USE OF NON-LIVE VACCINES IN PREGNANCY

Background

This document summarises the available evidence regarding the safety of vaccines that are either inactivated, replication-deficient or structural components (e.g. toxoid, subunit/acellular proteins) of the viral/bacterial pathogen.

In the United Kingdom (UK), these vaccines include the inactivated vaccines for hepatitis A, seasonal influenza, poliomyelitis (given as Tdap-IPV) and rabies, and the subunit, recombinant, polysaccharide, or conjugate vaccines for haemophilus influenza type B, hepatitis B, human papillomavirus, pertussis (whooping cough – also given as Tdap-IPV), pneumococcal and meningococcal disease.[1] Recently the MHRA have approved the use of COVID-19 vaccines with novel mechanisms of action (see below for more details).[2-5][8]

As these vaccines are either inactivated, only contain components of the viral/bacterial pathogen, or are replication-deficient, they cannot cause the disease against which they protect.[1]

Human data

Often, data from observational sources or case reports, including data collected by UKTIS, may be confounded by maternal co-ingestion of a number of drugs, at varying doses, and for a range of indications. The severity of the underlying maternal condition, where relevant, is frequently unknown and information on other potential confounding variables may be incomplete. These factors should be considered when interpreting observational human pregnancy data.

COVID-19

Since mid-December 2021 pregnant women have been considered a priority group for vaccination.^[6] In July 2022, it was announced that pregnant women were considered a clinical risk group within the COVID-19 vaccination programme^[7], and will be offered a further booster dose in the autumn of 2022. This is due to both the risks of COVID-19 in pregnancy (see below), and the amount of data amassed regarding the safety of COVID-19 vaccination in pregnancy (see below). Safety data, although incomplete, are currently highly reassuring and do not identify any concerns, and as such, pregnant women should be encouraged to have their COVID-19 vaccines.

About COVID-19 vaccines

There are currently five COVID-19 vaccines approved for use in the UK. Two of these (Pfizer and Moderna) contain messenger RNA (mRNA) encoding the SARS-CoV-2 spike protein antigen, which, after administration, is delivered into host cells and the spike protein is subsequently expressed, stimulating cellular and neutralising antibody immune responses.^{[4, 5]} Another two (AstraZeneca and Janssen) are monovalent vaccines composed of recombinant, replication-deficient adenovirus vectors encoding the SARS-CoV-2 spike protein antigen.^{[2, 3]} Similar to the mRNA vaccines, the spike protein is expressed by the vector following administration and stimulates a cellular and neutralising antibody immune response. The final vaccine (Novavax) is composed of purified full-length SARS-CoV-2 recombinant spike protein stabilised in its pre-fusion conformation, and a saponin-based adjuvant which facilitates immune cell response to the spike protein.^[8]

Risks associated with COVID-19 in pregnancy

Pregnant women are at increased risk of severe illness from COVID-19. Risks appear to be increased in later pregnancy. Additional risk factors for severe illness include being from an ethnic minority group, maternal age ≥35, BMI ≥30, and pre-existing maternal comorbidity, specifically chronic hypertension, heart disease, asthma and pre-pregnancy diabetes.^[9]

Severe COVID-19 in pregnancy has been associated with impaired fetal growth, an approximate 2-fold increased risk of stillbirth, and an approximate 3-fold increased risk of preterm birth (likely influenced by iatrogenic deliveries).^[10]

High quality evidence has shown that vaccination is highly effective at decreasing hospitalisation and intensive care admission among pregnant women.^[11-13] Additionally, booster doses have been associated with improved efficacy.^{[11, 13]}

COVID-19 vaccine in pregnancy outcome data

All of the vaccines approved for use in the UK have been assessed for reproductive toxicity in animal models, with no vaccine-related adverse effects being described.^{[2-5, 8]}

A large amount of post-marketing observational pregnancy and fetal outcome data have rapidly accumulated since June 2021. Studies from the USA, Australia, Israel, England, Scotland, Canada, Norway, Romania and Sweden have described the outcomes of at least 170,000 unique vaccinated pregnancies.^[13-44] Combinations of these data have also been included in two meta-analyses.^{[45, 46]} The majority of these pregnancies were vaccinated using mRNA vaccines (Pfizer/BioNTec or Moderna), mainly in the second or third trimester. These studies provide evidence relating to each of the following fetal/pregnancy outcomes:

1. Miscarriage – Studies which collectively include at least 20,000 vaccinated pregnancies have not identified increased risks for either mRNA[17, 18, 20, 37, 42, 46, 47] or viral vector[26, 27] vaccines. Although reassuring, methodological limitations associated with these studies (including limited consideration of time-varying risks and data confounding), mean that higher quality studies are required to provide further reassurance. UKTIS are aware of additional data that are in press, which once peer reviewed, are expected to provide additional reassurance regarding miscarriage risks.
2. Malformation – Studies which collectively include at least 28,000 vaccinated pregnancies (mainly mRNA vaccines) have not identified increased risks.[14, 34, 39, 41, 46, 47] However, the number of first trimester vaccinated pregnancies included in these studies is smaller than the collective total (n~5350 vaccinated pregnancies), and only two studies have specifically analysed malformation risks following first trimester exposure alone (n~3000 vaccinated pregnancies).[34, 41]
3. Stillbirth – Studies which collectively include at least 150,000 vaccinated pregnancies (mainly mRNA vaccines) have not identified increased risks[13, 15, 17, 29, 31, 32, 35, 39, 42, 43, 45, 46, 48] (note, some of these studies investigated stillbirth risks in composite outcomes with other perinatal losses[15, 31, 42]). Additionally, four studies (including one meta-analysis of data from seven studies) have indicated statistically significant decreased risks of stillbirth following vaccination in pregnancy.[29, 31, 39, 46] One study investigated the outcomes of women who received a booster vaccine dose in pregnancy, in comparison with vaccinated but non-boosted pregnancies, identifying a statistically significant decreased risk.[13]
4. Preterm delivery – Studies which collectively include at least 140,000 vaccinated pregnancies (mainly mRNA vaccines) have not identified increased risks.[16, 17, 22, 24, 30-32, 34-36, 38-40, 42, 43, 46] Additionally, three studies (including one meta-analysis of data from six studies) have indicated statistically significant decreased risks of preterm delivery[39, 45], or very or extreme preterm birth[32]. Two studies have investigated the outcomes of women who received a booster vaccine dose in pregnancy, in comparison with vaccinated but non-boosted pregnancies.[13, 38] Neither of these identified increased risks of preterm delivery[13, 38], and one suggested a statistically significant decreased risk.[13]
5. Fetal growth restriction – Studies which collectively include at least 170,000 vaccinated pregnancies (mainly mRNA vaccines) have not identified increased risks.[13, 16, 17, 22-25, 30, 32, 34, 35, 38-40, 43, 45-47] Two studies have investigated the outcomes of women who received a booster vaccine dose in pregnancy, in comparison with vaccinated but non-boosted pregnancies.[13, 38] Neither of these identified increased risks of small for gestational age.[13, 38]
6. Neonatal complications – Studies which collectively include at least 110,000 vaccinated pregnancies (mainly mRNA vaccines) have not identified increased risks of neonatal[22] or infant death[15, 34], NICU admission[24, 33, 35, 39, 40, 45, 46] or hospitalisation[13, 34], decreased 5-minute Apgar scores[25, 33, 38-40, 45, 46], respiratory complications[25, 40, 45] and fever[25, 45]. One study has described a small increased risk of infant phototherapy following first trimester vaccination which was not observed among those vaccinated anytime during pregnancy.[34] This finding lacks a biologically plausible explanation, and it is possible that the finding was produced due to chance.
7. Pregnancy complications – Studies which collectively include at least 30,000 vaccinated pregnancies (mainly mRNA vaccines) have not identified increased risks of pre-eclampsia[17], maternal death[17], thromboembolic events[17, 23], post-partum haemorrhage[16, 33, 39, 45], hypertensive disorders[23, 24] placental abruption[45], chorioamnionitis[33] and delivery complications[14]. One study has described a small increased risk of post-partum haemorrhage following booster exposure at any time in pregnancy, which was not observed when analysed for exposure within two weeks.[38] As this finding contradicts the findings of other studies, and an increased risk has not been observed among those exposed within two weeks of delivery, it is not currently considered reliable evidence for an increased risk.

Although adverse pregnancy/fetal/neonatal outcomes have been described in adverse drug reaction reports^[22] , as healthy pregnancy outcomes are not similarly described, these data cannot be used to estimate risk.

Given the mechanism of action of COVID-19 vaccines which do not contain live SARS-CoV-2 virus, and that there is currently no known fetal risk with using vaccines that are inactivated, replication-deficient, or contain only structural components of the viral/bacterial pathogen, it is considered unlikely that these vaccines would be harmful if administered in pregnancy. The pregnancy/fetal safety data available are also highly reassuring.

COVID-19 vaccination in pregnancy and impacts on fertility

Unfounded claims have suggested that anti-S protein antibodies developed following COVID-19 vaccination may cross-react with the human placental protein syncytin-1, and thereby damage the placenta.^[49] These claims are contradicted by several studies including findings from: i) animal DART studies^[2-5]; ii) protein amino acid sequencing studies which show limited similarities between the S protein and syncytin-1^[49]; and iii) observational studies of clinical pregnancy success rates in patients undergoing assisted reproductive techniques.^[50-53] Preliminary data describing fertility rates among women who received the AstraZeneca viral vector vaccine in clinical trials also provide no evidence of impaired fertility following vaccination prior to conception.^[26]

Viral vector vaccines and the risk of vaccine-induced thrombotic thrombocytopenia (VITT)

A very rare side effect has been linked to viral vector COVID-19 vaccine use, whereby healthy or medically stable, young (<50 years) adults developed thromboses at unusual sites (including cerebral venous sinus thrombosis, or thrombosis in portal, splanchnic or hepatic veins) following vaccination. The pathogenesis of this adverse reaction has been attributed to an idiosyncratic autoimmune response where platelet factor 4 (PF4)–polyanion complex antibodies develop within three weeks of vaccine administration.^[54]

As this very rare adverse reaction (affecting approximately 1 in 250,000 people) is not correlated to an individual patient’s clotting risk, it is not currently thought that administration of this vaccine in pregnancy (a naturally pro-thrombotic state) would increase the risk of thrombosis or thrombotic thrombocytopenia.^[10] However, the JCVI have advised that all patients under the age of 40 who are at very low risk of experiencing severe COVID-19 (particularly when the prevalence of the disease is low) and may be at higher risk of the adverse reaction should seek vaccination with an mRNA vaccine (Pfizer-BioNTech or Moderna) where possible. Given that there are no reports of VITT following exposure to a second dose of viral vector vaccine, the JCVI have further advised that those who have already received their first dose should also receive their second dose, irrespective of age.^[6]

Hepatitis A and B

In the UK, the adult hepatitis A vaccine contains inactivated whole virus and is available as either a monovalent vaccine, or in combination with hepatitis B or typhoid polysaccharide. The available data regarding hepatitis A vaccine exposure in pregnancy is provided from a total of six studies which together include more than 700 preconception-exposed women and 1,700 women exposed during pregnancy, with approximately 800 exposed in the first trimester.^[55-57] These studies do not indicate that women exposed to hepatitis A vaccine within the 90 days preceding conception are at increased risk of miscarriage. Studies investigating malformation risk specifically are limited, but do not provide evidence of any pattern of birth defects.^{[55, 57]} One study identified a small but statistically significant 1.3-fold increased risk of small for gestational age following early pregnancy vaccination.^[56] However, this finding may have been produced due to unmeasured confounding. No other associations with adverse pregnancy outcomes have been described, but the available data are limited. More information about the risks and benefits of hepatitis A vaccine exposure in pregnancy can be found on the ‘Use of hepatitis A vaccine in pregnancy’ summary monograph.

In the UK, the adult hepatitis B vaccine contains the viral surface antigen and is available as a monovalent inactivated vaccine or in combination with hepatitis A. The available data regarding hepatitis B vaccine exposure in pregnancy is provided from seven uncontrolled case series of small to medium size^{[55, 58, 59]} and a single large controlled cohort study.^[60] Together, these studies include more than 2,000 exposed women, with approximately 1,000 exposed in the first trimester.^{[55, 58-60]} Although the available data are limited for some specific outcomes, there is currently no evidence that exposure to hepatitis B vaccine in pregnancy increases the risk of adverse pregnancy outcomes. More information about the risks and benefits of hepatitis B vaccine exposure in pregnancy can be found on the ‘Use of hepatitis B vaccine in pregnancy’ summary monograph.

Influenza

Seasonal influenza vaccines are inactivated whole virus polyvalent vaccines produced in anticipation of the expected active circulating strains of seasonal influenza virus; hence the antigen formulation can vary on a yearly basis. As influenza infection during pregnancy is associated with a significant risk of morbidity and mortality, Public Health England (PHE) recommends that all pregnant women, regardless of stage of pregnancy, should receive the seasonal influenza vaccine. As a result, hundreds of thousands of pregnant women are immunised with seasonal influenza vaccines each year, and published data describe the outcomes of >165,000 exposed pregnancies.^[61] Overall, there is no indication that exposure to inactivated influenza vaccines in pregnancy is associated with an increased risk of adverse fetal effects. More information about the risks and benefits of influenza vaccine exposure in pregnancy can be found on the ‘Use of seasonal influenza vaccines in pregnancy’ summary monograph.

Tetanus, diphtheria, pertussis and poliomyelitis (Tdap-IPV)

The combined Tdap-IPV vaccine contains tetanus and diphtheria toxoids, acellular pertussis and inactivated poliovirus. In response to rising rates of pertussis infection identified in 2012, the UK Department of Health (DoH) recommended that all pregnant women should be offered vaccination with Tdap-IPV between 16 and 32 weeks of pregnancy. As a result, hundreds of thousands of pregnant women are immunised with Tdap-IPV vaccines each year in the UK. Published data describe the outcomes of >200,000 Tdap or Tdap-IPV exposed pregnancies.^[62] The risk of congenital malformation or miscarriage following first trimester exposure is undetermined, as vaccination during this stage of pregnancy is uncommon. Data regarding risks of stillbirth, low birth weight/intrauterine growth restriction and reduced gestational length following Tdap-IPV vaccination in pregnancy do not provide any evidence of increased risk for these outcomes. More information about the risks and benefits of tetanus/diphtheria/pertussis/polio vaccine exposure in pregnancy can be found on the ‘Use of tetanus/diphtheria/pertussis/polio (Tdap-IPV) vaccine in pregnancy’ summary monograph.

Rabies

There are currently two rabies vaccines licensed for use in the UK, both containing inactivated whole virus. The available data regarding the safety of rabies vaccine exposure in pregnancy are highly limited. A 2020 systematic review identified several uncontrolled case reports/series describing 362 women exposed to rabies vaccine at any stage of pregnancy, without any safety concerns.^[63]

Haemophilus influenza type B

Haemophilus influenza type B (Hib) vaccines are made from capsular polysaccharide extracted from cultures of Hib bacteria that are subsequently conjugated to another protein.^[1] In the UK, the vaccine is administered in infancy; as such, there are very limited human pregnancy exposure data. Three small studies investigating vaccination of pregnant women near term have described transfer of Hib antibodies to the offspring with persistent protective titres for 1 year.^[64] No additional pregnancy exposure have been identified.

Human papillomavirus

The human papillomavirus (HPV) vaccine is an adjuvanted non-infectious recombinant vaccine prepared from highly purified virus-like particles of the major capsid L1 protein of oncogenic HPV types 16 and 18.^[65] In the UK, the HPV vaccine is administered to girls at age 12 to 13 years;^[1] as such, it is unlikely that exposure would arise during pregnancy.

Studies on the safety of HPV vaccine exposure during pregnancy have included pooled analyses of clinical trials, post-marketing surveillance pregnancy registries, and large observational cohort studies which together describe >7,000 exposed pregnancies.^{[66, 67]} The results of these studies do not provide evidence that HPV vaccine exposure in pregnancy increases the risk of miscarriage, major malformation, preterm delivery, low birth weight or small for gestational age.^{[66, 67]}

Pneumococcal disease

There are three types of pneumococcal vaccine licensed in the UK, each containing capsular polysaccharide, providing protection against different pneumococcal serotypes.^[1] Published data regarding the safety of pneumococcal vaccine are highly limited. There are a small number of uncontrolled reports which describe the maternal use of pneumococcal vaccines during pregnancy without adverse effects on the fetus,^[68] and a single randomised controlled study of third trimester vaccination with pneumococcal polysaccharide vaccine (PPV23, n=75 exposed).^[69] The randomised controlled trial did not identify any statistically significant increased risks of preterm delivery, low birth weight or small for gestational age.^[69]

Meningococcal disease

There are several meningococcal vaccines licensed for use in the UK which contain conjugated polysaccharides of different meningococcal serogroups and a multicomponent protein vaccine produced with recombinant DNA.^[1] Published data collected from post-marketing surveillance pregnancy registries, adverse event monitoring, and large observational cohort studies together describe approximately 1,900 exposed pregnancies.^[70] No concerning patterns of adverse pregnancy outcomes were identified from these studies.

Conclusions

Large amounts of pregnancy exposure safety data are available for some of these vaccines, with >100,000 exposed pregnancies being reported in the literature for COVID-19, seasonal influenza and tetanus, diphtheria, pertussis and poliomyelitis (Tdap-IPV) vaccines.

There are currently no proven fetal risks with using vaccines that are inactivated, replication-deficient, or contain only structural components of the viral/bacterial pathogen (‘non-live’). It is therefore considered highly unlikely that such vaccines would be harmful if administered in pregnancy. However, for some of these vaccines, information regarding the safety of administration in pregnancy is either limited or lacking.

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