Archives of Academic Emergency Medicine. 2022; 10(1): e76 REV I EW ART I C L E Complications of COVID-19 Vaccines during Pregnancy; a Systematic Review SeyedAhmad SeyedAlinaghi1, Mehrzad MohsseniPour1, Solmaz Saeidi2, Pedram Habibi1, Mohsen Dashti3, Newsha Nazarian4, Tayebeh Noori5, Zahra Pashaei1, AmirBehzad Bagheri6, Afsaneh Ghasemzadeh3, Amir Masoud Afsahi7, Narjes Aghaie8, Paniz Mojdeganlou9, Ghazal Arjmand9, Ghazal Zargari10, Roshanak Modiri1, Hengameh Mojdeganlou11, Armin Razi12, Esmaeil Mehraeen 13∗, Omid Dadras1,14 1. Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High Risk Behaviors, Tehran University of Medical Sciences, Tehran, Iran. 2. Department of Nursing, Khalkhal University of Medical Sciences; Khalkhal, Iran. 3. Department of Radiology, Tabriz University of Medical Sciences, Tabriz, Iran. 4. School of Medicine, Islamic Azad University, Tehran, Iran. 5. Department of Health Information Technology, Zabol University of Medical Sciences, Zabol, Iran. 6. Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 7. Department of Radiology, School of Medicine, University of California, San Diego (UCSD), California, USA. 8. School of Nursing and Midwifery, Tehran University of Medical Sciences, Tehran, Iran. 9. Shahid Beheshti University of Medical Sciences, Tehran, Iran. 10.School of Medicine, Iran University of Medical Sciences, Tehran, Iran. 11.Department of Pathology, Urmia University of Medical Sciences, Urmia, Iran. 12.School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 13.School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 14.Department of Global Public Health and Primary Care, Graduate School of Medicine, University of Bergen, Bergen, Norway. Received: July 2022; Accepted: August 2022; Published online: 24 September 2022 Abstract: Introduction: Rare serious complications have been documented after COVID-19 vaccination as clinical re- search proceeded and new target populations, such as children and pregnant women, were included. In this study, we attempted to review the literature relevant to pregnancy complications and maternal outcomes of COVID-19 immunization in pregnant women. Methods: We searched the databases of PubMed, Scopus, Cochrane, and Web of Science on 31 August 2022. The records were downloaded and underwent a two-step screening; 1) title/abstract and then 2) full-text screening to identify the eligible studies. We included English original studies that evaluated the adverse effects of COVID-19 vaccines during pregnancy. Information such as the type of study, geographical location, type of vaccine injected, gestational age, maternal underlying dis- eases, and complications following the vaccination were extracted into pre-designed tables. Results: According to the findings of included studies, in most of them vaccination had a positive impact and no negative effects were observed. Also, no medical history was reported in 11 articles, and pregnant women had no underlying diseases. Some serious adverse events were reported after vaccination, including miscarriage, paresthesia, uter- ine contraction, vaginal bleeding, preterm birth, major congenital anomalies, intrauterine growth restriction, and seizure. Conclusion: Because of limited data availability and the cross-sectional design of most studies, we could neither infer causation between vaccines and incidence of adverse effects nor comment with certainty about any possible adverse outcome of COVID-19 vaccines in vaccinated pregnant women. Consequently, more longitudinal and experimental studies are needed to define the exact adverse effects of COVID-19 vaccines in pregnant women. Keywords: Drug-related side effects and adverse reactions; COVID-19; COVID-19 vaccines; pregnancy; SARS-CoV-2 Cite this article as: SeyedAlinaghi SA, MohsseniPour M, Saeidi S, Habibi P, Dashti M, et al. Complications of COVID-19 Vaccines during Pregnancy; a Systematic Review. Arch Acad Emerg Med. 2022; 10(1): e76. https://doi.org/10.22037/aaem.v10i1.1622. ∗Corresponding Author: Esmaeil Mehraeen, Department of Health Infor- mation Technology, Khalkhal University of Medical Sciences, Khalkhal, Iran. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem SA. SeyedAlinaghi et al. 2 1. Introduction Putting an end to the pandemic has been the ultimate goal of humanity since the commencement of the COVID-19 pan- demic and substantial efforts have been made to develop an effective vaccine to curb the virus ever since. As a result of ad- vancements in COVID-19 prevention research, many coun- tries have developed coronavirus vaccines (1-3). The devel- opment of these vaccines, each of which inhibit Coronavirus infection using a different mechanism, raises the hopes of ending the COVID-19 pandemic. Although COVID-19 vac- cination lowers the chance of acquiring the coronavirus and its mortality with no or minimal major side effects (4, 5), rare serious complications have been documented after COVID- 19 vaccination as clinical research proceeded and new target populations, such as children and pregnant women, were in- cluded (6). Serious side effects of vaccines have been reported in the past, and such side effects have not been specific to COVID- 19 vaccines. For instance, the Influenza vaccine may have some serious side effects such as Guillain-Barré syndrome and acute transverse myelitis (7-9). Likewise, COVID-19 im- munization may potentially cause acute transverse myelitis in rare cases (10). It has been shown that pregnant women could be at a higher risk of severe COVID-19 infection (11) and COVID-19 infec- tion in a pregnant mother is more likely to harm her or her fetus. It appeared that caesarean sections and premature de- liveries may be more likely in severe COVID-19 among preg- nant patients (12). These findings emphasize the important role of COVID-19 immunization in pregnant women. There- fore, it is of paramount importance to explore the possible side effects of COVID-19 vaccination in pregnant women us- ing available data. Since pregnant women were not included in initial vaccine trials, limited information exists on the vac- cine’s efficacy and safety during pregnancy. Although several studies reported different side effects of COVID-19 vaccines in the general population, there is a scarcity of literature on pregnant women (3, 13, 14). Therefore, more research con- cerning the effectiveness and possible side effects of COVID- 19 vaccination in pregnant women is needed. Due to the novelty of COVID-19 vaccination, we attempted to review the literature relevant to pregnancy complications and maternal outcomes of COVID-19 immunizations in this systematic re- view. Postal Code: 5681761351, Tel: +98-45-32426801, Fax: +98-45-32422305, E-mail: es.mehraeen@gmail.com. 2. Methods 2.1. Search strategy This systematic review was reported in adherence to the Pre- ferred Reporting Items for Systematic Reviews and Meta- Analysis (PRISMA) checklist. We searched the databases of PubMed, Cochrane, Scopus, and Web of Science on 31 August 2022. To develop our search strategy, we checked the keywords from previous studies and the medical sub- ject headings (MeSH) website. The search strategies for each database are reported below as an example: (((COVID-19 [Title] OR SARS-CoV-2 [Title] OR Novel coron- avirus [Title] OR 2019-nCoV [Title]) AND (vaccine [Title] OR vaccination [Title] OR vaccinated [Title] OR immunization [Title])) AND (side effect [Title] OR adverse effect [Title] OR adverse reaction [Title] OR adverse event [Title] OR safety [Title])) AND (pregnancy [Title] OR pregnant [Title] OR ges- tation [Title] OR gestational [Title]) PICO 1. Population: Pregnant women 2. Intervention: Receiving COVID-19 vaccines 3. Comparison: Not receiving COVID-19 vaccines 4. Outcomes: Various adverse events Inclusion/exclusion criteria We included English original studies that evaluated the ad- verse effects of COVID-19 vaccines during pregnancy. We did not impose any restrictions regarding the date of the studies or the length of their follow-up in this systematic review. The exclusion criteria were the following: 1) Non-original studies (reviews, opinions, etc.) 2) Non-English studies 3) Studies not related to the aim of this systematic review (e.g. not related to COVID-19 vaccines, not related to pregnancy, did not measure adverse effects, etc.) 4) Studies not conducted in humans 5) Abstracts or studies that lacked available full-texts 2.2. Study selection process Two independent researchers screened the studies in a two- step method. First, they screened the studies based on the contents of their title and abstracts. Then, the eligible stud- ies entered the second step, which was the full-text screening. Studies that adhered to the inclusion criteria in both steps were finally included in this systematic review. In case of any disagreements between the researchers, they asked the opin- ion of another researcher to resolve the matter. 2.3. Data extraction Three independent researchers extracted the data of the in- cluded studies into a pre-designed word table (one third of the studies were given to each researcher). The following in- formation were extracted: type of the study, country, study This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2022; 10(1): e76 population, vaccine type, gestational age (week/trimester), past medical history, and reported complications (typical side effects or serious adverse events). Another researcher checked the extracted data and corrected any possible mis- takes. The extracted data were qualitatively synthesized, but we did not aim to perform statistical analysis as the study is not a meta-analysis. 2.4. Risk of bias/quality assessment We assessed the risk of bias/quality of the studies using the Newcastle-Ottawa scale (NOS) checklist. This scale allocates a 0-9 score to each study based on selection, comparability, and exposure/outcome (15). Studies that scored 4 or below were considered of poor quality. 3. Results A total of 1447 relevant studies were identified applying dif- ferent combinations of keywords and search strategies in on- line databases. Following the initial review, 408 duplicates were deleted. The remaining articles (n=1039) were screened by two independent researchers based on their title and ab- stract. In the next step, the full-text of 470 remaining arti- cles were thoroughly read and based on eligibility criteria, the most relevant records were selected for final qualitative syn- thesis. During data extraction, 450 articles were removed be- cause they were non-English articles (n=25), papers with the lack of experimental data (n=392), and animal or pure lab- based studies (n=33). Finally, 20 studies met the inclusion criteria and were included (Figure 1). Variables including type of vaccine, sample population, age, complications, gestational age, and prior medical history were extracted and are reported in Table 1. Included articles investigated the side effects and adverse events of COVID-19 vaccines including Pfizer-BioNTech, Moderna, and Janssen. The study designs included case report, case series, and cross-sectional and cohort studies. According to the findings of included studies, in most cases vaccination had a positive impact and no negative effects were observed. There were no notable differences between the vaccinated and unvaccinated groups in 11 studies. In two studies, complications were reported more in the vacci- nated group than in the unvaccinated group. In a study con- ducted among 390 pregnant women, paresthesia was signif- icantly more common among vaccinated pregnant women compared to unvaccinated group. Also, in those who re- ceived the 2nd dose in the third-trimester, uterine contrac- tions were significantly more common (16). Two newborn babies of 84 pregnant women who had received Pfizer (49%), and Moderna (51%) vaccines, were admitted to the intensive care unit to receive respiratory support. One baby received continuous positive airway pressure (CPAP) and one of them had transient tachypnea of the newborn (17). No medical history was reported in 11 articles, and preg- nant women had no underlying diseases. However, in a co- hort study conducted on 7350 pregnant women, underly- ing disease of diabetes mellitus, hypertension, Immunosup- pression/cancer, obesity (BMI ≥30), infertility, chronic kid- ney disease, cardiovascular disease, and chronic obstructive pulmonary disease were reported (18, 19). In another cohort study in 84 pregnant women who were in their first (13.1%), second (46.4%), and third (40.5%) trimesters of pregnancy, diabetes mellitus, hypertension, obesity (BMI≥30), asthma, Immunosuppression/cancer, and previous SARS-CoV-2 in- fection were reported as underlying diseases (17). Chronic liver disease, chronic heart disease, diabetes mellitus, and hypertension in 390 pregnant women in all three trimesters of pregnancy were reported (16). The time between vac- cine inoculation and the onset of adverse events of idiopathic thrombocytopenic purpura (ITP) symptoms was 11 days in a woman who was in her first trimester of pregnancy (20) and it was 12 days in 30 pregnant women who were in their first (17%), second (50%), and third (33%) trimesters of pregnancy (21). In a matched cohort of 133 vaccinated and 399 unvaccinated pregnant women who had received Pfizer and Moderna, the rates of adverse pregnancy outcomes were similar between vaccinated and unvaccinated pregnant women: postpartum hemorrhage (9.8% vs 9%), fetus small for gestational age (12% vs 12.8%), maternal high-dependency unit or intensive care admission (6% vs 4%), neonatal intensive care unit ad- mission (5.3% vs 5%), fetal abnormalities (2.2% vs 2.5%), and stillbirth (0% vs 0.2%). In the vaccinated group, three fetal abnormalities including spina bifida, ventriculomegaly, and hydronephrosis were reported. The spina bifida case was diagnosed before the first dose of the COVID vaccine. The ventriculomegaly case was diagnosed at 37 weeks gestation with no associated brain abnormalities. The hydronephro- sis appeared to be mild with no associated abnormality at birth (22). In another cohort study conducted on 827 preg- nant women who received Moderna (46%) and Pfizer (54%) vaccines, 46 cases of spontaneous abortion, and three cases of stillbirth, premature rupture of membrane, and vaginal bleeding, each, were reported. No congenital anomalies were observed (23). In a case report, a pregnant woman who received Moderna in the first trimester manifested ITP symptoms including acute bruising and petechiae, she was discharged after three days of hospitalization and completely recovered following a course of steroid treatment (20). In a case-control study, 390 pregnant women who received Pfizer in their first (19.5%), second (49.5%), and third (31%) trimesters, experienced the following adverse events: axillary lymphadenopathy (0.3%), paresthesia (2.3%), uterine contraction (1.3%), and vagi- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem SA. SeyedAlinaghi et al. 4 Table 1: Complications of COVID-19 vaccination during pregnancy ID The first author (r) Type of study Sample size Type of Vaccine Gestational Age (%) Medical history (%) Complication (%) Other findings Adverse events Side effects 1 Blakeway, H. (22) UK Cohort 1328 PB, M N/A N/A Spina bifida, ventriculomegaly, hydronephrosis, fetal abnormalities, postpartum hemorrhage N/A N/A 2 Carrie Bennett (20) USA Case report 1 M First trimester N/A ITP symptoms: acute bruising and petechiae N/A Discharged after 3 days of hospitalization, to continue steroids for one week and taper over 6 weeks. 3 S. Book- steinPeretz (16) Israel Case- control 390 PB First trimester (19.5), second trimester (49.5), third trimester (31) Diabetes mellitus (3.3), chronic heart disease (0.8), chronic liver disease (5.4), hyper- tension (0.5) Axillary lymphadenopathy (0.3), paresthesia (2.3), uterine contraction (1.3), vaginal bleeding (0.3), two babies admitted to ICU Local pain (91.8), rash (0.8), fever (1.5), severe fatigue (25.6), arthralgia (1), myalgia (5.9), headache (4.6) Paresthesia among pregnant women was significantly more common. In those who received 1st dose during the third trimester, local pain/swelling was significantly less common and in those who received 2nd in third-trimester uterine contractions were significantly more common. 4 Tom T. Shimabukuro (23) USA Cohort 827 PB (54) M (46) N/A N/A Pregnancy losses (13.9), preterm birth (9.4), small for gestational age (3.2), major congenital anomalies (2.2) N/A live-born infants=724 multiple gestation=12 5 Megan E Trostle (24) USA Cross- sectional 424 mRNA First trimester (34), second trimester (54.4), third trimester (11) N/A Spontaneous abortions (2.12), Terminated pregnancies (0.7), Intrauterine growth restriction (0.6), anomalies (1.5), preterm birth (5.9), need for NICU (15.3), small for gestational age (12.2) N/A N/A 6 Regan N. Theiler (28) USA Cohort 2002 mRNA Median gesta- tional age 32 weeks N/A No adverse events were reported. N/A N/A 7 Tamar Wainstock (29) Israel Cohort 913 PB 3rd trimester N/A No adverse events were reported. N/A N/A 8 Lauren Head Zauche (27), USA Cohort 2456 mRNA Prior to 20 weeks’ gestation N/A N/A N/A N/A This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2022; 10(1): e76 Table 1: Complications of COVID-19 vaccination during pregnancy ID The first author (r) Type of study Sample size Type of Vaccine Gestational Age (%) Medical history (%) Complication (%) Other findings Adverse events Side effects 9 Renuka Ananth (25) USA cross- sectional 38 PB (52.6) M (47.4) N/A N/A Seizure (2.6) Sore arm or pain (97.3), fatigue (57.8), headache (50), chills (47.3), myalgia (34.2), nausea (28.9), fever (15.7), sweating (15.7), feelings of joy (10.5), rash (10.5), joint pains (7.8), swelling (7.8), flushing (7.8), reduced mental clarity (7.8), itching (5.2), decreased appetite (5.2), decreased sleep quality (5.2), Palpitations or increased heart rate (5.2), heat or cold intolerance (5.2), anxiety (5.2), heartburn (5.2), muscle spasm (2.6), nasal congestion (2.6), increase in sleep (2.6), vomiting (2.6) N/A 10 Kathryn J. Gray (17) USA Cohort 84 PB (49) M (51) Trimester of first vaccine dose: first (13.1), second (46.4), third (40.5) Chronic hy- pertension (4), diabetes mellitus or gestational diabetes (4%), BMI of >30 (12%), asthma (19), immuno- suppres- sion/cancer (4), previous SARS-CoV-2 infection (2) N/A Injection site soreness (67.8), injection site reaction or rash (1.2), headache (9.5), muscle aches (2.4), fatigue (16.6), fever or chills (1.2), elevated heart rate, joint pain, nausea, swollen lymph node, and sore throat, joint pain, nausea, sore throat, dizziness, stomach ache, night sweats, clogged ears Two newborn babies were admitted to the intensive care unit to receive respiratory support. One baby received CPAP and one of them had TTN. 11 Collier A-RY (21) Israel Cohort 30 PB (36.6) M (63.3) 1st trimester (17), 2nd trimester (50), and 3rd (33) N/A N/A Fever (13.3) N/A 12 Goldshtein I (18) Israel Cohort 7530 PB N/A Obesity (BMI ≥30), infertility, cancer, hy- pertension, chronic kidney disease, diabetes prediabetes, cardiovascu- lar disease, chronic obstructive pulmonary disease SARS-CoV-2 hospitalization (0.2), abortion (1.7), intrauterine growth restriction (0.5), stillbirth (<0.1), preeclampsia (0.3), preterm birth (<37 weeks) (5.6) Headache (0.1), general weakness (0.1), stomachache (<0.1), non-specified pain (<0.1), dizziness (<0.1), rash (<0.1), eye burning or blurred vision (<0.1) There were no notable differences between the vaccinated and unvaccinated groups. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem SA. SeyedAlinaghi et al. 6 Table 1: Complications of COVID-19 vaccination during pregnancy ID The first author (r) Type of study Sample size Type of Vaccine Gestational Age (%) Medical history (%) Complication (%) Other findings Adverse events Side effects 13 Kachikis A (39) USA Cohort 7809 PB (61.2) M (38) J (0.8) 1st trimester (23.3), 2nd trimester (47.3), 3rd trimester (26.8) N/A Miscarriages (0.7), Pain at the injection site, fatigue, myalgia, headache, chills, fever N/A 14 Abraham B (35) Qatar case report 1 (fe- male) PB 25 ± 2 weeks Hypothyroid- ism, mild COVID-19 infection Acute respiratory distress syndrome with the following signs and symptoms: hypotention, decreased O2 saturation, bilateral bronchial breath sounds, right lower lobe consolidation with extensive diffuse infiltrates in CXR, dilated pulmonary trunk and right lower lobe consolidation with an associated bilateral diffuse area of ground glass consolidation in CT scan, myocarditis, mild rise in troponin-I, tachypnea, increased white blood cell count (22.09 £ 109), increased C-reactive protein (356 mg/L), need to a short period of mechanical ventilation and steroid therapy Fever, pleuritic chest pain, shortness of breath on exertion, sweating, palpitation, A healthy term male baby was born 15 Ben- Mayor Bashi T (37) Israel cohort 58:(32.7% re- ceive only a single dose, 67.3% re- ceive two doses) PB First dose: 34.5 weeks Second dose: 37.0 weeks BMI ≥30 (3.6), Admission to NICU (1.7) At first/second dose of vaccine: pain at injection site (24.1)/ (20.5) back pain (3.4)/0 fatigue/weakness (15.5)/ (23.0) chills (5.1)/ (12.8) myalgia (5.1)/ (12.8) fever 0/ (2.5) headache (8.6)/ (5.1) peripheral facial nerve paralysis (1.7)/0 nausea (1.7)/0 dizziness (1.7)/ (2.5) unspecified illness (5.1)/ (10.2), enhanced fetal movements perception (1.7)/0 13 days after administra- tion of the first dose of the covid-19 vaccine the levels of covid-19 IgG antibody in maternal sera of vaccinated women were positively correlated with same antibody level in cord blood sera 16 Arulappen AL (36) China cohort 121 mRNA First trimester (4.9%), Second trimester (71.9%), third trimester (23.1%) Gestational diabetes mellitus (14.5%), anemia (8.1%), hyperthy- roidism (1.6%), asthma (0.8%), impending eclampsia (0.8%), Miscarriages (0.82%), small for gestational age (5.8%), anomalies (bilateral clubfoot, glucose-6phosphate dehydrogenase (G6PD) deficiency and sacral dimple): (2.5%) jaundice (85.8%), serious complaints during the first month of life (constipation, need for oxygen therapy because of Respiratory Distress Syndrome) (1.7%), preterm birth (≤37 weeks) (11.7%), admission to NICU (22.5%), neonatal infection (11.7%) Pain, body ache, headache, chills, shivering, and fatigue No neonatal death was reported This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 7 Archives of Academic Emergency Medicine. 2022; 10(1): e76 Table 1: Complications of COVID-19 vaccination during pregnancy ID The first author (r) Type of study Sample size Type of Vaccine Gestational Age (%) Medical history (%) Complication (%) Other findings Adverse events Side effects 17 Blakeway H (38) UK Cohort 1328V (vacci- nated: 140, un- vacci- nated: 1188) PB (90.7%), viral vector vaccine (9.3%) 2nd trimester (14.3%), 3rd trimester (85.7%) Obesity (BMI >30 kg/m2) (10.7%) smoker (0.7%) alcohol use (0.7%) pregestational diabetes mellitus (4.3%) antenatal medication (32.9%) hypertension on medication (9.3%) twin pregnancy (2.9%) High-dependency unit admission: was 2% more in vaccinated people than non-vaccinated people, neonatal intensive care unit admission: was 0.3% more in vaccinated people than non-vaccinated people Fever: was 2.7% more in vaccinated people than non-vaccinated people Postpartum hemorrhage: was 0.8% more in vaccinated people than non-vaccinated people Small for gestational age at birth: were equal Fetal abnormalities: were 0.3% less in vaccinated people than in non-vaccinated people Instrumental delivery: was 5.3% more in vaccinated people than non-vaccinated people - 18 Peretz- Machluf R (19) Israel Cohort 3240 PB N/A Obesity=BMI ≥30(30.7), Hypertension (1), Diabetes (1) Gestational diabetes (13.7), preeclampsia (1.2), small for gestational age (12.8), premature pre-labor rupture of membranes (3.1), preterm birth (6), maternal fever (1.7), neonate respiratory complication (1.9), neonate respiratory distress syndrome (0.5), neonate mechanical ventilation (0.8), NICU hospitalization (2.7), neonate hypoglycemia (4.9) N/A Significantly decreased percentage of Meconium- stained amniotic fluid in the vaccinated group 19 Toussia- Cohen S (40) Israel Cohort 162 PB N/A Autoimmune disease(19.7) N/A Rash/local pain/local swelling (82.7), gastrointestinal symptoms (12.9), fever (9.2), weakness and fatigue (47.5), myalgia (23.4), axillary lymphadenopathy (4.9), remote lymphadenopathy (6.1), paresthesia (4.9), headache (4.9) N/A 20 Moro PL (41) USA Cohort 323 PB, M N/A N/A Spontaneous abortion (26), vaginal bleeding (2.5), still birth (1.5), preeclampsia (1.2), preterm delivery (0.6), neonatal death (0.3), birth defects (0.6), NICU admission (0.9) Headache, fatigue, pyrexia, pain, chills, nausea, pain in extremity, dizziness, injection site pain, vomiting N/A NICU: Neonatal Intensive Care Unit; ICU: Intensive Care Unit; SGA: Small for Gestational Age; PB: PfizerBioNTech; M: Moderna; J: Janssen; N/A: not available; ITP: idiopathic thrombocytopenic purpura; BMI: body mass index; CXR: chest X-ray; CPAP: continuous positive airway pressure; TTN: transient tachypnea of the newborn; CT: computed tomography. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem SA. SeyedAlinaghi et al. 8 Figure 1: Flow diagram of included studies. nal bleeding (0.3%) (16). In other included studies, ad- verse events were as follows: spontaneous abortions, termi- nated pregnancies, intrauterine growth restriction, anoma- lies, preterm birth, need for Neonatal Intensive Care Unit (NICU), fetus small for gestational age (24), seizure (25), SARS-CoV-2 hospitalization, abortion, stillbirth, preeclamp- sia (18), and miscarriages (26). The main local side effect was injection site pain, and the main systemic side effect was fever. Other local and sys- temic side effects were as follows: rash, fever, severe fatigue, arthralgia, myalgia, headache, sore arm or pain, fatigue, chills, nausea, vomiting, sweating, feelings of joy, joint pain, swelling, flushing, reduced mental clarity, itching, decreased appetite, decreased sleep quality, palpitations or increased heart rate, heat or cold intolerance, anxiety, heartburn, mus- cle spasm, nasal congestion, increase in sleep, swollen lymph node and sore throat, dizziness, stomachache, clogged ears, general weakness, non-specified pain, and eye burning or This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 9 Archives of Academic Emergency Medicine. 2022; 10(1): e76 blurred vision (16-18, 25, 26). The results of the risk of bias assessment are presented in Ta- ble 2. The most common encountered problem was the lack of adequate matching for cases and controls. 4. Discussion Currently, Pfizer-BioNTech, Moderna, and Janssen vaccines are the main recommended choices for preventing SARS- CoV-2 infection in pregnant women. This review aimed to describe the possible adverse outcome of COVID-19 vaccines among pregnant women using the current evidence. Eight of the included studies were cohort (61.5%), two were cross- sectional, one was case report, and one was case-control. Following Pfizer-BioNTech and Moderna vaccinations, the vast majority of pregnant women reported injection-site pain or soreness (16, 25-27). The most frequently experienced sys- temic adverse events were fatigue, headache, chills, myal- gia, fever, and nausea (16, 25-29). The majority of pregnant women received their vaccine in the second trimester fol- lowed by the third trimester and first trimester, respectively (16, 21, 23, 26-28). The adverse events were not statisti- cally different between vaccinated and unvaccinated preg- nant women (29). Serious adverse effects that impacted pregnancy, delivery, and neonatal outcomes were reported in some studies (16-18, 20, 21, 25, 27, 29), however; due to lack of information and the absence of a control group, we were not able to infer the causation or comment with certainty about the possible adverse outcomes. Some studies reported no adverse events (22, 23) and found no significant difference between vaccinated and unvaccinated pregnant women (18). Limited data are available on COVID-19 vaccines’ efficacy and safety during pregnancy as almost all the vaccine trials excluded this population. Pregnant women and their ob- stetricians can use available data to weigh the benefits and risks of COVID-19 vaccines, even though they are limited. Most available data come from animal studies and inadver- tently exposed pregnant women during vaccine clinical trials and include data concerning the potential risks of vaccines during pregnancy due to vaccine reactogenicity, the timing of vaccination during pregnancy, evidence for the safety of other vaccines during pregnancy, risk of COVID-19 compli- cations in pregnancy among those with underlying condi- tions, risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and potential for risk mitigation (30). In our study, the majority of pregnant women were vac- cinated in the second trimester or median gestational age. Likewise; in Zauche’s study, vaccinated pregnant participants were in the second trimester (27). Additionally, in Wain- stock’s study, women who received the second dose vacci- nation were at a slightly higher gestational age (29). In the present review, no medical history or underlying disease was documented in most of the included articles. Likewise, in Trostle’s study, the majority of pregnant women had no pre- pregnancy comorbidities (24). In this review, the main local side effect was injection site pain, and the main systemic side effect was fever. Other local and systemic side effects were rash, fever, severe fa- tigue, arthralgia, myalgia, headache, sore arm or pain, fa- tigue, chills, nausea, vomiting, etc. Similarly, in Gray’s study, injection site soreness and fever were the most reported side effects (17). In Sukarno’s review study, fever, headache, pain, weakness, and arthralgia were common side effects of COVID-19 vaccination in pregnant and lactating women (31). Likewise, Oriji’s study showed that the most common side ef- fect was fever and pain at the injection site, but other side effects such as headache, tiredness, and chills were less fre- quent (32). In another observational study, injection site pain was the most common local side effect in healthcare workers, and fatigue, headache, muscle pain, and chills were the most common systemic side effects; however, fever was less com- mon (33). Fever with non-specific symptoms after COVID- 19 vaccination may be due to a common tropical infection, especially if recovery from fever does not occur within 48 hours post-vaccination (34). The reason for the slight vari- ation in the prevalence of complications could be the differ- ences in study population, number of participants, comor- bidities, physical conditions, the type of vaccine, and time of vaccination. Few studies reported serious maternal adverse effects includ- ing ITP, axillary adenopathy, vaginal bleeding, uterine con- traction and convulsion (16, 25, 35-38). Mild systemic side effects including fever, headache, and fatigue appeared to be similar to non-pregnant women. Hospital admission was re- ported in one study, but only in 0.2% of cases (18). Most stud- ies have focused on fetus-related complications (16, 21, 23, 24). Major congenital abnormality was rare (22, 23). Preg- nancy loss rarely occurred, except in a cohort study from the USA, which reported a relatively high percentage of preg- nancy loss, about 13.9%, among 827 pregnant women (23). Premature labor has been mentioned in three studies with an incidence of less than 10% (18, 23, 24). Abortion was re- ported among 0.7% in one study (26) ,1.7% in another study (18) and 2.12% in another one (24); intrauterine growth re- striction (IUGR) was reported in 0.5% in one study (18) and 3.2% in another one (23) among pregnant women who re- ceived COVID-19 vaccine during their pregnancy. The need for NICU admission was reported only in three studies (16, 21, 26). The reported rates in which were 0.5%, 2.4%, and 15.3%, respectively. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem SA. SeyedAlinaghi et al. 10 Table 2: Assessment of studies’ quality using the Newcastle-Ottawa scale (NOS) The first author (reference) Selection (out of 4) Comparability (out of 2) Exposure/outcome (out of 3) Total score (out of 9) Blakeway, H. (22) *** ** ** 7 Carrie Bennett (20) *** * ** 6 S. BooksteinPeretz(16) **** ** * 7 Tom T. Shimabukuro (23) *** ** *** 8 Megan E Trostle(24) *** ** ** 7 Regan N. Theiler (28) ** ** ** 6 Tamar Wainstock(29) ** * *** 6 Lauren Head Zauche(27) *** ** *** 8 RenukaAnanthKalyanKadali(25) *** ** ** 7 Kathryn J. Gray (17) *** * ** 6 Collier A-RY (21) **** ** ** 8 Goldshtein I (18) *** * ** 6 Kachikis A (39) *** ** *** 8 Abraham B (35) *** ** ** 7 Ben-Mayor Bashi T (37) *** * ** 6 Arulappen AL (36) *** ** ** 7 Blakeway H (38) *** ** *** 8 Peretz-Machluf R (19) **** ** ** 8 Toussia-Cohen S (40) *** ** ** 7 Moro PL (41) *** ** ** 7 5. Research implication Although larger studies and randomized controlled trials (RCTs) are required to address long term and infrequent ad- verse events and possible side effects associated with COVID- 19 vaccination, as well as the effect of vaccination at ear- lier stages of pregnancy, the current findings support the safety of the mRNA vaccines considering pregnancy and de- livery complications. Furthermore, future studies with larger sample sizes, which include vaccine administration in each trimester and evaluation of fetal/neonatal Immunoglobulin transfer via the umbilical cord and breast milk, may help us develop evidence-based recommendations for vaccine ad- ministration. 6. Clinical implication Policy-makers and healthcare professionals (HCPs) should use this knowledge to strongly recommend and advise preg- nant women to accept COVID-19 vaccination and encour- age them with the extending evidence that the COVID-19 vaccines are safe and effective during pregnancy, consider- ing the maternal morbidity associated with COVID-19 during pregnancy. 7. Limitations The novelty of the topic and scarcity of research concern- ing the possible side effects of COVID-19 vaccine in pregnant women limited our ability to provide reliable evidence. Be- sides, the study design of included studies did not allow for reliable causal inferences. It is also difficult to clinically ran- domize pregnant patients into diverse groups for vaccina- tion and therefore, most of the trials excluded this vulnera- ble population from their study. Thus, it is recommended for future studies to encourage pregnant women to participate to enable the decision-maker to determine the safety of the vaccine. 8. Conclusion We found that similar to non-pregnant women, pregnant women could experience some local and systemic side ef- fects with no significant difference. Fever and chills, as the systemic side effects, along with local pain and redness, as the local side effects, were the most commonly reported symptoms in pregnant women who received the COVID- 19 vaccine. There were also some reports of ITP, adenopa- thy, vaginal bleeding, uttering contraction and convulsion in some pregnant women. Some studies also reported abortion and premature labor in vaccinated pregnant women. How- ever, these incidences could not certainly be attributed to the COVID-19 vaccine’s adverse effects and more longitudi- nal and experimental studies are needed to define the exact adverse effects of the COVID-19 vaccine in pregnant women. 9. Declarations 9.1. Acknowledgments The present study was conducted in collaboration with Khalkhal University of Medical Sciences, Iranian Research This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 11 Archives of Academic Emergency Medicine. 2022; 10(1): e76 Center for HIV/AIDS, Tehran University of Medical Sciences, and Bergen University. 9.2. Authors’ contributions The conception and design of the study: Esmaeil Mehraeen, SeyedAhmad SeyedAlinaghi Acquisition of data: Mehrzad MohsseniPour, Solmaz Saeidi Analysis and interpretation of data: Pedram Habibi, Mohsen Dashti Drafting the article: Newsha Nazarian, Tayebeh Noori, Zahra Pashaei, AmirBehzad Bagheri, Afsaneh Ghasemzadeh, Amir Masoud Afsahi, Narjes Aghaie, Paniz Mojdeganlou, Ghazal Arjmand, Ghazal Zargari, Roshanak Modiri, Hengameh Mojdeganlou, Armin Razi Revising it critically for important intellectual content: SeyedAhmad SeyedAlinaghi, Omid Dadras and Esmaeil Mehraeen Final reading and approval of the version to be submitted: all authors 9.3. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 9.4. Competing interests The authors declare that there is no conflict of interest re- garding the publication of this manuscript. 9.5. 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This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Research implication Clinical implication Limitations Conclusion Declarations References