A reasoned approach towards administering COVID‐19 vaccines to pregnant women

Abstract

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.

Key points

What is already known about this topic?

• COVID‐19 infection in pregnancy leads to an increase in adverse maternal outcomes.

• Owing to paucity of data regarding SARS‐CoV‐2 vaccine use in pregnancy there is uncertainty regarding safety of use and subsequent pregnancy outcomes.

What does this study add?

• Provides an overview of the available SARS‐CoV‐2 vaccines, their mechanisms of action and feasibility of use in pregnancy.

• Summarises recommendations regarding vaccination of pregnant or lactating women.

1. INTRODUCTION

On 8th December, 2020, a 90‐year‐old woman in the United Kingdom was the first clinical recipient of a SARS‐CoV‐2 vaccine.¹ At the time of writing this article, almost 1.5 billion doses of SARS‐CoV‐2 vaccine have been administered. As much as globalisation has contributed to the rapid spread of COVID‐19, with almost 130 million infected and three million lives lost, it has also promoted a high degree of international cooperation and collaboration in therapeutics and vaccine development. Emergency‐use authorisation (EUA) and federal level investments in the United States of America (USA), European Union (EU), China and India have expedited development of the SARS‐CoV‐2 vaccine and implementation of global vaccination programs.²

2. PATHOPHYSIOLOGY AND IMMUNOLOGY OF SARS‐COV‐2 IN PREGNANCY

SARS‐CoV‐2, like other human coronaviruses, consists of a single‐stranded positive sense RNA genome encased in a helical nucleocapsid, with an outer envelope of four structural proteins: envelope (E), spike (S), membrane (M) and nucleocapsid (N) proteins. The S1 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 epitopes6, 7 have been observed in convalescent individuals, correlating with CD4+ T cell response.⁸ Convalescent plasma has, thus, been used for treatment⁹ 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 anti‐inflammatory, T_H2‐biased microenvironment with increased immunoglobulin synthesis and decreased cell‐mediated response to infection. This switches to a pro‐inflammatory T_H1‐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_H1‐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 activation14, 15 at the maternal‐fetal interface. These disrupt the protective anti‐inflammatory milieu maintained at the maternal‐fetal interface by decidual natural killer cells and T_reg cells11, 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 reports28, 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 co‐expressing 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 mothers38, 39 and, together with IgM and IgA, has been found in breastmilk of mothers in active or convalescent phase of SARS‐CoV‐2 infection40, 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.

3. COVID‐19 VACCINES

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 they retain replication potential, may be trafficked transplacentally and are therefore relatively contraindicated in pregnancy. Reassuringly though, observational studies of women inadvertently vaccinated during early pregnancy with rubella, plio, yellow‐fever and dengue LAV have not demonstrated an increased incidence of malformations, prematurity, stillbirth, neonatal death or miscarriage.47, 48, 49, 50 Smallpox⁵¹ and anthrax⁵² LAVs, however, have been associated with a small increase in malformations.

TABLE 1.

Various vaccines and recommendations for use in pregnancy

Type	Examples	Recommendation for use in pregnancy
Inactivated	Inactivated influenza	Recommended in pregnancy.
	Inactivated polio
	Hepatitis A	Use if high‐risk of exposure and benefits outweigh risks of vaccination.
	Rabiesa
Peptide/toxoid	Diphtheria	Recommended in pregnancy.
	Tetanus
	Acellular pertussis
	Haemophilus influenza B	Generally safe. Use if high‐risk of exposure and benefits outweigh risks of vaccination.
	Hepatitis B
	Pneumococcal
	Meningococcal
	Typhoid vi capsular polysaccharide
Live attenuated	Mumps, measles and rubella	Avoid in pregnancy. Risks of complications in event of inadvertent vaccination is low.
	Rotavirus
	Varicella zoster
	Smallpoxa
	Anthrax
	Influenza
	Oral polio
	Live typhoid
	Yellow fever	Consider if travel to endemic regions is unavoidable.
Nucleic acid vaccines (DNA plasmid, mRNA)	Zika, HIV, SARS‐CoV‐1	Under investigation.
	SARS‐CoV‐2	Approved for emergency use in some countries. Correlate with local guidelines.
Viral vector	SARS‐CoV‐2	Under investigation.
	Ebola rVSV‐ZEBOV

^a Should be given post‐exposure.

At the time of writing this paper, 50 SARS‐CoV‐2 vaccines, utilising both familiar and novel mechanisms, are either in Phase 2 or 3 clinical trials53, 54 (Table 2) or in clinical use. While it normally takes about 3 years for vaccines to complete Phase 3 trials, in the face of a 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.

TABLE 2.

SARS‐CoV‐2 vaccines which have been approved for use or are in Phase 2 or 3 Trials (Updated 15th May 2021)

TABLE 3.

SARS‐CoV‐2 vaccines approved for use in two or more countries (updated 15th May 2021)

Vaccine candidate (Manufacturer – Name)	Type	No. of doses	Storage temperature (°C)	Vaccine efficacy against symptomatic, laboratory‐confirmed COVID‐19 in Phase III trials (%)	Significant adverse effects	DART studies & pregnancy data
BioNTech–Pfizer – BNT162b2 or Tozinameran/Comirnaty	mRNA vaccine	2	−70	95	Injection‐site pain ∼80% versus 10%–15% (placebo) Temperature ≥ 38°C 11%–16% versus <1% (placebo) Fatigue 59%, headache 52% Severe systemic events <2% Anaphylaxis 11.1 per million doses	DART in progress. Unpublished reports cite no adverse effects to female reproduction or fetal/postnatal development. Prospective cohort studies – vaccine‐induced titres similar to non‐pregnant population Neutralising antibodies seen in umbilical cord blood and breast milk, higher after 2nd dose No increase in adverse pregnancy outcomes in post‐vaccination registry review Reduced efficacy against B.1.1.17 and B.1.351 variants
Moderna – mRNA‐1273	mRNA vaccine	2	2–8 up to 30 days −20 for long‐term storage	94.1	Severe injection‐site reaction 7% versus 0.5% (placebo) Severe systemic side effects e.g. fever, myalgia, fatigue, nausea, vomiting, arthralgia, chills: 15.8% versus 1.9% (placebo) Temperature ≥ 38°C 15.5% versus 0.3% (placebo) Anaphylaxis 2.5 per million doses	DART – No adverse effects on female reproduction or fetal/postnatal development Prospective cohort studies ‐vaccine‐induced titres similar to non pregnant population Neutralising antibodies seen in umbilical cord blood and breast milk, higher after 2nd dose No increase in adverse pregnancy outcomes in post‐vaccination registry review
AstraZeneca & University of Oxford – AZD1222/Vaxzevria	ChADOx1 non‐replicating chimpanzee adenoviral vector	2	2–8	70.4	No difference in serious adverse effects. Pyrexia <0.1% 1 case of transverse myelitis (<0.1%) Risk of TTS 10.9:1,000,000 doses	• DART in progress
Johnson & Johnson – Janssen – Ad26.COV2.S	Ad26 non‐replicating human adenoviral vector	1	2–8 up to 3 months −4 for long‐term storage	65.5–66.3a	In cohort age 18–55 years oldb Local adverse events: 64%–78% versus 9% (placebo) Grade 3 systemic adverse events: 9%–20% versus 0% (placebo) Temperature 39°–40°C: 5%–9% Risk of TTS 2:1,000,000 vaccines amongst women age <50	DART – No adverse effects on female reproduction or fetal/postnatal development 8 inadvertently pregnant women (3 in vaccine group) 1 spontaneous abortion and 1 ectopic pregnancy in vaccine group. Pregnancy outcomes unknown.
Gamelaya research Institute – Sputnik V	Ad5 and Ad26 non‐replicating human adenoviral vector	2	2–8	91.6	Flu‐like illness: 15.2% versus 8.8% (placebo) Serious adverse events: 0.3% versus 0.4% (placebo) Local reactions: 5.4% versus 1.2% (placebo) Pyrexia: 0.5% versus 0.3% (placebo)	• No data
Sinopharm – BBIBP‐CorV	Inactivated SARS‐CoV‐2 (vero cells)	2	2–8	79–86a	Injection site reactions 35%b	• No data
Sinovac – CoronaVac	Inactivated SARS‐CoV‐2	2	2–8	50–91.25a	Injection site reactions 27.5%b	• No data

Abbreviations: DART, Developmental and Reproductive Toxicity studies; TTS, Thrombosis with thrombocytopenia syndrome.

^a Self‐reported from interim analysis published in press, but not in a peer‐reviewed journal.

^b Based on phase 1/2 studies.

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 mRNA‐based 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 trials58, 59 and above 85% in real‐world cohort studies60, 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 Moderna’s mRNA‐1273 is uncommon at 11.1^{66 , 67} and 2.5⁶⁸ cases per million doses, respectively. While this rate is higher than the seasonal influenza vaccine (1.3 cases per million doses),⁶⁹ it is similar to penicillin (1.9–27.2 per million).⁷⁰

Developmental and reproductive toxicity (DART) studies for the mRNA‐1273 in pregnant and lactating female Sprague Dawley rats did not demonstrate adverse effects on the female reproductive system or fetal development following administration of the therapeutic dose.⁷¹ DART animal data for BNT162b2 vaccine have not been published although preliminary reports do not reveal any safety concerns.⁶⁵ A review of 35,691 pregnant vaccine‐recipients who submitted data to the CDC's ‘v‐safe’ smartphone‐based post COVID‐19 vaccination health checker reported more frequent injection‐site pain but less frequent systemic side‐effects compared to non‐pregnant women. The v‐safe pregnancy registry with 3958 pregnant women reported similar miscarriage, stillbirth, congenital anomaly, intrauterine growth restriction and other antenatal complications compared to background rates,⁷² however robust long term data spanning the entire gestational length of pregnancy and beyond is required.

Two prospective cohort studies73, 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 double‐dose 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 vaccines⁷⁵ 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 Johnson & Johnson–Janssen Pharmaceutical's Ad26.COV2.S is a single‐dose non‐replicating human adenoviral vector vaccine that has been recently approved by the FDA and European Union with interim efficacy reported at 65.5%–66.3%.⁷⁹ DART studies for Ad26.COV.S vaccine in pregnant and lactating female rabbits did not demonstrate adverse effects on the female reproductive system or fetal development. While in Phase 3 trials, 8 participants had inadvertent pregnancies during vaccination but no adverse effects were reported except for one spontaneous miscarriage and one ectopic pregnancy in the study arm.⁸⁰

Vaccine‐induced thrombosis with thrombocytopenia syndrome (TTS) is autoimmune‐mediated and guidelines have been formulated for its effective management.⁸¹ Reports of TTS have emerged82, 83 in association with AZD122284, 85 and Ad26.COV2.S⁸⁶ with a higher predisposition for the latter amongst women less than 50‐years‐age (7 per million vaccine doses in women less than 50‐years‐age vs. 0.9 for older women and none amongst males for Ad26.COV2.S).⁸⁶ A maternal death due to stroke at 23‐weeks‐gestation in an AZD1222 recipient in Brazil attracted further attention⁸⁷ and several countries have started restricting their usage in younger persons with varying upper age limits.⁸⁸ Regulatory bodies, currently, maintain that there remains an overall positive benefit‐risk profile with absolute rates remaining very low89, 90 when seen in the context of COVID‐19's mortality rate of 116 deaths per million infections. Further investigation and long‐term monitoring for these events are required.⁹¹ mRNA vaccines have not been implicated in TTS86, 92 although a pre‐print has reported a higher incidence of cerebral venous sinus thrombosis (CVST), the hallmark of TTS, in individuals vaccinated with the Pfizer and Moderna vaccines. This incidence is higher than that following influenza infection but much lower than following natural COVID‐19 infection.⁹³ While CVST is rare, it has been associated with pregnancy and larger observational studies are required to ascertain the modification of CSVT risk in pregnant vaccines.

Russia's Gamaleya Research Institute's Sputnik V vaccine utilises Ad5 and Ad26 adenoviruses and has obtained early approval within Russia, Hungary, Belarus and Argentina⁵³ with Phase 3 trials reporting 91.6% efficacy and no significant increase in serious adverse effects, the finalised clinical trial results are awaited. A potential limitation of viral vector vaccines is the possibility of pre‐existing or vaccine‐induced anti‐vector immunity, which could reduce the efficacy of the starting or booster vaccines, respectively.⁹⁴

The Peoples Republic of China (PRC) has developed two inactivated vaccines: Sinovac's CoronaVac⁹⁵ and Sinopharm's BBIBP‐CorV.⁹⁶ The latter has received EUA within the PRC, Indonesia, Bahrain, and United Arab Emirates. Unpublished Phase 3 interim analysis show vaccine efficacies of 50%–91.3%97, 98 and 79%–86%99, 100, respectively. Favourable safety profiles in Phase 1 and 2 trials have been published, with febrile symptoms reported in <5% of subjects.95, 96, 101

Novavax is a recombinant Spike protein peptide vaccine¹⁰² that is undergoing Phase 3 trials and is likely to receive FDA EUA. Virus‐like particles have been used in human papillomavirus vaccines, which involves particles mimicking viral structures that can present antigenic proteins to antigen‐presenting cells.

SARS‐CoV‐2 variants of concern (VOC) B.1.1.7, B.1.351, P.1, B.1.427, B.1.429, B.1.617 with S protein mutations have emerged from England, South Africa, Brazil and India. These VOCs have slightly higher transmissibility,⁸⁵ increased disease severity⁸⁵ along with concerns of reduced vaccine efficacy¹⁰³ and immune escape.¹⁰⁴ The B.1.617 variant, in particular, is thought to be responsible for India's second wave.¹⁰⁵ Analysis of B.1.351's neutralization activity titres for AZD1222 and BNT162b2 show reductions of 9‐fold and 7.6‐fold, respectively.⁸⁵ One cohort study amongst pregnant and lactating BNT162b2 and mRNA‐1273 vaccine recipients showed reduced neutralising antibody titres against B.1.1.17 and B.1.351 but preserved T‐cell response.⁷⁴ Amongst vaccinated healthcare workers, BNT162b2 has shown efficacy against B.1.1.17.⁶² Real world data corroborates that the currently licensed vaccines are effective against the major VOCs.¹⁰⁶ The role of additional booster doses and pre‐clinical candidate variant‐specific boosters are being evaluated.¹⁰⁷

Figure 1 illustrates the mechanism of action of various types of SARS‐CoV‐2 vaccines.

FIGURE 1.

Mechanism of action of various types of SARS‐CoV‐2 vaccines

As of 15th May 2021, of the 50 candidate vaccines in Phase 2 or 3 trials, 40.0% (20) are protein or virus‐like protein vaccines, 28.0% (14) are DNA or RNA‐based, 10.0% (5) are viral vector vaccines, 22.0% (11) are live attenuated. Of these, 42.0% (21) are undergoing Phase 3 clinical trials and 12 have been approved in at least 2 countries (Table 2). Almost all the trials exclude pregnancy except for AZD1222⁷⁸ and BNT162b2.¹⁰⁸

As vaccination campaigns progress, the herculean tasks of large‐scale 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, 109, 110, 111 The WHO's Strategic Advisory of Experts (SAGE) recommends a three‐staged prioritisation process depending on each country's vaccine availability. Where vaccine availability exists for 1%–10% of a population, the highest Stage 1 targets healthcare workers and seniors.¹¹² Uniquely, pregnant healthcare workers who care for a largely unvaccinated pregnant population may find themselves at a higher risk of exposure. While there has been conflicting evidence on whether COVID‐19 in pregnancy is associated with adverse effects113, 114, 115, 116 larger studies demonstrate a higher risk of death, intensive care unit admission, invasive ventilation and extracorporeal membrane oxygenation¹¹⁷ as well as increased preterm delivery and stillbirth rates.18, 19 Despite this, pregnant women have been placed in the lowest prioritisation Stage 3. With over 130 million births per year globally, increases in maternal mortality will have significant societal impacts. Awaiting long‐term vaccine safety and efficacy data may lead to pregnant women and their offspring bearing a disproportionate burden of disease. It is thus critical, to address the issue of vaccination of pregnant women.

Currently, a clear global consensus on vaccination of pregnant women against COVID‐19 is yet to be formulated (Table 4). The American College of Obstetrics and Gynecology (ACOG) and the Society for Maternal Fetal Medicine (SMFM)65, 120 endorse the inclusion of pregnant and lactating women in vaccination campaigns. The UK's Joint Committee of Vaccination and Immunisation (JCVI)⁷⁵ and Royal College of Obstetricians and Gynaecologists¹²¹ opine that pregnant women should be offered vaccination based on their age and clinical risks and preferable vaccines would be Pfizer‐BioNTech's BNT162b2 or Moderna's mRNA‐1273. Those at risk of SARS‐CoV‐2 exposure (healthcare or social workers, residential carers, drivers, cleaners) or COVID‐19 complications with infection (diabetes, solid organ transplant, immunosuppression, chronic respiratory, heart, or kidney disease, BMI > 40) should be offered vaccination.⁷⁵ Royal Australian and New Zealand College of Obstetricians and Gynecologists (RANZCOG)¹²² recommend risk based discussion of vaccination with women who are susceptible to complicated COVID‐19 infection. Additionally, RANZCOG recommends that pregnant women with high SARS‐CoV‐2 exposure risk should have their duties adjusted to reduce exposure or, if this is not possible, consider vaccination. The European Medicines Agency states that BNT162b2123, 124 and mRNA‐1273¹²⁵ can be considered on a case‐by‐case basis after close consultation on the risks and benefits but more studies are needed. The Society of Obstetricians and Gynaecologists of Canada¹²⁶ additionally recommends against counselling for termination of pregnancy in the event of inadvertent pregnancy during a vaccination series and to discuss the pros and cons of continuing or delaying of subsequent dose(s) depending on the woman's vulnerability factors. Determining the local rate of community transmission and individualised exposure risk would facilitate a risk‐benefit based discussion tailoring the recommendations to the individual.¹¹⁹

TABLE 4.

Recommendations by international professional and regulatory bodies regarding SARS‐CoV‐2 vaccination in pregnancy (updated 15th May 2021)

Country/region	Professional or regulatory body	Key recommendations
United States of America	American College of Obstetricians and Gynecologists	Pregnant women should have access to COVID‐19 vaccines. Vaccine should be offered to lactating women similar to non‐lactating individuals. Permissive recommendation based on appropriate risk/benefit discussion and shared clinical decision making between clinicians and pregnant patients. Defer influenza & TDaP vaccines for 14 days after COVID‐19 vaccination. Claims linking COVID‐19 vaccines to infertility have been scientifically disproven. Risk of thrombosis and thrombocytopenia with Janssen vaccine should be discussed.
	Food and Drug Administration	Vaccine sponsors should conduct developmental & reproductive toxicity studies. Encourages inclusion of pregnant & women of childbearing age in studies. Recommends maintenance of pregnancy exposure registry and follow up data.
	Centre for Disease Control and Prevention	Pregnant or lactating women can receive COVID‐19 vaccination. Women should be allowed to make an informed decision, providing current knowledge of COVID‐19 vaccines with pregnancy and risk of disease. Pregnant women receiving vaccine should consider participating in the v‐safe pregnancy registry. No evidence of COVID‐19 vaccines causing fertility issues. COVID‐19 vaccines can be co‐administered with or within 14 days of other vaccines.
	American Society for Reproductive Medicine	Patients who are undergoing fertility treatment, are pregnant or breastfeeding should be encouraged to receive vaccination, based on eligibility criteria
Europe	European Society of Human Reproduction & Embryology	Women with co‐morbidities putting them at higher risk of complicated COVID‐19 should be encouraged for vaccination before conception. Consider postponing assisted reproduction treatment for a few days after vaccination to allow immune response to settle or up to 2 months to allow antibody development.
	European Medicines Agency	Vaccinating pregnant women with BNT162b2 or mRNA‐1273 can be considered on a case‐by‐case basis and after close consultation with a healthcare professional while considering the benefits and risks.
United Kingdom	Joint Commission on Vaccination & Immunisation	Pregnant women should be offered COVID‐19 vaccine based on their age and clinical risk, followed by a joint decision after discussing benefits and risks. Available data does not indicate safety concerns or harm in pregnancy. Pfizer‐BioNTech's BNT162b2 or Moderna mRNA‐1273 is preferable for pregnant women. Vaccination should be offered to pregnant women at high risk of Complicated COVID‐19: solid organ transplant recipients, severe respiratory conditions (e.g., cystic fibrosis or severe asthma), homozygous sickle cell disease, significant congenital or acquired heart disease, on immunosuppression or on dialysis, BMI >40, gestational diabetes. SARS‐CoV‐2 infection: frontline health/social workers & residential home carers. Breastfeeding can continue during the course of vaccination. Women planning for pregnancy can be vaccinated. No evidence of vaccines affecting fertility. Recommends maintenance of pregnancy exposure registry and follow up data.
	Royal College of Obstetricians & Gynaecologists
Canada	Society of Obstetricians & Gynaecologists of Canada	Vaccination should be offered to eligible pregnant or breastfeeding individuals in the absence of contraindications, with informed consent following discussion regarding the absence of evidence. Individuals who get pregnant during vaccine series should not be counselled for termination of pregnancy. Decision to complete or delay second dose should be individualised and discussed. A 28 days interval is recommended between completion of COVID‐19 vaccine and other vaccines; 14 days interval between other vaccine and starting COVID‐19 vaccine. These can be individualised depending on indications.
	National Advisory Committee on Vaccination
Australia & New Zealand	Royal Australian and New Zealand College of Obstetrics & Gynaecology	Discuss vaccination with pregnant women who are vulnerable to complicated COVID‐19. There is insufficient evidence to recommend routine vaccination in pregnancy. Pregnant workers with increased exposure risk should be allotted lower risk duties or be offered vaccination. Pregnancy need not be delayed following vaccination. Pfizer BioNTech vaccine if preferred for those less than 50 years of age.
	Australian Technical Advisory Group on Immunisation (ATAGI)
Global	World Health Organisation118	Pregnant women with comorbidities or high risk of exposure may be offered vaccination. Lactating woman can be offered vaccination if they are part of a vaccine recommended group.
	International Federation of Obstetrics and Gynecology119	In the absence of risks outweighing benefits, pregnant and lactating women should be offered vaccination. Healthcare workers should support women in making an informed decision.

While emerging data from observational studies⁷³ and post‐vaccination surveillance data⁷² suggest minimal harm with vaccinating pregnant or lactating women, there is still insufficient data to be certain about the safety of COVID‐19 vaccines in this population until longer‐term studies can be conducted. Current guidelines recommend risk‐based vaccination of breastfeeding women and those vaccinated can continue breastfeeding.86, 98 Women planning pregnancy can be vaccinated and there is no evidence that vaccines affect fertility.

While endorsement of universal vaccination in pregnancy is not feasible at present, these organisations recognise that pregnancy or lactation is not be an absolute contraindication for vaccination, and individualisation of risk and informed decision making is crucial.

4. ETHICAL CONSIDERATIONS

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 non‐pandemic situation.¹³⁰ For example, during the West African Ebola pandemic of 2013–2016, pregnant women faced a case fatality rate of 89%–93%.¹³¹ While inclusion of pregnant women in drug and vaccine trials under such circumstances could have been justified, they were excluded despite the World Health Organisation Ethics Review Committee¹³² recommending protocol amendments when there were no objective reasons to exclude pregnancy. A review of 927 SARS‐CoV‐2 clinical trials found that only 3 (1.7%) were 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

TABLE 5.

Ethical principles guiding SARS‐CoV‐2 vaccination in pregnancy

Ethical principle	Application
Justice	Pregnant women, just as any other human subject, should have the right to be included in research trials and participate in vaccination campaigns where there are no compelling scientific or ethical reasons to exclude them.
Non‐maleficence	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.
Autonomy	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.

With no precedent for mRNA vaccines and accelerated vaccine‐development 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 studies73, 74 and post‐vaccination registry reviews⁷² do not suggest significant risk of harm while demonstrating comparable levels of vaccine efficacy. Additionally, cohort studies suggest that vaccinating pregnant women may benefit the offspring through the passive transfer of antibodies. The safety of adenoviral vector 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.

5. RECOMMENDATIONS

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 decision regardless of whether she is in favour of, or against Covid 19 vaccination.

Pregnant women with risk factors (advanced maternal age, obesity, diabetes, hypertension, solid organ transplant, immunosuppression, sickle cell disease, chronic lung, kidney or heart disease27, 117, 138, 139, 140) or high exposure risks (healthcare workers, drivers, cleaners or residential home carers)121, 122, 126, 141 may be prioritised for early vaccination. Healthcare workers are within the highest WHO SAGE Stage 1 vaccine priority¹¹² and women comprise about 70% of that workforce,¹⁴² a large proportion being of reproductive age. Other high risk groups, are those who are socially disadvantaged, including African American and Hispanic women in USA,65, 143 as they have higher rates of COVID‐19 infection¹⁴⁴ and death.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 anaphylaxis66, 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 of 11.1⁶⁷ (Pfizer‐BioNTech's BNT162b2) and 2.5⁶⁸ (Moderna's mRNA's‐1273) cases per million doses after the first dose, compared to 1.3 cases per million following inactivated influenza vaccine.⁶⁹ Majority of the cases occurred within 30 min of vaccination, mostly in women, and/or in persons with history of allergies. Reasons for female predisposition are unclear and has also been seen with the 2009H1N1 influenza vaccine.68, 154 While a history of allergy to the mRNA vaccine, polyethylene glycol or polysorbate are strict contraindications to vaccination,146, 155 drug or food allergies and previous anaphylaxis should be declared for closer post‐vaccination anaphylaxis monitoring. Despite low absolute risks of TTS in adenoviral‐vector vaccines, women of reproductive age or those pregnant or breastfeeding should be allowed the autonomy to select alternate vaccines¹⁵⁶ pending more conclusive data.

Maternal vaccination should be done in units with capacity for emergency obstetric resuscitation and management.¹²¹ Equipment and medication for managing anaphylaxis should be within easy access with at least three doses of epinephrine on hand, preferably in prefilled syringes or autoinjectors.¹⁴⁶ Currently, post‐vaccination observation of 30 min is recommended.118, 146 Additionally, all healthcare workers at vaccination centres, first‐responders, frontline medical services such as emergency departments and primary care providers should be educated on early recognition and management of anaphylaxis in pregnancy,152, 153, 157 which may present atypically with delayed features of shock, preterm labour, low back pain and uterine cramps. Additionally, they should be proficient in the principles of maternal resuscitation.¹⁵⁸

A personalised vaccine card stating pregnancy status, vaccine name, dosage and schedule should be provided along with patient information leaflets outlining expected symptoms and red flags requiring urgent medical review. As a cautionary measure, a two‐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 trials58, 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 fetus¹⁵⁹ 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 the nature and duration of protection from reinfection is presently unknown. Similar to other coronavirus infections, SARS‐Cov‐2 neutralising antibody titres demonstrate a decline, especially in individuals with less severe infection.¹⁶¹ As circulating antibody titres may not indicate B‐memory cell efficacy and cell‐mediated T_H1 response, it is unclear if this reduction in titres is associated with increased re‐infection risk7, 8, 40, 162, 163, 164 although convalescent individuals demonstrate strong CD4+ & CD8+ T cell memory responses against S⁴⁰ and N¹⁶⁵ proteins. Additionally, there have been concerns of antibody‐dependent enhancement due to the waning of neutralising antibodies,¹⁶⁶ although clinical evidence from vaccine trials, treatment with passive antibodies and infections in patients with previous human coronavirus infections have not conclusively demonstrated this.10, 167 Furthermore, Phase 1 studies for Moderna's mRNA‐1273 vaccine¹⁶⁸ suggest superior vaccine‐mediated immunity when compared to natural infection,169, 170, 171 though this requires validation through the larger Phases 3 and 4 cohorts.

Caution is necessary and more vaccine safety data in pregnancy is vital. Safety surveillance systems should be maintained by public health bodies, professional medical organisations or healthcare facilities at a local, regional or national level with attention to pregnant women172, 173 such as the UK Obstetric Surveillance System (UKOSS)/UK Teratology Information Service (UKTIS) and the CDC's ‘v‐safe’ COVID‐19 Vaccine Pregnancy Registry.⁶⁶ Maternity services may take the lead in registering pregnant women under their jurisdiction either by administering these vaccines or coordinating notification of vaccination.¹²¹ While awaiting results from prospective trials,¹⁰⁸ recommendations on vaccinating pregnant women should 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.

Box 1. Proposed recommendations regarding vaccination of pregnant women.

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.

6. CONCLUSION

COVID‐19 in pregnancy is associated with higher rates of pregnancy‐related complications. With a likely future of intermittent outbreaks, exclusion of pregnant women from vaccination may lead to a disproportionately higher burden being borne by this vulnerable cohort and their offspring. This must be balanced against the risks related to vaccination. Given the rapidity of new information emerging, it is vital that healthcare providers keep abreast of recent developments and guidelines.

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 co‐morbidities 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.

CONFLICT OF INTEREST

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

Pramanick A, Kanneganti A, Wong JLJ, et al. A reasoned approach towards administering COVID‐19 vaccines to pregnant women. Prenatal Diagnosis. 2021;41(8):1018–1035. 10.1002/pd.5985

DATA AVAILABILITY STATEMENT

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