key: cord-0957935-zhksptff
authors: RAWAL, Smita; TACKETT, Randall L.; STONE, Rebecca H.; YOUNG, Henry N.
title: COVID-19 Vaccination among Pregnant People in the U.S.: A Systematic Review
date: 2022-03-10
journal: Am J Obstet Gynecol MFM
DOI: 10.1016/j.ajogmf.2022.100616
sha: 3c76474d1b2d7a2585adf8739ebe7ef57239a9b0
doc_id: 957935
cord_uid: zhksptff

Objectives: Pregnant people are at increased risk of COVID-19 related morbidity and mortality, and vaccination presents an important strategy to prevent negative outcomes. However, pregnant people were not included in vaccine trials, and there is limited data on COVID-19 vaccines during pregnancy. The objectives of this systematic review were to identify the safety, immunogenicity, effectiveness, and acceptance of COVID-19 vaccination among pregnant people in the U.S. Data Sources: Four databases (PubMed, Web of Science, CINAHL, and Google Scholar) were used to identify eligible studies published from January 01, 2020, through February 06, 2022. Study Eligibility Criteria: Inclusion criteria were peer-reviewed empirical research conducted in the U.S., published in English, and addressed one of the following topics: safety, immunogenicity, effectiveness, and acceptance of COVID-19 vaccination among pregnant people. Study Appraisal and Synthesis Methods: A narrative synthesis approach was used to synthesize findings. Critical appraisal was done using the Joanna Briggs Institute (JBI) tool. Results: Thirty-two studies were identified. The majority of studies (n = 25) reported the use of Pfizer and Moderna COVID-19 vaccines among pregnant people; only six reported the Janssen vaccine. Of the 32 studies, 11 examined COVID-19 vaccine safety, 10 investigated immunogenicity and effectiveness, and 11 assessed vaccine acceptance among pregnant people. Injection site pain and fatigue were the most common adverse events. One case study reported immune thrombocytopenia (ITP). COVID-19 vaccination did not increase the risk of adverse pregnancy or neonatal outcomes in comparison to unvaccinated pregnant people. After COVID-19 vaccination, pregnant people elicited a robust immune response, and vaccinations conferred protective immunity to newborns through breast milk and the placental transfer. COVID-19 vaccine acceptance was low among pregnant people in the U.S. African American race, Hispanic ethnicity, younger age, low education, prior refusal of the influenza vaccine, and lack of provider counseling were associated with low vaccine acceptance. Conclusions: Peer-reviewed studies support COVID-19 vaccine safety and protective effects on pregnant people and their newborns. Future studies that use rigorous methodologies and include diverse populations are needed to confirm current findings. In addition, targeted and tailored strategies are needed to improve vaccine acceptance especially among minorities.

Pregnant people are at an increased risk of COVID-19 related morbidity and mortality. The heightened morbidities are noted in terms of an increased risk of preterm birth 1,2 and increased need for intensive care unit admission, invasive ventilation, and death. [3] [4] [5] Vaccination presents an important strategy to prevent negative outcomes in this population. The Center for Disease Control (CDC), American College of Obstetricians and Gynecologists (ACOG), and the Society for Maternal-Fetal Medicine (SMFM) recommend that pregnant people receive COVID-19 vaccines. [6] [7] [8] Because pregnant people were not included in the COVID-19 vaccine trials, there is limited data on vaccination safety and pregnancy outcomes compared to the general population. 9, 10 The lack of safety and efficacy data means that pregnant people are left with two options: get the vaccine, with limited safety and efficacy data, or skip the vaccine, thus leaving themselves and their fetuses vulnerable to adverse effects of COVID-19. Reviews of recent studies indicate that COVID-19 vaccination during pregnancy produces immune responses and does not cause major adverse effects and negative pregnancy or neonatal outcomes. 11, 12 While there is exponential growth in research on COVID-19 vaccination during pregnancy, many of these reviews included vaccines that are not authorized in the United States (U.S.). 11, 12 Furthermore, these reviews included studies conducted in international settings where vaccine availability, vaccine guidelines, and healthcare systems differ from the U.S. In addition, none of the reviews provided information about the acceptance and uptake of COVID-19 vaccines among pregnant people. Therefore, there is an urgent need for a clear understanding of the safety, efficacy, and acceptance of COVID-19 vaccination during pregnancy so that pregnant people may be supported in making the best decision for their individual situations.

Studies were included if they were peer-reviewed empirical studies conducted in the U.S. from January 01, 2020, through February 06, 2022, published in English, and addressed at least 1 of the following topics: (1) Initial screening of all abstracts and titles was conducted by SR and checked by another author (HNY) to determine whether to include or exclude a study based on the inclusion criteria.

All full-text screening disagreements were reconciled through discussion between the authors (SR, RHS, RLT, and HNY) to achieve mutual consensus before moving to full-text review.

Critical appraisals of included studies were conducted to evaluate the methodological quality of research; to what extent a study was designed, conducted, analyzed, interpreted, and reported to avoid systematic errors. 15 Appraisals focused on methodological domains through which bias may be introduced into the results. 15 All studies identified as meeting the inclusion criteria were assessed for risk of bias by using the Joanna Briggs Institute (JBI) critical appraisal checklist for cohort studies, case-control, case report, case series, quasi-experimental (pre-post), and crosssectional studies. 16 The checklist response options included: Yes (the criteria are clearly identifiable through the report description); Unclear (the criteria are not clearly identified in the report); and No (the criteria are not identifiable). Based on the number (%) of "Yes" responses, the risk of bias was ranked as "high" (less than or equal to 49%), "moderate" (50% to 69%), and "low" (greater than or equal to 70%). 16 Two independent reviewers (SR and HNY) conducted the appraisals, and both reviewers were blinded to each other's quality appraisal reviews. After independent review, the results were then collected by the first reviewer (SR), and discrepancies were discussed with a third reviewer (RLT). There were no exclusions made on the basis of a minimum threshold.

A standard data extraction form was used to collect the following information: study author(s) and year published, study title, study design, study setting, participants, COVID-19 vaccine type, outcomes, and conclusion(s). Data extraction and data synthesis were initially conducted by the first reviewer (SR) but discussed regularly with the review team (RHS, RLT, and HNY) to obtain agreement on all included studies and resolve any disagreements. A narrative synthesis approach was used to analyze studies included in this review. 17 The narrative synthesis approach synthesizes findings from multiple sources and primarily uses words and text to summarize and explain findings. 17 This approach is used when meta-analysis is not feasible due to high heterogeneity across studies.

A total of 522 studies were obtained from PubMed, Web of Science, and CINAHL and imported into Endnote Software (Clarivate Analytics, Philadelphia, PA, U.S.). Removal of 93 duplicates yielded 429 studies. Of those, 363 studies were removed based on exclusion criteria during the title and abstract screening. The remaining 66 studies were screened for full-text review. Of these, 34 were excluded for not meeting the eligibility criteria. As a result, 32 studies were included in the review (Figure 1 ).

The characteristics of included studies are described in Table 1 . All of the included studies used observational study designs; 15 were cohort, 10 were cross-sectional, 4 were case reports, 1 was pre-post, 1 was case-control, and 1 was case series. No randomized controlled trials were identified. Seven studies used COVID-19 vaccination registries and had sample sizes ranging from n = 2,002 to n =135,968; the remaining 25 had sample sizes less than n = 1,030. Twentyone studies reported the use of Pfizer and Moderna COVID-19 vaccines among pregnant people; six reported the Janssen vaccine. Only one study reported the use of COVID-19 vaccine booster in pregnant people. Five studies compared vaccinated pregnant people with vaccinated nonpregnant people, and 5 studies compared vaccinated pregnant people with unvaccinated pregnant people.

Critical appraisals showed that 16 studies had a low risk of bias, 14 had moderate risk, and 2 exhibited high risk. One case-control study included in this review did not match participants, and only seven studies controlled for confounders. Three studies were purely descriptive, and two studies did not explain which statistical test was used to compare differences in observations before and after an intervention. Cross-sectional studies assessing vaccine acceptance did not use valid and reliable instruments to measure acceptance. Additional details regarding the risk of bias are summarized in Supplementary Materials (Table S2 -S7) .

Eleven of the 32 (34%) studies (Figure 2 ) discussed COVID-19 vaccination-related side effects in pregnant people, 18-23 pregnancy outcomes (gestational hypertension, pre-eclampsia, thromboembolism, placental injuries, miscarriage, and stillbirth), 19,24-28 and neonatal outcomes (preterm birth, congenital anomalies, small size for gestational age, neonatal ICU admission, and neonatal death). 19, [27] [28] [29] Included studies that evaluated pregnancy and neonatal outcomes following COVID-19 vaccination did not demonstrate harmful effects with respect to pregnancy, 19,24,25,26,27,28 fetal development, 19,27,28 or neonatal outcomes. 19,27-29 There were no statistical differences in pregnancy outcomes such as gestational hypertension (p = 0.60), pre-eclampsia (p = 1.00), and thromboembolism incidence (p = 1.00) between vaccinated and unvaccinated pregnant people. 28 There were no placental injuries 25 and no stillbirths. 27 Side-effects reported in pregnant people were similar to the general population, and the most common side-effects included injection-site pain, 18-20 injection-site soreness, 20,21 fevers or chills, 18-21,23 fatigue, 18,20 and itching. 20 Immune thrombocytopenia (ITP) was reported in a case study. 22 Studies showed that the incidence of side-effects (injection-site pain, injection-site soreness, and fatigue) was higher in the second dose of vaccination compared with the first dose. 18,19,21

Ten of the 32 (31%) studies (Figure 2 ) in pregnant people examined the immunogenicity or the ability of the COVID-19 vaccine to elicit an immune response. 21,28,37-44 These studies demonstrated that COVID-19 vaccination during pregnancy produced a robust immune response, and the antibody production was similar to those of non-pregnant people. 21,39 These antibodies were also found in umbilical cord blood, 21,37,40-44 which means COVID-19 vaccination during pregnancy may convey some immunity to neonates against COVID-19. In addition, the highest maternal and umbilical cord antibody levels were achieved through the completion of a full vaccination series and a booster dose. 44 Regarding the strength of the vaccine, immunity produced by the COVID-19 vaccination was found to be significantly stronger than after natural infection with the virus (p < 0.05). 21

There was a rapid immunologic response following the first dose of the vaccine, and administration of the second dose further increased the antibody level among vaccinated pregnant people. 21 Similar results were observed in an age-matched cohort study where pregnant people had lower antibody levels after the first dose, but by follow-up after the second dose, immune responses were achieved comparable to that of non-pregnant people. 45 

Eleven of the 32 (34%) studies (Figure 2) 

This study reviewed the available literature on COVID-19 vaccination amongst pregnant people in the U.S. Peer-reviewed observational studies support the assertion that the COVID-19 vaccine is safe during pregnancy and provides protective effects for both pregnant people and their newborns. Most of the reported side-effects such as injection site pain, soreness, fever or chills, and fatigue were not severe and similar to those reported in the general population.

Immune thrombocytopenia (ITP) was reported in one case study. 22 This very rare event has an incidence ranging from 1 case per 26,000 to 1 case per 127,000 doses, 57 and may be resolved by oral corticosteroids without subsequent complications. 22 The protective effects of COVID-19 vaccines in pregnant people were similar to that of the general population. Pregnant people elicited a robust immune response after vaccination with immunogenicity equivalent to non-pregnant people. 21 The vaccines also conferred protective immunity to newborns through breast milk and placental transfer. 21, 27, 40 This demonstrates that COVID-19 vaccination in pregnancy likely has a dual benefit: both the mother and newborn 

To the best of our knowledge, this is the first systematic review exploring COVID-19 vaccination among pregnant people in the U.S. This comprehensive review included all peerreviewed empirical studies published so far on this topic. However, certain limitations of the present study should be acknowledged. First, all studies included in this review were observational, non-randomized, and lacked long-term safety and effectiveness data. Thus, the evidence presented in this review may be limited due to prior study designs. Second, studies included in this review were not excluded based on critical appraisals of the research (i.e., risk of bias assessments). It was considered important to include all studies irrespective of the risk of bias to obtain a more comprehensive picture of relevant research pertaining to the aim of this review. However, it is acknowledged that the lack of a minimum threshold may hold some limitations for the findings. Lastly, the evidence presented in this review may be limited for the Janssen COVID-19 vaccine, since only six studies reported the use of the Janssen COVID-19 vaccine among pregnant people.

Peer-reviewed studies support COVID-19 vaccine safety and protective effects on pregnant people and their newborns. Future studies that use rigorous methodologies and include diverse populations (e.g., minorities and rural residents) are needed to confirm current findings and examine the effectiveness of COVID-19 vaccines and boosters on emerging SARS-CoV-2 variants during pregnancy. In addition, targeted and tailored strategies may help improve vaccine acceptance among pregnant people, especially vulnerable populations. 

Author ( 

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