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Coronavirus Disease 2019 (COVID-19) Vaccines and Pregnancy

Coronavirus Disease 2019 (COVID-19) Vaccines and Pregnancy Current Commentary Coronavirus Disease 2019 (COVID-19) Vaccines and Pregnancy What Obstetricians Need to Know Sonja A. Rasmussen, MD, MS, Colleen F. Kelley, MD, MPH, John P. Horton, MD, and Denise J. Jamieson, MD, MPH pregnancy of vaccine reactogenicity, timing of vaccina- Coronavirus disease 2019 (COVID-19) vaccines have tion during pregnancy, evidence for safety of other begun to be distributed across the United States and to vaccines during pregnancy, risk of COVID-19 complica- be offered initially to priority groups including health tions due to pregnancy and the pregnant person’s under- care personnel and persons living in long-term care lying conditions, and risk of exposure to severe acute facilities. Guidance regarding whether pregnant persons respiratory syndrome coronavirus 2 (SARS-CoV-2) and should receive a COVID-19 vaccine is needed. Because potential for risk mitigation. The Centers for Disease pregnant persons were excluded from the initial phase 3 Control and Prevention, the American College of Obste- clinical trials of COVID-19 vaccines, limited data are tricians and Gynecologists, and the Society for Maternal- available on their efficacy and safety during pregnancy. Fetal Medicine have each issued guidance supportive of After developmental and reproductive toxicology studies offering COVID-19 vaccine to pregnant persons. As addi- are completed, some companies are expected to con- tional information from clinical trials and from data col- duct clinical trials in pregnant persons. Until then, lected on vaccinated pregnant persons becomes pregnant persons and their obstetricians will need to available, it will be critical for obstetricians to keep up use available data to weigh the benefits and risks of to date with this information. COVID-19 vaccines. Issues to be considered when (Obstet Gynecol 2021;137:408–14) counseling pregnant persons include data from animal DOI: 10.1097/AOG.0000000000004290 studies and inadvertently exposed pregnancies during vaccine clinical trials when available, potential risks to ess than a year after identification of the severe acute L respiratory syndrome coronavirus 2 (SARS-CoV-2) From the Departments of Pediatrics, Obstetrics and Gynecology, and Epidemi- ology, University of Florida College of Medicine and College of Public Health and that causes coronavirus disease 2019 (COVID-19), safe Health Professions, Gainesville, Florida; and the Division of Infectious Diseases and effective vaccines are beginning to be distributed and the Department of Gynecology and Obstetrics, Emory University School of across the United States, with the hope of bringing the Medicine, Atlanta, the Grady Healthcare System, Infectious Diseases Program, Atlanta, and the Hope Clinic of the Emory Vaccine Center, Decatur, Georgia. COVID-19 pandemic to an end. Here we summarize Each author has confirmed compliance with the journal’s requirements for what is currently known about COVID-19 vaccines and authorship. their use during pregnancy. Published online ahead-of-print December 23, 2020. Corresponding author: Denise J. Jamieson, MD, MPH, Department of COVID-19 VACCINES AND THE VACCINE Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, APPROVAL PROCESS IN THE UNITED STATES GA; email: djamieson@emory.edu. Six leading vaccine candidates have received some Financial Disclosure Sonja A. Rasmussen reports serving on the Teva Pregnancy Registry Advisory form of federal government support through Opera- Committee and the Solriamfetol Pregnancy Registry Advisory Committee. In tion Warp Speed, the partnership between the U.S. addition, she serves as a litigation consultant on behalf of Hoffmann-La Roche government and the pharmaceutical industry (Table 1); for a product liability claim regarding an alleged birth defect. These are not relevant to this article or COVID-19. Colleen F. Kelley is supported by research of these, two are messenger RNA (mRNA)–based grants to her institution from Gilead Sciences, ViiV, Moderna, and Novavax. The vaccine candidates, two are based on viral vectors, other authors did not report any potential conflicts of interest. and two are recombinant proteins manufactured in a © 2020 by the American College of Obstetricians and Gynecologists. Published baculovirus (DNA virus that infects insect cells) system by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/21 that are co-formulated with adjuvants (substances that 408 VOL. 137, NO. 3, MARCH 2021 OBSTETRICS & GYNECOLOGY © 2020 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Table 1. Leading Vaccine Candidates Under Consideration in the United States No. of Candidate Technology Doses Storage Issues Stage BioNTech–Pfizer mRNA, encodes stabilized 2 270˚C, can be refrigerated Phase 3 clinical trial, BNT162b2 spike, lipid nanoparticle (2–8˚C) for up to 5 d after preliminary results thaw reported Moderna mRNA, encodes stabilized 2 220˚C, can be refrigerated Phase 3 clinical trial, mRNA-1273 spike, lipid nanoparticle (2–8˚C) for up to 30 preliminary results d after thaw reported AstraZeneca and the Replication-incompetent 2 Refrigerator Phase 3 trial in University of Oxford chimpanzee adenovirus temperature (2–8˚C) progress AZD1222 vector, wild type spike Johnson & Johnson– Replication-incompetent 1 Refrigerator Phase 3 trial in Janssen Pharmaceuticals human adenovirus 26 temperature (2–8˚C) progress Ad26.COV2.S vector- stabilized spike Novavax Baculovirus-expressed stabilized 2 Refrigerator Phase 2; phase 3 spike protein (recombinant) + temperature (2–8˚C) anticipated soon Matrix M adjuvant GSK–Sanofi Baculovirus-expressed stabilized 2 Refrigerator Phase 1; phase 2–3 spike protein (recombinant) + temperature (2–8˚C) anticipated in 2021 AS03 adjuvant are added to vaccines to boost the immune than full FDA approval through a Biologics License response). As of December 13, 2020, applications Application, the FDA issued guidance in October for Emergency Use Authorization (EUA) have been 2020 that set a higher standard for COVID-19 vaccines, submitted to the U.S. Food and Drug Administra- given that they would be used on large populations of tion (FDA) for the two mRNA-based vaccine candi- healthy people. In their guidance, the FDA recommen- dates; the other vaccines have not yet completed the ded that, for issuance of an EUA, the evidence would clinical trial process. Emergency Use Authorization need to be similar to that for full approval: benefits of is an authority provided to the FDA to allow unap- the vaccine would need to outweigh its risks based on proved medical products to be used in a public health data from at least one well-designed phase 3 clinical trial emergency to diagnose, treat, or prevent serious or life- (a trial in which participants are randomized to receive a threatening conditions when there are no adequate, new product or a placebo) that demonstrated the vac- approved, and available alternatives. Although the pro- cine’s safety and efficacy in a clear and compelling cess of EUA is usually considered to be less rigorous manner. VOL. 137, NO. 3, MARCH 2021 Rasmussen et al COVID-19 Vaccines and Pregnancy 409 © 2020 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Efficacy No. of Participants in Based on Clinical Trial Randomized Candidate (Vaccine/Placebo) Clinical Trial DART Studies Pregnant Persons in Trials BioNTech–Pfizer Enrolled 45,000 95% In progress; expected Pregnant, breastfeeding, and BNT162b2 completion in December those attempting pregnancy 2020 excluded. 23 inadvertently exposed pregnancies (12 vaccine and 11 placebo) as of November 14, 2020. Pregnancies exposed to vaccine are ongoing. Moderna Enrolled 30,000 94.5% Combined developmental and Pregnant, breastfeeding, and mRNA-1273 perinatal and postnatal those attempting pregnancy reproductive toxicity study in excluded. rats submitted to the FDA on 13 inadvertently exposed December 4, 2020; no pregnancies (6 vaccine, 7 adverse effects on female placebo) as of December 2, reproduction, fetal or 2020. Pregnancies exposed embryonic development, or to vaccine are ongoing. postnatal development noted AstraZeneca and Enrolled 20,000 70.4% In progress Pregnant, breastfeeding, and the University those attempting pregnancy of Oxford excluded. No data on AZD1222 unintended vaccination in pregnancy available at this time. Johnson & 60,000 planned to be NA In progress; preliminary report Pregnant, breastfeeding, and Johnson– recruited expected January 2021 those attempting pregnancy Janssen Phar- excluded. No data on maceuticals unintended vaccination in Ad26.COV2.S pregnancy available at this time. Novavax 30,000 anticipated NA In progress Pregnant, breastfeeding, and those attempting pregnancy to be excluded. Phase 3 trials not yet started. GSK–Sanofi Phase 1–2 interim results NA In progress Pregnant, breastfeeding, and showed vaccine generated those attempting pregnancy insufficient neutralizing to be excluded. Phase 3 antibody titers in adults 50 y trials not yet started. of age and older; phase 3 trial delayed; plans are to nd begin in 2 quarter of 2021 DART, developmental and reproductive toxicology; mRNA, messenger RNA; FDA, U.S. Food and Drug Administration; NA, not available. Several levels of review are required before FDA’s issuance of an EUA, the Advisory Commit- authorization and distribution of a COVID-19 tee on Immunization Practices (ACIP), an indepen- vaccine. The first level of review is by the clinical dent advisory committee to the Centers for Disease trial’s Data and Safety Monitoring Board, a panel of Control and Prevention (CDC), reviews the EUA independent scientists selected to review the evi- and provides recommendations for populations to dence from the phase 3 clinical trial. Next, data be vaccinated. Because the demand for COVID-19 are reviewed by career scientists at the FDA, fol- vaccines is believed to initially exceed the supply, lowed by a review by the Vaccines and Related the ACIP released interim recommendations on Biological Products Advisory Committee December 3, 2020, prioritizing health care person- (VRBPAC), an independent advisory committee to nel and persons living in long-term care facilities to the FDA, before issuance of the EUA. After the be the first to be offered COVID-19 vaccines. 410 Rasmussen et al COVID-19 Vaccines and Pregnancy OBSTETRICS & GYNECOLOGY © 2020 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The six vaccine candidates developed against Human Services, recognized that, “inclusion of preg- COVID-19 use different technologies. Most previ- nant women and lactating women in clinical trials is ously approved vaccines work by introducing an essential, unless there are compelling scientific rea- antigen into the body to produce an immune sons for their exclusion.” Despite the recognition of response. The antigen can be an infectious agent that the need for inclusion of pregnant persons in clinical has been inactivated or a purified protein from the trials, the speed at which the COVID-19 vaccines infectious agent. In contrast, the COVID-19 mRNA were developed and trials conducted precluded inclu- vaccines developed by Pfizer–BioNTech and Mod- sion of pregnant persons. In guidance released in June erna work by carrying the genetic information nec- of 2020, the FDA recommended that pharmaceutical essary to manufacture the spike protein of SARS- companies conduct developmental and reproductive CoV-2, the protein found on the surface of the virus. toxicology studies before enrolling pregnant people or Once the vaccine is injected into muscle cells, they persons who are not actively avoiding pregnancy in manufacture the spike protein, which is recognized their trials. Developmental and reproductive toxicol- by the immune system. The mRNA never enters the ogy studies, which typically use animals to assess the nucleus and is thus not integrated into DNA; within potential effects of a new medication or vaccine on the hours to days, the mRNA is degraded in the cell cyto- full spectrum of reproduction, have not yet been com- plasm. The vaccines developed by AstraZeneca– pleted for any of the COVID-19 vaccines, except for Oxford and Janssen–Johnson and Johnson use a the Moderna vaccine, which submitted results to the modified viral vector to deliver the spike protein of FDA on December 4, 2020 ; thus, pregnant persons SARS-CoV-2 into the cells, which then triggers an have yet to be enrolled. A preliminary report of devel- immune response. The AstraZeneca–Oxford vaccine opmental and reproductive toxicology studies on the uses a chimpanzee adenovirus that has been modified Pfizer–BioNTech vaccine is expected to be sent to the so that it is unable to replicate, whereas the Janssen– FDA in the near future. According to the VRBPAC Johnson and Johnson vaccine uses a human adeno- briefing documents on the Moderna vaccine, a virus 26 that has also been modified to be non- combined developmental and perinatal and postnatal replicating. The adenovirus 26 vector was previously study was conducted in rats and showed no adverse used to make a successful vaccine against Ebola. The effects on female reproduction, fetal or embryonic vaccines developed by Novavax and GSK–Sanofi are development, or postnatal development. It is antici- protein subunit vaccines in which a baculovirus is pated that clinical trials of COVID-19 vaccine safety used to produce the recombinant protein in insect and immunogenicity for pregnant persons could cells. Both of these vaccines will be mixed with begin in January 2021. Because the vaccine is already adjuvants to boost the immune response. The protein shown to be efficacious in adults and adolescents old- subunit approach has been used to make other vac- er than 16 years of age, the trials may use correlates of cines in common use (eg, types of influenza, hepatitis immunity (eg, neutralizing antibodies) rather than B, and human papillomavirus vaccines). COVID-19 acquisition as an outcome. Some companies that developed COVID-19 COVID-19 VACCINES AND PREGNANCY vaccines may plan to include pregnant persons in As is the case thus far with COVID-19 vaccines, clinical trials in the future, but all current studies not pregnant persons have traditionally been excluded only excluded pregnant participants but requested from clinical trials of new medications and vaccines confirmation of a contraception plan for weeks to because of concerns for effects on the fetus. However, months after injection. Thus, very little information is in recent years, federal agencies have recognized the currently available on safety and efficacy in preg- challenges to this approach. In 2013, the National nancy. As of November 14, Pfizer reported that there Institutes of Health’s National Institute of Allergy and were 23 pregnant persons inadvertently enrolled in Infectious Diseases established an expert panel that their clinical trial, including 12 in the vaccine group; developed guidelines for protocol design and safety these pregnancies are ongoing. Moderna reported 13 assessment for clinical trials conducted in pregnant pregnancies in their clinical trial, including six in the persons. In 2018, the FDA published draft guidance vaccine group and seven in the placebo group. The that provided a framework for consideration of inclu- pregnancies exposed to vaccine are ongoing. The sion of pregnant persons in clinical trials. Also in CDC’s ACIP released interim guidance recommend- 2018, the Task Force on Research Specific to Preg- ing that health care personnel be included in the initial nant Women and Lactating Women, a federal group phase to receive the vaccine because of the high risk established to advise the Secretary of Health and of exposure. Given that approximately 75% of the VOL. 137, NO. 3, MARCH 2021 Rasmussen et al COVID-19 Vaccines and Pregnancy 411 © 2020 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. health care workforce are women, the CDC estimates ommend the Pfizer–BioNTech COVID-19 vaccine for that approximately 300,000 health care personnel persons 16 years of age and older in the U.S. popula- could be pregnant or recently postpartum at the time tion under the FDA’s EUA, a recommendation that of vaccine implementation. was subsequently accepted by the CDC Director. The vast majority of vaccines are allowed during The ACIP noted that persons who are part of a group pregnancy when the benefit of vaccine is deemed to recommended to receive the COVID-19 vaccine (eg, outweigh the potential risk. Unfortunately, other than health care personnel) who are pregnant may choose to the small number of inadvertent exposures during preg- be vaccinated and that a discussion with their obstetri- nancy reported in recent COVID-19 vaccine clinical cian might assist them in making an informed deci- trials, no previous experience with pregnant persons is sion, consistent with a recent statement from the available for mRNA vaccines, the type of vaccines first Society for Maternal-Fetal Medicine (SMFM) and a to be available in the United States. However, there is Practice Advisory from the American College of no reason to expect that mRNA vaccines will work Obstetricians and Gynecologists (ACOG). differently in pregnant persons than in other adults. As COUNSELING PREGNANT PERSONS ABOUT is often the case with vaccines, data on the Pfizer– COVID-19 VACCINES BioNTech mRNA vaccines show reactogenicity in a proportion of patients, with fever, fatigue, headache, In weighing the risks and benefits of COVID-19 chills, and muscle and joint pain. Fever (38°C or higher) vaccination, several issues should be considered (Box occurred in 3.7% of participants after dose 1 and 15.8% 1). The obstetrician should review what is known from after dose 2 of the Pfizer–BioNTech mRNA vaccines in developmental and reproductive toxicology studies on persons aged 18–55 years in the clinical trials. Neo- animals regarding the vaccine (when available) and the nates born to pregnant persons with fevers in their first limited data on outcomes of pregnant persons inadver- trimester of pregnancy have been shown to have an tently exposed to vaccine during the clinical trials. increased risk for certain types of birth defects, although Another issue to be discussed is the risks of COVID- the absolute risk is small. The risks associated with 19 illness to a pregnant person and the fetus. Current fever appear to be lowered with antipyretic medication. data suggest that pregnant persons are more likely to be Judicious use of antipyretic medications after vaccina- admitted to an intensive care unit, to require invasive tion is recommended, given the possible concerns that ventilation, to receive extracorporeal membrane oxy- have been raised about acetaminophen use during genation, and to die than nonpregnant women of repro- 12 18 pregnancy as well as concerns regarding whether ductive age. The effects on the fetus are not completely antipyretic medications could decrease vaccine effi- understood. Intrauterine transmission can occur but 13 19 cacy. Recommendations from the ACIP are to use appears to be rare ; however, data suggest that neo- antipyretic medications for treatment rather than for nates born to persons with SARS-CoV-2-infection may prophylaxis. Based on what is known about how be more likely to be born preterm. The risk of com- mRNA vaccines act locally (at the site of injection) and plications to the pregnant person based on factors other are rapidly degraded and removed by the lymphatic than pregnancy also need to be considered: does the system, the likelihood of the vaccine reaching and person have an underlying condition (eg, diabetes, obe- crossing theplacentaisbelievedtobelow. sity, or heart disease) that could cause increased risk for The VRBPAC meeting to discuss the Pfizer– severe COVID-19 complications. Another consider- BioNTech vaccine was held on December 10, 2020, ation is whether the risk of acquiring infection can be and the meeting to discuss the Moderna vaccine is mitigated. Pregnant persons who can minimize their scheduled for December 17, 2020. At the meeting on exposure to persons with SARS-CoV-2 infection (eg, December 10, the VRBPAC voted to support an EUA those who can work from home) are at less risk. for the Pfizer–BioNTech vaccine, and the next day, the Whether there is a risk of exposure to children who FDA announced an EUA for this vaccine. In a news might acquire infection in schools or other settings also briefing held on December 12, 2020, Dr. Peter Marks, needs to be considered. Timing during pregnancy is Director of the FDA’s Center for Biologics Evaluation another consideration. Given the vaccine reactogenicity, and Research, noted that, given that pregnant persons including fever, vaccination in the first trimester could were not enrolled in vaccine clinical trials, there were increase the risk of neural tube and other congenital insufficient data to make a recommendation; however, defects. In addition, exposures earlier in pregnancy he stated, “it will be something that providers will need are more likely to cause adverse outcomes. However, to consider on an individual basis for patients.” On the risks of vaccine reactogenicity on the pregnant per- December 12, 2020, the CDC’s ACIP voted to rec- son and the fetus need to be weighed against the risks of 412 Rasmussen et al COVID-19 Vaccines and Pregnancy OBSTETRICS & GYNECOLOGY © 2020 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. REFERENCES Box 1. Considerations for Counseling Pregnant 1. 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Coronavirus Disease 2019 (COVID-19) Vaccines and Pregnancy

Obstetrics and Gynecology , Volume 137 (3) – Feb 3, 2021

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© 2020 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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Abstract

Current Commentary Coronavirus Disease 2019 (COVID-19) Vaccines and Pregnancy What Obstetricians Need to Know Sonja A. Rasmussen, MD, MS, Colleen F. Kelley, MD, MPH, John P. Horton, MD, and Denise J. Jamieson, MD, MPH pregnancy of vaccine reactogenicity, timing of vaccina- Coronavirus disease 2019 (COVID-19) vaccines have tion during pregnancy, evidence for safety of other begun to be distributed across the United States and to vaccines during pregnancy, risk of COVID-19 complica- be offered initially to priority groups including health tions due to pregnancy and the pregnant person’s under- care personnel and persons living in long-term care lying conditions, and risk of exposure to severe acute facilities. Guidance regarding whether pregnant persons respiratory syndrome coronavirus 2 (SARS-CoV-2) and should receive a COVID-19 vaccine is needed. Because potential for risk mitigation. The Centers for Disease pregnant persons were excluded from the initial phase 3 Control and Prevention, the American College of Obste- clinical trials of COVID-19 vaccines, limited data are tricians and Gynecologists, and the Society for Maternal- available on their efficacy and safety during pregnancy. Fetal Medicine have each issued guidance supportive of After developmental and reproductive toxicology studies offering COVID-19 vaccine to pregnant persons. As addi- are completed, some companies are expected to con- tional information from clinical trials and from data col- duct clinical trials in pregnant persons. Until then, lected on vaccinated pregnant persons becomes pregnant persons and their obstetricians will need to available, it will be critical for obstetricians to keep up use available data to weigh the benefits and risks of to date with this information. COVID-19 vaccines. Issues to be considered when (Obstet Gynecol 2021;137:408–14) counseling pregnant persons include data from animal DOI: 10.1097/AOG.0000000000004290 studies and inadvertently exposed pregnancies during vaccine clinical trials when available, potential risks to ess than a year after identification of the severe acute L respiratory syndrome coronavirus 2 (SARS-CoV-2) From the Departments of Pediatrics, Obstetrics and Gynecology, and Epidemi- ology, University of Florida College of Medicine and College of Public Health and that causes coronavirus disease 2019 (COVID-19), safe Health Professions, Gainesville, Florida; and the Division of Infectious Diseases and effective vaccines are beginning to be distributed and the Department of Gynecology and Obstetrics, Emory University School of across the United States, with the hope of bringing the Medicine, Atlanta, the Grady Healthcare System, Infectious Diseases Program, Atlanta, and the Hope Clinic of the Emory Vaccine Center, Decatur, Georgia. COVID-19 pandemic to an end. Here we summarize Each author has confirmed compliance with the journal’s requirements for what is currently known about COVID-19 vaccines and authorship. their use during pregnancy. Published online ahead-of-print December 23, 2020. Corresponding author: Denise J. Jamieson, MD, MPH, Department of COVID-19 VACCINES AND THE VACCINE Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, APPROVAL PROCESS IN THE UNITED STATES GA; email: djamieson@emory.edu. Six leading vaccine candidates have received some Financial Disclosure Sonja A. Rasmussen reports serving on the Teva Pregnancy Registry Advisory form of federal government support through Opera- Committee and the Solriamfetol Pregnancy Registry Advisory Committee. In tion Warp Speed, the partnership between the U.S. addition, she serves as a litigation consultant on behalf of Hoffmann-La Roche government and the pharmaceutical industry (Table 1); for a product liability claim regarding an alleged birth defect. These are not relevant to this article or COVID-19. Colleen F. Kelley is supported by research of these, two are messenger RNA (mRNA)–based grants to her institution from Gilead Sciences, ViiV, Moderna, and Novavax. The vaccine candidates, two are based on viral vectors, other authors did not report any potential conflicts of interest. and two are recombinant proteins manufactured in a © 2020 by the American College of Obstetricians and Gynecologists. Published baculovirus (DNA virus that infects insect cells) system by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/21 that are co-formulated with adjuvants (substances that 408 VOL. 137, NO. 3, MARCH 2021 OBSTETRICS & GYNECOLOGY © 2020 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Table 1. Leading Vaccine Candidates Under Consideration in the United States No. of Candidate Technology Doses Storage Issues Stage BioNTech–Pfizer mRNA, encodes stabilized 2 270˚C, can be refrigerated Phase 3 clinical trial, BNT162b2 spike, lipid nanoparticle (2–8˚C) for up to 5 d after preliminary results thaw reported Moderna mRNA, encodes stabilized 2 220˚C, can be refrigerated Phase 3 clinical trial, mRNA-1273 spike, lipid nanoparticle (2–8˚C) for up to 30 preliminary results d after thaw reported AstraZeneca and the Replication-incompetent 2 Refrigerator Phase 3 trial in University of Oxford chimpanzee adenovirus temperature (2–8˚C) progress AZD1222 vector, wild type spike Johnson & Johnson– Replication-incompetent 1 Refrigerator Phase 3 trial in Janssen Pharmaceuticals human adenovirus 26 temperature (2–8˚C) progress Ad26.COV2.S vector- stabilized spike Novavax Baculovirus-expressed stabilized 2 Refrigerator Phase 2; phase 3 spike protein (recombinant) + temperature (2–8˚C) anticipated soon Matrix M adjuvant GSK–Sanofi Baculovirus-expressed stabilized 2 Refrigerator Phase 1; phase 2–3 spike protein (recombinant) + temperature (2–8˚C) anticipated in 2021 AS03 adjuvant are added to vaccines to boost the immune than full FDA approval through a Biologics License response). As of December 13, 2020, applications Application, the FDA issued guidance in October for Emergency Use Authorization (EUA) have been 2020 that set a higher standard for COVID-19 vaccines, submitted to the U.S. Food and Drug Administra- given that they would be used on large populations of tion (FDA) for the two mRNA-based vaccine candi- healthy people. In their guidance, the FDA recommen- dates; the other vaccines have not yet completed the ded that, for issuance of an EUA, the evidence would clinical trial process. Emergency Use Authorization need to be similar to that for full approval: benefits of is an authority provided to the FDA to allow unap- the vaccine would need to outweigh its risks based on proved medical products to be used in a public health data from at least one well-designed phase 3 clinical trial emergency to diagnose, treat, or prevent serious or life- (a trial in which participants are randomized to receive a threatening conditions when there are no adequate, new product or a placebo) that demonstrated the vac- approved, and available alternatives. Although the pro- cine’s safety and efficacy in a clear and compelling cess of EUA is usually considered to be less rigorous manner. VOL. 137, NO. 3, MARCH 2021 Rasmussen et al COVID-19 Vaccines and Pregnancy 409 © 2020 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Efficacy No. of Participants in Based on Clinical Trial Randomized Candidate (Vaccine/Placebo) Clinical Trial DART Studies Pregnant Persons in Trials BioNTech–Pfizer Enrolled 45,000 95% In progress; expected Pregnant, breastfeeding, and BNT162b2 completion in December those attempting pregnancy 2020 excluded. 23 inadvertently exposed pregnancies (12 vaccine and 11 placebo) as of November 14, 2020. Pregnancies exposed to vaccine are ongoing. Moderna Enrolled 30,000 94.5% Combined developmental and Pregnant, breastfeeding, and mRNA-1273 perinatal and postnatal those attempting pregnancy reproductive toxicity study in excluded. rats submitted to the FDA on 13 inadvertently exposed December 4, 2020; no pregnancies (6 vaccine, 7 adverse effects on female placebo) as of December 2, reproduction, fetal or 2020. Pregnancies exposed embryonic development, or to vaccine are ongoing. postnatal development noted AstraZeneca and Enrolled 20,000 70.4% In progress Pregnant, breastfeeding, and the University those attempting pregnancy of Oxford excluded. No data on AZD1222 unintended vaccination in pregnancy available at this time. Johnson & 60,000 planned to be NA In progress; preliminary report Pregnant, breastfeeding, and Johnson– recruited expected January 2021 those attempting pregnancy Janssen Phar- excluded. No data on maceuticals unintended vaccination in Ad26.COV2.S pregnancy available at this time. Novavax 30,000 anticipated NA In progress Pregnant, breastfeeding, and those attempting pregnancy to be excluded. Phase 3 trials not yet started. GSK–Sanofi Phase 1–2 interim results NA In progress Pregnant, breastfeeding, and showed vaccine generated those attempting pregnancy insufficient neutralizing to be excluded. Phase 3 antibody titers in adults 50 y trials not yet started. of age and older; phase 3 trial delayed; plans are to nd begin in 2 quarter of 2021 DART, developmental and reproductive toxicology; mRNA, messenger RNA; FDA, U.S. Food and Drug Administration; NA, not available. Several levels of review are required before FDA’s issuance of an EUA, the Advisory Commit- authorization and distribution of a COVID-19 tee on Immunization Practices (ACIP), an indepen- vaccine. The first level of review is by the clinical dent advisory committee to the Centers for Disease trial’s Data and Safety Monitoring Board, a panel of Control and Prevention (CDC), reviews the EUA independent scientists selected to review the evi- and provides recommendations for populations to dence from the phase 3 clinical trial. Next, data be vaccinated. Because the demand for COVID-19 are reviewed by career scientists at the FDA, fol- vaccines is believed to initially exceed the supply, lowed by a review by the Vaccines and Related the ACIP released interim recommendations on Biological Products Advisory Committee December 3, 2020, prioritizing health care person- (VRBPAC), an independent advisory committee to nel and persons living in long-term care facilities to the FDA, before issuance of the EUA. After the be the first to be offered COVID-19 vaccines. 410 Rasmussen et al COVID-19 Vaccines and Pregnancy OBSTETRICS & GYNECOLOGY © 2020 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The six vaccine candidates developed against Human Services, recognized that, “inclusion of preg- COVID-19 use different technologies. Most previ- nant women and lactating women in clinical trials is ously approved vaccines work by introducing an essential, unless there are compelling scientific rea- antigen into the body to produce an immune sons for their exclusion.” Despite the recognition of response. The antigen can be an infectious agent that the need for inclusion of pregnant persons in clinical has been inactivated or a purified protein from the trials, the speed at which the COVID-19 vaccines infectious agent. In contrast, the COVID-19 mRNA were developed and trials conducted precluded inclu- vaccines developed by Pfizer–BioNTech and Mod- sion of pregnant persons. In guidance released in June erna work by carrying the genetic information nec- of 2020, the FDA recommended that pharmaceutical essary to manufacture the spike protein of SARS- companies conduct developmental and reproductive CoV-2, the protein found on the surface of the virus. toxicology studies before enrolling pregnant people or Once the vaccine is injected into muscle cells, they persons who are not actively avoiding pregnancy in manufacture the spike protein, which is recognized their trials. Developmental and reproductive toxicol- by the immune system. The mRNA never enters the ogy studies, which typically use animals to assess the nucleus and is thus not integrated into DNA; within potential effects of a new medication or vaccine on the hours to days, the mRNA is degraded in the cell cyto- full spectrum of reproduction, have not yet been com- plasm. The vaccines developed by AstraZeneca– pleted for any of the COVID-19 vaccines, except for Oxford and Janssen–Johnson and Johnson use a the Moderna vaccine, which submitted results to the modified viral vector to deliver the spike protein of FDA on December 4, 2020 ; thus, pregnant persons SARS-CoV-2 into the cells, which then triggers an have yet to be enrolled. A preliminary report of devel- immune response. The AstraZeneca–Oxford vaccine opmental and reproductive toxicology studies on the uses a chimpanzee adenovirus that has been modified Pfizer–BioNTech vaccine is expected to be sent to the so that it is unable to replicate, whereas the Janssen– FDA in the near future. According to the VRBPAC Johnson and Johnson vaccine uses a human adeno- briefing documents on the Moderna vaccine, a virus 26 that has also been modified to be non- combined developmental and perinatal and postnatal replicating. The adenovirus 26 vector was previously study was conducted in rats and showed no adverse used to make a successful vaccine against Ebola. The effects on female reproduction, fetal or embryonic vaccines developed by Novavax and GSK–Sanofi are development, or postnatal development. It is antici- protein subunit vaccines in which a baculovirus is pated that clinical trials of COVID-19 vaccine safety used to produce the recombinant protein in insect and immunogenicity for pregnant persons could cells. Both of these vaccines will be mixed with begin in January 2021. Because the vaccine is already adjuvants to boost the immune response. The protein shown to be efficacious in adults and adolescents old- subunit approach has been used to make other vac- er than 16 years of age, the trials may use correlates of cines in common use (eg, types of influenza, hepatitis immunity (eg, neutralizing antibodies) rather than B, and human papillomavirus vaccines). COVID-19 acquisition as an outcome. Some companies that developed COVID-19 COVID-19 VACCINES AND PREGNANCY vaccines may plan to include pregnant persons in As is the case thus far with COVID-19 vaccines, clinical trials in the future, but all current studies not pregnant persons have traditionally been excluded only excluded pregnant participants but requested from clinical trials of new medications and vaccines confirmation of a contraception plan for weeks to because of concerns for effects on the fetus. However, months after injection. Thus, very little information is in recent years, federal agencies have recognized the currently available on safety and efficacy in preg- challenges to this approach. In 2013, the National nancy. As of November 14, Pfizer reported that there Institutes of Health’s National Institute of Allergy and were 23 pregnant persons inadvertently enrolled in Infectious Diseases established an expert panel that their clinical trial, including 12 in the vaccine group; developed guidelines for protocol design and safety these pregnancies are ongoing. Moderna reported 13 assessment for clinical trials conducted in pregnant pregnancies in their clinical trial, including six in the persons. In 2018, the FDA published draft guidance vaccine group and seven in the placebo group. The that provided a framework for consideration of inclu- pregnancies exposed to vaccine are ongoing. The sion of pregnant persons in clinical trials. Also in CDC’s ACIP released interim guidance recommend- 2018, the Task Force on Research Specific to Preg- ing that health care personnel be included in the initial nant Women and Lactating Women, a federal group phase to receive the vaccine because of the high risk established to advise the Secretary of Health and of exposure. Given that approximately 75% of the VOL. 137, NO. 3, MARCH 2021 Rasmussen et al COVID-19 Vaccines and Pregnancy 411 © 2020 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. health care workforce are women, the CDC estimates ommend the Pfizer–BioNTech COVID-19 vaccine for that approximately 300,000 health care personnel persons 16 years of age and older in the U.S. popula- could be pregnant or recently postpartum at the time tion under the FDA’s EUA, a recommendation that of vaccine implementation. was subsequently accepted by the CDC Director. The vast majority of vaccines are allowed during The ACIP noted that persons who are part of a group pregnancy when the benefit of vaccine is deemed to recommended to receive the COVID-19 vaccine (eg, outweigh the potential risk. Unfortunately, other than health care personnel) who are pregnant may choose to the small number of inadvertent exposures during preg- be vaccinated and that a discussion with their obstetri- nancy reported in recent COVID-19 vaccine clinical cian might assist them in making an informed deci- trials, no previous experience with pregnant persons is sion, consistent with a recent statement from the available for mRNA vaccines, the type of vaccines first Society for Maternal-Fetal Medicine (SMFM) and a to be available in the United States. However, there is Practice Advisory from the American College of no reason to expect that mRNA vaccines will work Obstetricians and Gynecologists (ACOG). differently in pregnant persons than in other adults. As COUNSELING PREGNANT PERSONS ABOUT is often the case with vaccines, data on the Pfizer– COVID-19 VACCINES BioNTech mRNA vaccines show reactogenicity in a proportion of patients, with fever, fatigue, headache, In weighing the risks and benefits of COVID-19 chills, and muscle and joint pain. Fever (38°C or higher) vaccination, several issues should be considered (Box occurred in 3.7% of participants after dose 1 and 15.8% 1). The obstetrician should review what is known from after dose 2 of the Pfizer–BioNTech mRNA vaccines in developmental and reproductive toxicology studies on persons aged 18–55 years in the clinical trials. Neo- animals regarding the vaccine (when available) and the nates born to pregnant persons with fevers in their first limited data on outcomes of pregnant persons inadver- trimester of pregnancy have been shown to have an tently exposed to vaccine during the clinical trials. increased risk for certain types of birth defects, although Another issue to be discussed is the risks of COVID- the absolute risk is small. The risks associated with 19 illness to a pregnant person and the fetus. Current fever appear to be lowered with antipyretic medication. data suggest that pregnant persons are more likely to be Judicious use of antipyretic medications after vaccina- admitted to an intensive care unit, to require invasive tion is recommended, given the possible concerns that ventilation, to receive extracorporeal membrane oxy- have been raised about acetaminophen use during genation, and to die than nonpregnant women of repro- 12 18 pregnancy as well as concerns regarding whether ductive age. The effects on the fetus are not completely antipyretic medications could decrease vaccine effi- understood. Intrauterine transmission can occur but 13 19 cacy. Recommendations from the ACIP are to use appears to be rare ; however, data suggest that neo- antipyretic medications for treatment rather than for nates born to persons with SARS-CoV-2-infection may prophylaxis. Based on what is known about how be more likely to be born preterm. The risk of com- mRNA vaccines act locally (at the site of injection) and plications to the pregnant person based on factors other are rapidly degraded and removed by the lymphatic than pregnancy also need to be considered: does the system, the likelihood of the vaccine reaching and person have an underlying condition (eg, diabetes, obe- crossing theplacentaisbelievedtobelow. sity, or heart disease) that could cause increased risk for The VRBPAC meeting to discuss the Pfizer– severe COVID-19 complications. Another consider- BioNTech vaccine was held on December 10, 2020, ation is whether the risk of acquiring infection can be and the meeting to discuss the Moderna vaccine is mitigated. Pregnant persons who can minimize their scheduled for December 17, 2020. At the meeting on exposure to persons with SARS-CoV-2 infection (eg, December 10, the VRBPAC voted to support an EUA those who can work from home) are at less risk. for the Pfizer–BioNTech vaccine, and the next day, the Whether there is a risk of exposure to children who FDA announced an EUA for this vaccine. In a news might acquire infection in schools or other settings also briefing held on December 12, 2020, Dr. Peter Marks, needs to be considered. Timing during pregnancy is Director of the FDA’s Center for Biologics Evaluation another consideration. Given the vaccine reactogenicity, and Research, noted that, given that pregnant persons including fever, vaccination in the first trimester could were not enrolled in vaccine clinical trials, there were increase the risk of neural tube and other congenital insufficient data to make a recommendation; however, defects. In addition, exposures earlier in pregnancy he stated, “it will be something that providers will need are more likely to cause adverse outcomes. However, to consider on an individual basis for patients.” On the risks of vaccine reactogenicity on the pregnant per- December 12, 2020, the CDC’s ACIP voted to rec- son and the fetus need to be weighed against the risks of 412 Rasmussen et al COVID-19 Vaccines and Pregnancy OBSTETRICS & GYNECOLOGY © 2020 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. REFERENCES Box 1. Considerations for Counseling Pregnant 1. 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Obstetrics and GynecologyPubmed Central

Published: Feb 3, 2021

References