,59 report a 15% rate of moderate to severe fever (38.5 ≥°C) after the second dose and potential complications of pyrexia in the first trimester include oral clefts, neural tube or congenital heart defects in the fetus 159 adequate and appropriate anti-pyrexial treatment is advisable.

Currently, women with positive SARS-CoV-2 IgG serology should still be offered vaccination, as although naturally acquired antibodies

and T-cell responses appear to be protective, 160 

Vaccination in pregnant women should be individualised based on risks and intended benefits. Informed consent should be obtained.

Relevant information and frequently asked questions regarding maternal vaccination should be posted on easily accessible media (websites, posters at vaccination sites, clinics and maternity units, patient information leaflets).

Priority for pre-conception or antenatal vaccination could be given to women who are at high risk for

• COVID-19 exposure: Healthcare workers, social workers, residential home carers.

• Complicated COVID-19: Advanced maternal age or co-morbidities such as obesity, diabetes, solid organ transplant, sickle cell disease and chronic cardiac, lung, or kidney diseases.

Priority for pre-conception or antenatal vaccination could be given to women who are at high risk for Women with positive SARS-CoV-2 IgG serology could still be offered vaccination as the degree and duration of immunity conferred by previous infection is unknown and vaccine-mediated immunity is superior to naturally acquired immunity.

Maternal vaccination should be performed in facilities with access to services competent in managing anaphylaxis and maternal resuscitation. Healthcare workers at vaccination centres, first responders and frontline health services should be educated on recognition of anaphylaxis in pregnancy and the principles of maternal resuscitation.

The following should be made available in all centres conducting maternal vaccination.

• Medical equipment, emergency medications, personnel competent in managing anaphylaxis and resuscitation in pregnancy.

• Clear written guidelines.

• Facility for post vaccination observation.

• Post-vaccination leaflet, tailored to pregnancy detailing common side effects, red flag symptoms for adverse effects and anaphylaxis, emergency contact information.

Anti-pyretic management should be pre-emptively provided, especially with mRNA vaccines.

Passive registries should be maintained to observe pregnancy outcomes of women who undergo vaccination. Data should be analysed to formulate regular updates to guide future vaccination strategies in pregnancy.

PRAMANICK ET AL.

be constantly reviewed based on accumulated observational evidence. Interim reports should be regularly released indicating vaccine-related adverse effects and efficacy, and rates of miscarriages, terminations of pregnancy, fetal anomalies, preterm births and perinatal mortality. 174 Contemporaneously updated guidelines and frequently asked questions featured in clinic posters, patient information leaflets, public health websites and maternity forums could serve as an adjunct to professional counselling prior to informed consent.

Improved patient education through easily understood and reliable information would complement pre-vaccination counselling and alleviate burdens on busy healthcare services.

These recommendations have been summarized in Box 1.

COVID-19 in pregnancy is associated with higher rates of pregnancy- While it was initially postulated that 'herd immunity' for SARS-CoV-2 could be achieved by attaining at least 70% population immunity, 175 logistical challenges in vaccine distribution, 176 the economic desire to open borders and the emergence of VOCs which may reduce vaccine-efficacy makes passive protection of pregnant women through herd immunity a long term objective which may take years.

While we await high vaccination rates, similar to that of measles, rubella and polio, periodic outbreaks may continue due to importation from low vaccination areas or vaccine non-response, albeit with lower severity. 62, [177] [178] [179] Mask wearing, hand hygiene and social distancing will remain important methods for pregnant women who remain unvaccinated either due to medical reasons, personal preference or exclusion from vaccination policies.

Informed consent and patient autonomy should be the cornerstones for decision-making regarding vaccination. Individualised discussion covering each woman's specific risks and possible benefits of vaccination should be conducted. Women at high priority for vaccination include those at high exposure risk or who have comorbidities that place them at high risk for severe COVID-19.

Pregnant women are a significant part of the spectrum of every population. We hope that future clinical trials will consider including pregnant women, whenever pre-clinical studies show no objective reason to exclude them.

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We would like to acknowledge Mr Mohesh K Mohan for his assistance in the illustration, Ms Cecille Laureano Asibal for her administrative support.

The authors have no conflicts of interest in connection with this article.

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

https://orcid.org/0000-0002-1544-4945Aniza Puteri Mahyuddin https://orcid.org/0000-0001-8570-8427Sebastian Enrique Illanes https://orcid.org/0000-0001-5433-9315Mahesh Choolani https://orcid.org/0000-0001-8336-0973