Print page

USE OF NON LIVE VACCINES IN PREGNANCY

Date of issue: October 2021
Version: 1.3

This is a UKTIS monograph for use by health care professionals. For case-specific advice please contact UKTIS on 0344 892 0909. To report an exposure please download and complete a pregnancy reporting form. Please encourage all women to complete an online reporting form.

A corresponding patient information leaflet on COVID 19 Vaccine is available at www.medicinesinpregnancy.org.

Summary

This document summarises the available evidence regarding the safety of vaccines that are either inactivated, replication deficient or only contain structural components of the viral/bacterial pathogen (i.e. ‘non-live’ vaccines). In the United Kingdom (UK), these vaccines are used to provide immunity against hepatitis A, hepatitis B, seasonal influenza, poliomyelitis, rabies, haemophilus influenza type B, human papillomavirus, pertussis, pneumococcal and meningococcal disease, and COVID-19.

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 both the seasonal influenza and tetanus, diphtheria, pertussis and poliomyelitis polyvalent vaccines.

There are currently no proven fetal risks following gestational exposure to ‘non-live’ vaccines. 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.

Exposure to ’non-live’ vaccines at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

This document is regularly reviewed and updated. Only use full UKTIS monographs downloaded directly from TOXBASE.org to be sure you are using the most up-to-date version. The summaries of these monographs are openly available on UKTIS.org


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 four COVID-19 vaccines with novel mechanisms of action.[2-5] Two of these are messenger RNA (mRNA) vaccines, and the other two are modified adenovirus vaccinew, all of which result in the expression of the SARS-CoV-2 spike protein antigen to stimulate cellular and neutralising antibody immune responses against the SARS-CoV-2 virus.

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.

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.[6-8] 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.[6, 8] One study identified a small but statistically significant 1.3-fold increased risk of small for gestational age following early pregnancy vaccination.[7] 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[6, 9, 10] and a single large controlled cohort study.[11] Together, these studies include more than 2,000 exposed women, with approximately 1,000 exposed in the first trimester.[6, 9-11] 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.[12] 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.[13] 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.[14]

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.[15] 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.[16] 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.[17, 18] 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.[17, 18]

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,[19] and a single randomised controlled study of third trimester vaccination with pneumococcal polysaccharide vaccine (PPV23, n=75 exposed).[20] The randomised controlled trial did not identify any statistically significant increased risks of preterm delivery, low birth weight or small for gestational age.[20]

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.[21] No concerning patterns of adverse pregnancy outcomes were identified from these studies.

COVID-19
There are currently four 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] The other 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.

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]

Post-marketing observational pregnancy and fetal outcome data have accumulated since June 2021, and studies from the US, Israel, England, Scotland and Canada have described the outcomes of more than 9,000 COVID-19 vaccinated pregnancies.[22-33] The majority of these pregnancies were vaccinated using the mRNA vaccines (Pfizer/BioNTec or Moderna), with most vaccinations occurring in the third trimester. The majority of these data are not currently suitable for assessing risks pertaining to early pregnancy vaccine exposure, such as malformation or miscarriage. However, two studies have provided preliminary data indicating that miscarriage is not associated with COVID-19 vaccination.[26, 28] The available studies were also highly reassuring with regards to the safety of later pregnancy exposure, describing no increased risks of stillbirth, preterm delivery, small for gestational age infants or neonatal death.[24, 25, 29, 30, 32]

The data were also reassuring with regards to the risk of maternal adverse reactions, with severe reactions (with the exception of nausea and vomiting following the second dose) not appearing any more likely among pregnant women in comparison with non-pregnant women of the same age.[30] Reports of adverse pregnancy/fetal/neonatal outcomes have also been described in adverse drug reaction reports.[30] However, as these reports are spontaneous and healthy pregnancy outcomes are not similarly described, they cannot be used to estimate risk.

Given the mechanism of action of these 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 preliminary pregnancy/fetal safety data available for the mRNA vaccines are also reassuring, particularly following third trimester exposure, but the data are incomplete. Therefore, it may not be possible to provide an informed risk assessment regarding the safety of COVID-19 vaccine use for all stages of pregnancy. Nonetheless, women may benefit from vaccination in pregnancy.

Current recommendations from the DoH/Joint Committee on Vaccination and Immunisation (JCVI) and the Royal College of Obstetricians and Gynaecologists (RCOG) state that, as of 16th April 2021, all pregnant women should be offered the COVID-19 vaccine at the same time as the rest of the population, based on their age and clinical risk group.[34] Given the availability of preliminary pregnancy/fetal safety data for the mRNA vaccines, the latest advice from the JCVI states that, where possible, it is preferable that pregnant women are offered one of the mRNA COVID-19 vaccines licensed for use in the UK (Pfizer-BioNTech or Moderna). More information about the risks and benefits of COVID-19 vaccination in pregnancy is provided by the RCOG.

Viral vector vaccines and the risk of vaccine-induced thrombotic thrombocytopenia (VITT)
A very rare side effect has been linked to the viral vector COVID-19 vaccines (AstraZeneca in the UK), where 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.[35] 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.[34] 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.[36]


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 both the seasonal influenza and tetanus, diphtheria, pertussis and poliomyelitis polyvalent 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.


References

1. Public Health England, The Green Book: Immunisation against infectious disease. 2021.
2. AstraZeneca, SmPC: Information for UK healthcare professionals - AstraZeneca COVID-19 Vaccine. 2020.
3. Janssen Pharmaceuticals, COVID-19 Vaccine Janssen suspension for injection. . 2021. PMID:
4. Pfizer/BioNtech, SmPC: Information for UK healthcare professionals - Pfizer/BioNTech COVID-19 Vaccine. 2020.
5. Moderna, SmPC: Information for UK healthcare professionals - Moderna COVID-19 Vaccine. 2021.
6. Celzo, F., H. Buyse, S. Welby, and A. Ibrahimi, Safety evaluation of adverse events following vaccination with Havrix, Engerix-B or Twinrix during pregnancy. Vaccine, 2020. 38(40): p. 6215-6223. PMID:
7. Groom, H.C., N. Smith, S.A. Irving, P. Koppolu, G. Vazquez-Benitez, E.O. Kharbanda, M.F. Daley, J.G. Donahue, D. Getahun, L.A. Jackson, N.P. Klein, N.L. McCarthy, J.D. Nordin, L. Panagiotakopoulos, and A.L. Naleway, Uptake and safety of hepatitis A vaccination during pregnancy: A Vaccine Safety Datalink study. Vaccine, 2019. 37(44): p. 6648-6655. PMID:
8. UKTIS, Use of Hepatitis A Vaccine in Pregnancy. 2016(3). PMID:
9. Moro, P.L., Y. Zheteyeva, F. Barash, P. Lewis, and M. Cano, Assessing the safety of hepatitis B vaccination during pregnancy in the Vaccine Adverse Event Reporting System (VAERS), 1990-2016. Vaccine, 2018. 36(1): p. 50-54. PMID:
10. UKTIS, Use of Hepatitis B Vaccine in Pregnancy. 2016(3). PMID:
11. Groom, H.C., S.A. Irving, P. Koppolu, N. Smith, G. Vazquez-Benitez, E.O. Kharbanda, M.F. Daley, J.G. Donahue, D. Getahun, L.A. Jackson, A. Tse Kawai, N.P. Klein, N.L. McCarthy, J.D. Nordin, L. Sukumaran, and A.L. Naleway, Uptake and safety of Hepatitis B vaccination during pregnancy: A Vaccine Safety Datalink study. Vaccine, 2018. 36(41): p. 6111-6116. PMID:
12. UKTIS, Use of Seasonal Influenza Vaccines in Pregnancy. 2017(3). PMID:
13. UKTIS, Use of Tetanus/Diphtheria/Pertussis/Polio (Tdap-IPV) Vaccine in Pregnancy. 2016(2). PMID:
14. Nasser, R., S. Rakedzon, Y. Dickstein, A. Mousa, I. Solt, N. Peterisel, T. Feldman, and A. Neuberger, Are all vaccines safe for the pregnant traveller? A systematic review and meta-analysis. Journal of travel medicine, 2020. 27(2). PMID:
15. Reprotox, Haemophilus Influenzae Type B Vaccine. Accessed via Micromedex, 2021. PMID:
16. GlaxoSmithKline, U.K., SmPC: Cervarix suspension for injection in a vial. 2020.
17. Bukowinski, A.T., C. Hall, R.N. Chang, G.R. Gumbs, and A. Marie S Conlin, Maternal and infant outcomes following exposure to quadrivalent human papillomavirus vaccine during pregnancy. Vaccine, 2020. 38(37): p. 5933-5939. PMID:
18. Reprotox, Human Papillomavirus Vaccine. Accessed via Micromedex, 2021. PMID:
19. Reprotox, Pneumococcal Vaccines. Accessed via Micromedex, 2021. PMID:
20. McHugh, L., M. Binks, R.S. Ware, T. Snelling, S. Nelson, J. Nelson, M. Dunbar, E.K. Mulholland, and R.M. Andrews, Birth outcomes in Aboriginal mother-infant pairs from the Northern Territory, Australia, who received 23-valent polysaccharide pneumococcal vaccination during pregnancy, 2006-2011: The PneuMum randomised controlled trial. The Australian & New Zealand journal of obstetrics & gynaecology, 2020. 60(1): p. 82-87. PMID:
21. Reprotox, Meningococcal Vaccines. Accessed via Micromedex, 2021. PMID:
22. Blakeway, H., S. Prasad, E. Kalafat, P.T. Heath, S.N. Ladhani, K. Le Doare, L.A. Magee, P. O'Brien, A. Rezvani, P.V. Dadelszen, and A. Khalil, COVID-19 Vaccination During Pregnancy: Coverage and Safety. Am J Obstet Gynecol, 2021. PMID: 34389291.
23. Bookstein Peretz, S., N. Regev, L. Novick, M. Nachshol, E. Goffer, A. Ben-David, K. Asraf, R. Doolman, E. Gal Levin, G. Regev Yochay, and Y. Yinon, Short-term outcome of pregnant women vaccinated with BNT162b2 mRNA COVID-19 vaccine. Ultrasound Obstet Gynecol, 2021. 58(3): p. 450-456. PMID: 34198360.
24. Born Ontario, COVID-19 Vaccination During Pregnancy in Ontario. 2021.
25. Goldshtein, I., D. Nevo, D.M. Steinberg, R.S. Rotem, M. Gorfine, G. Chodick, and Y. Segal, Association Between BNT162b2 Vaccination and Incidence of SARS-CoV-2 Infection in Pregnant Women. JAMA, 2021. 326(8): p. 728-735. PMID: 34251417.
26. Head Zauche, L., B. Wallace, A.N. Smoots, C.K. Olson, T. Oduyebo, S.Y. Kim, E.E. Peterson, J. Ju, J. Beauregard, A.J. Wilcox, C.E. Rose, D. Meaney-Delman, and S.R. Ellington, Receipt of mRNA COVID-19 vaccines preconception and during pregnancy and risk of self-reported spontaneous abortions, CDC v-safe COVID-19 Vaccine Pregnancy Registry 2020-21. Res Sq, 2021. PMID: 34401872.
27. Kachikis, A., J.A. Englund, M. Singleton, I. Covelli, A.L. Drake, and L.O. Eckert, Short-term Reactions Among Pregnant and Lactating Individuals in the First Wave of the COVID-19 Vaccine Rollout. JAMA Netw Open, 2021. 4(8): p. e2121310. PMID: 34402893.
28. Kharbanda, E.O., J. Haapala, M. DeSilva, G. Vazquez-Benitez, K.K. Vesco, A.L. Naleway, and H.S. Lipkind, Spontaneous Abortion Following COVID-19 Vaccination During Pregnancy. JAMA, 2021. PMID: 34495304.
29. Public Health Scotland, COVID-19 Statistical Report. 2021.
30. Shimabukuro, T.T., S.Y. Kim, T.R. Myers, P.L. Moro, T. Oduyebo, L. Panagiotakopoulos, P.L. Marquez, C.K. Olson, R. Liu, K.T. Chang, S.R. Ellington, V.K. Burkel, A.N. Smoots, C.J. Green, C. Licata, B.C. Zhang, M. Alimchandani, A. Mba-Jonas, S.W. Martin, J.M. Gee, and D.M. Meaney-Delman, Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons. The New England journal of medicine, 2021. PMID:
31. Theiler, R.N., M. Wick, R. Mehta, A.L. Weaver, A. Virk, and M. Swift, Pregnancy and birth outcomes after SARS-CoV-2 vaccination in pregnancy. Am J Obstet Gynecol MFM, 2021: p. 100467. PMID: 34425297.
32. Trostle, M.E., M.A. Limaye, M.V. Avtushka, J.L. Lighter, C.A. Penfield, and A.S. Roman, COVID-19 vaccination in pregnancy: early experience from a single institution. Am J Obstet Gynecol MFM, 2021: p. 100464. PMID: 34411758.
33. Wainstock, T., I. Yoles, R. Sergienko, and E. Sheiner, Prenatal maternal COVID-19 vaccination and pregnancy outcomes. Vaccine, 2021. 39(41): p. 6037-6040. PMID: 34531079.
34. Royal College of Obstetricians and Gynaecologists, COVID-19 vaccines, pregnancy and breastfeeding. 2021.
35. Cines, D.B. and J.B. Bussel, SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia, in The New England journal of medicine. 2021.
36. Joint Committee on Vaccination and Immunisation, Independent report - JCVI statement on use of the AstraZeneca COVID-19 vaccine. 2021.

This is a summary of the full UKTIS monograph for health care professionals and should not be used in isolation. The full UKTIS monograph and access to any hyperlinked related documents is available to health care professionals at www.toxbase.org.

If you have a patient with exposure to a drug or chemical and require assistance in making a patient-specific risk assessment, please telephone UKTIS on 0344 892 0909 to discuss the case with a teratology specialist.

If you would like to report a pregnancy to UKTIS please click here to download our pregnancy reporting form. Please encourage all women to complete an online reporting form.

Disclaimer: Every effort has been made to ensure that this monograph was accurate and up-to-date at the time of writing, however it cannot cover every eventuality and the information providers cannot be held responsible for any adverse outcomes of the measures recommended. The final decision regarding which treatment is used for an individual patient remains the clinical responsibility of the prescriber. This material may be freely reproduced for education and not for profit purposes within the UK National Health Service, however no linking to this website or reproduction by or for commercial organisations is permitted without the express written permission of this service. This document is regularly reviewed and updated. Only use UKTIS monographs downloaded directly from TOXBASE.org or UKTIS.org to ensure you are using the most up-to-date version.