Safety profile of COVID-19 vaccines in pregnant and postpartum women in brazil

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Although COVID-19 vaccine s are curr ently unde r use in pr egnant an d postpar tum women , 19 ther e is still lack of evidence regarding safety and effectiveness in these popula ti ons. This study aims to 20 describe the safe ty profile of COVID-19 vaccines in pregnant and postpar tum women in the early stage 21 of vaccination campaign in Br azil. Met hods: This is an observation al cross-sec tional st udy using data 22 from the Brazilian surveillance informa tion system for adverse events (SI-EAP V) to characteri ze th e 23 safety of COVID-19 vaccines available (Sinovac/Butant an, Pfizer/Bio NTech, As tra Zeneca and Janssen) i n 24 Brazilian pr egnant and postp artum wo men after receiving it from April to August 2021. A descriptive 25 analysis was performed to assess th e frequency and incidence ra te of the a dverse events (AE) for 26 COVID-19 vaccines. Results: A total of 3,333 adverse events following COVID- 19 immunization were 27 repor ted fo r th e study p opula tion in th e SIEAPV. The i ncidence of AE found w as 309.4/100,000 doses 28 (95% CI 297.23, 321.51). Regarding the four vaccines available in the country, Sin ovac/Butanta n had the 29 lowest incidence (74.08/100,000 doses; 95% CI 63.47, 84.69). Systemic events w ere th e most frequent 30 notified for the group (82.07%), followe d by local (11.93%) and mate rnal (4.74 %), being most of th em 31 classified as non-severe (90.65%). Conclusion: A similar patt ern of AE as st at e d in othe r studies was 32 found, with even be tt er results for non- viral vector vaccin es, cor robor ating to t he recomm endati on of 33 vaccination for thes e groups. Even thou gh, further studi es appraisi ng a longer o bservation time are s till 34 neede d to provid e a broad er safe ty aspe ct for the vaccines curr ently unde r use fo r this popula tion. 35 36 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 2

37 The Coronavirus diseas e 2019 (COVID-19 ) has been shown to be less le thal t han p revious coronavirus 38 diseases, al though it is highly contagious . Also, a higher risk of severe dis ease has been associa ted with 39 aging and comorbiditi es. 1 Equally import ant incre ased risk has be en not ed in preg nant and pos tpar tum 40 women, making them par ticularly vulner able to COVID-19. 1 Studi es have shown t hat, when compa red t o 41 non-pregnan t, pr egnant women might d evelop more seve re symptoms, being a t i ncreased risk of 42 requiring hospi taliza tion in in tensive car e unit, alo ng with invasive ventilati on, e x tra corp ore al 43 membrane o xygenati on and mor tality. 2,3 In Brazil, more th an 18 thousa nd cases of severe acut e 44 respira tory syndrome (SARS) by COVID-19 were recor ded in pr egnant an d postpa r tum women, resulting 45 in almost 1,500 dea ths by June 2021. 4 Likewise, a 20% increase in mat ern al mortal ity rate was obse rved 46 in 2020. 4 47 Until now, th ere is still lack of evidence r egarding safety and efficacy of the vaccines in pregnan t and 48 postpar tum women, since th ey were no t in included in initial stu dies of COVID-19 vaccines. 5 Even 49 though, conside ring thei r higher suscep ti bility to COVID-19, vaccination for this gr oup has been 50 conducted by assessing risks and ben efit s. 6 COVID-19 immunization start ed on Ja nuary 2021 in Brazil 51 and, in March 2021, pr egnant and postp artum women with comorbid ities wer e d efined as priori ty 52 group. 7 In Ap ril 2021, Ministry of Heal th (MoH) recommended that this subgroup should be vaccinated , 53 as long as a careful assessment was car ri ed out with t he physician, r egardless of t he gesta tional age . 7 54 Due to adverse events e xpe rience by this subgroup, in May 2021 vaccination was changed again only for 55 those women with comor bidity, and , in J uly 2021, changed to include th e enti re matern al popula tion . 7 56 Four COVID-19 vaccines were initially rec ommended - Sinovac/Butan tan, Janssen, AstraZen eca and 57 Pfizer/BioNTech, although afte r May 2021 there was a r ecommenda tion t o remai n onl y 58 Sinovac/Butant an and Pfizer/BioNT ech vaccines for this group 8,9 59 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 3 By November 2021, abou t 1,7 million do ses have been adminis ter ed in this group , with an estima tive to 60 vaccinate more than 2,5 million pr egnant and postpar tum women in th e country . 8,10 Post authoriza tion 61 safety studies ar e a way to provide mo re evidence for this population . However , up to now, th ere a re 62 few evidence regarding the safe ty profile of those vaccines for pregnan t and post partum women from 63 real world evide nce persp ective, consid e ring pharmacovigilance systems as main source of information , 64 especially for low and middle-income co untries (LMIC), such as Brazil. 11 In th at w ay, this study aims to 65 describe th e incidence of adverse even ts (AE) reported by pr egnant an d postpa rtu m women after 66 receiving vaccines approved for use in th e early stage of vaccination campaign (April 2021 to August 67 2021) in Brazil. 68

69 Surveillance Systems and Covered Population 70 71 In Brazil , recor ds of adverse even ts follo wing immunization (AEFI) in vaccinated individuals in the public 72 services are mad e available by th e Ge ner al Coordinati on of the N atio nal Immuniz ation Program (NIP). 73 The NIP is responsibl e for the r egistr atio n, investigatio n and causality an alysis of AEFI repo rt ed by the 74 public health system . 12 For this study we reques ted t he SI-EAPV (AEFI Surveillance Information Syst em) 75 datase t to the B razilian M oH, using the F ala BR platfo rm ( https://www.gov.br/acessoainformacao/pt-76 br/falabr ). 13 This system is linked to the n ational syst em for repor ting AE rel ate d t o the use of drugs and 77 vaccines in VigiMed, adopt ed at t he end of 2018 by Anvisa, as a result of its partn ership with th e 78 Uppsala Moni toring Cen tre (UMC). 14 The SI-EAPV has the purpose t o systematic all y monitor the 79 notifications , investigat e and consolid ate data rel ating t o AEFI occurri ng at th e Na tional, S tat e, Regio nal, 80 Municipal and local levels , contrib uting t o improve the safe ty in the use of immu nizations, wit h a passive 81 surveillance app roach. F ollowing the st a blished flow, during the COVID-19 pande mic, all AEFI rela ted to 82 COVID-19 vaccines have been notified in SI-EAPV. 15 To assess the total numb er of vaccines doses 83 administer ed in th e country, the N ation a l Vaccination Campaign against COVID-19 databas e 84 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 4 (“Campanha Nacional de Vacinação contra a COVID-19 ”), from OpenDatasus , wer e used. 16 This datase t 85 is updated dai ly and, for this study, we u sed data from 3 Novemb er 2021. Pregna nt women were 86 identified in the da tase ts as those who r eport ed to b e pregn ant a t the time th ey received th e vaccine 87 and postpa rtum wer e consider ed thos e women who repor ted t o be br eastfe edin g in the SI-EAPV and 88 who declared to be a t postpa rtum a t th e moment of the vaccinati on. 89 Registries of AEF I with more t han 50% of variables with missing data wer e exclud ed from the study . 90 Quality check procedu res within th e da ta set were p erformed ; this led to th e exclu sion of São Paulo 91 Stat e from the an alysis to minimize pot e ntial selec tion and inform ation bi as since the dat a was 92 underr epor ted . 93 Study setting and outcomes 94 95 We analyze d AEFI no tifications r epor ted by pregnant and p ostpa rtum women wh o received any COVID-96 19 vaccine authoriz ed and availabl e in Br azil for use. AEF I could be re por ted as ad verse event (AE) or 97 immunization e rror (IE), afte r receiving a t least on e dose of a COVID-19 vaccine, including: CoronaVac 98 (Sinovac/Butantan), Ad26 .COV2.S (Janss en), ChAdOx1 nCoV-19 and BBV152 (Astr aZeneca) and/ or 99 BNT162b2 (Pfizer/BioNTech). 100 Demographic charact eristics wer e descri bed according to the age , race/e thnicity, region of the coun try 101 where th e notifica tion was repo rt ed and the mat ernal si tuati on of the woman . The AE were describ ed 102 according to th e type (local, systemic an d matern al) 17 , severity (severe and non-s evere) as well as the 103 case evolution (dea th, und er investiga tio n, cure withou t sequel ae, unknown/ loss of follow-up and 104 under investiga tion). AE r epor ted as “CO VID-19”, “PCR positive to COVID-19” and the like wer e classified 105 as inconclusive and those r epor ted as “v accination e rror”, “inadver ten t e xposur e to vaccine”, 106 “contraindica tion” was classified as inconsistent . 107 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 5 Addition ally, considering t hat M oH chan ged the r ecommenda tion to vaccina te th is groups only with 108 vaccines that do no t cont ain viral vector , the same woman could have r eceived dif ferent vaccines as first 109 and second dose . 7,8 110 Statistical Analysis 111 Description of AE notifica tions charac teri stics were perfo rmed for women rep orti ng to be pregna nt or a t 112 postpar tum afte r receiving a COVID-19 vaccine from April to August 2021. AE wer e presen ted as numb er 113 and frequency (%) for the outcomes of in ter est. The incid ence ra te (IR) of AE per 1 00,000 doses applied 114 was also estimat ed with 95% confidence interval (CI). IR was calculat ed dividing th e number of AE 115 notified during t he pe riod of the s tudy by the number of doses adminis ter ed in t he same group in th e 116 same period . Data an alyses were conduc ted using Python version 3.6 .5 (Python Software Found ation). 117 Datasets use d were public and anonymiz ed, pro tecting the confiden tiali ty and pri vacy of all patients. 18 118 All activities wer e conduct ed according t o the applica ble fede ral laws. 19 119

120 From April t o August 2021, a t otal of 3,3 33 AEFI repo rte d by Brazilian p regnan t a nd postpar tum women 121 who received COVID-19 vaccines in the SI-EAPV were included in the s tudy. Of th ose, 473 were from 122 women who received Sinovac/But antan , 788 Pfizer/BioNTech, 2,016 Astr aZeneca and 56 Janssen (Figure 123 1). AE was the most common repo rte d A EFI by this populati on (74.59%). Regardin g IE, they were 124 repor ted in 25.29% of the n otificati ons, b eing more frequ ent among pr egnant and postpar tum women 125 who received Sinovac/Buta ntan and Pfizer/BioNTech vaccines (60.47% and 73.21 %, respectively) 126 (Supplementa ry materi al 1). 127 Adverse Events reported in SIEAPV 128 AE notifications wer e more fr equen t am ong pregnant a nd postp artum women ag ed 20 to 35 years old, 129 with a mean age of 28.56 (Standa rd Deviation 7.2), who rep ort ed as white (42.84 %) and brown (36.89%) 130 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 6 (Table 1). From a regional pe rspective , e ven excluding th e stat e of São Paulo, t he South (34.31%) and 131 Southe ast (33.79%) regions had most par t of the no tification from pr egnant an d postpar tum women, 132 although it chang ed according t o the vac cine received : for Sinovac/Butan tan t he highest were no ted in 133 the Sou th (40.64%), for Pfizer/BioNTech in the Sou theas t (45.45%), for AstraZenec a in the Sou th 134 (35.75%) and for Janssen in the No rth eas t (46.67%). According to the ma ter nal sit uation, few women 135 repor ted as b eing at pos tpar tum (1.53%) and the dist ributi on within th e thr ee t ri mesters of pregn ancy 136 were similar (25.34% in the first, 30 .01% in the second an d 32.82% in the thi rd tri mester of pr egnancy) 137 (Table 1). 138 Incidence of adverse events 139 The overall incidenc e of AE among pregn ant and pos tpar tum women was 309.4 / 100,000 doses of 140 vaccines administer ed (95% CI 297.23, 321.51). In the a nalysis according to th e mater nal situa tion, IR by 141 pregnan t women was 404.3 / 100,000 doses (95% CI 388.75, 420.75) and by postp artum 19.6 / 100,000 142 doses (95% CI 13.47, 25.78). Regarding t he four vaccines available in th e count ry, Sinovac/Butanta n 143 vaccine had the lowes t IR (74.08 / 100,000 doses; 95% CI 63.47, 84.69) (Table 2). 144 Stra tifying the AE according to type, amo ng pregnant women, syst emic events we re the mos t freque nt 145 notified (82.03%), followed by local (11.93%) and maternal (4.78%), being most of them classified as 146 non-severe (90.65%) (Supplementary ap pendix 2). Also, the I R of systemic events in the Brazi lian 147 pregnan t women was the highes t (249.88/ 100,000 doses: 95% CI 238.97, 260.8). Mater nal AE IR was 148 14.56/ 100,000 doses (95% CI 11.92, 17.2) (Table 3). 149 The most common matern al AE notifie d by pregnant and p ostpa rtum women incl uded spont aneous 150 aborti on (2.37%) pregnancy bleeding (0.76%) and neonatal de ath (0.52%). Amon g the non-mate rnal AE, 151 headache (18.54%), fever (13.79%), myalgia (10.30%) and pain (7.60% ) were the most repo rte d. The 152 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 7 most frequen t AE were similar among th e four vaccines, exce pt for pain , which was less frequen t 153 repor ted for those who r eceived Sinovac /Butant an vaccine (Table 4). 154 Regarding th e case evolu tion of the even ts, 53.30% were missing and 30.85% rep orted as being cured 155 without sequ elae (Suppl ement ary mate ri al 3). 156

157 158 In the COVID-19 pandemic re ality, despi t e the r ecognition of t he ne ed for inclusio n of pregnant and 159 postpar tum women in clinical tri als, the s peed a t which the COVID-19 vaccines were develop ed, and 160 trials conduct ed pr ecluded inclusion of t hem. 20 In tha t sense, pos t aut horiz ation s afety studies a re a way 161 to provide mor e evidence for this popula tion. 162 Using surveillance dat a, we found more t han 3,000 events no tifications by pregn a nt and postp art um 163 women after r eceiving at leas t one dos e of a COVID-19 vac cine in the ear ly stage of the campaign in 164 Brazil. AE were th e most common, al tho ugh for some vaccines IE were more freq uent – which may 165 reflect th e changes in rec ommenda tion t o vaccinate this group disp osed by the B r azilian MoH . 8,21 166 Concerning the freq uency of AE, the dis t ribution acco rding to th e age and race/e t hnicity was similar 167 within all vaccines available . However, in a regional pe rspective , it differed as eac h region/stat e could 168 have differences in th e cold chain distri b ution str at egies. 8 Among th e mate rnal p opulatio n, pregn ant 169 women were resp onsible for most of th e notifications r epor ted in t he pe riod. 170 The overall incidenc e of AE found for this population was 309.4/ 100,000 doses. Al though th ere is a lack 171 of evidence regard ing the safe ty of these vaccines in the mate rnal popul ation , our findings are in 172 accordance with the availabl e lit era ture f or oth er studi es tha t assessed safe ty of C OVID-19 in different 173 populati ons groups. An epidemiol ogical bulletin from th e Bra zilian MoH from J an uary to Feb ruary of 174 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 8 2021 showed a 350.9 AEFI notifica tions/ 100,000 doses of vaccines early administ ered in t he Br azilian 175 populati on. 22 Anot her st udy conducted i n Minas Ge rais sta te th at assess ed safety of COVID-19 vaccines 176 from January to March 2021 found an in cidence ra te of 777.12 AEFI p er 100,000 doses applied , with 177 97% of them classified as non-severe AE. 23 178 In rela tion t o the magni tude of our findin gs when compared to o ther vaccines r ec ommended to 179 pregnan t and postp art um women in Braz il, a study from Silveira IO et al , ass essing adverse even ts from 180 the SI-EAPV datab ase from 2015 to 2019 in Minas Ge rais sta te, found an ove rall in cidence of 76.9 AEFI 181 notifications/100,000 doses . 24 Findings relat ed to r ace/ ethnici ty, type of event a nd case evolution we re 182 also similar to th e pa tte rns found in our r esults. 24 183 As for the systemic even ts found in our s tudy, the mos t frequen t types follow a si milar pat tern d escribed 184 by Gatt ás VL, et al in rela tion t o the o nes found for influenza vaccine, which is recommended for any 185 gestati onal age in Br azil, as COVID-19 vaccines are. 25 Although we have no t compa red pregn ant t o non-186 pregnan t women, th ere a re studi es suggesting tha t th e physiologic changes in pr egnancy seems to not 187 materi ally affect non-mate rnal even ts. 26,27 188 Addition ally, our study descri bes with m ore emphasis systemic even ts classified a s maternal , showing an 189 incidence of 14.56 AE notificat ions/ 100,000 doses, of which spontaneous a bort io n was the most 190 frequen t type of event (2.37%) and with differences in the fr equency found for th e different types of 191 vaccines available. B razilian d ata up to 2 019 showed a propor tion of 3.4% of spontane ous abor tion in 192 the coun try. Me anwhile, spon tan eous ab ortion incid ence in th e lite rat ure vari es from 6.5% to 21% of 193 pregnancies, and it is recogniz ed as one of the most common complications du ri ng a pregnancy. 28–30 In 194 addition , a study assessing safety of mRN A COVID-19 vaccines in pregnant popula t ion in the Uni ted 195 Stat es assessed by th e V-Safe pregnancy registry system found an over all frequen cy of spontaneous 196 aborti on of 12.6% among pregnan t women who received a COVID-19 vaccines. 26 Cardoso BB et al 31 , 197 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 9 however, argu es tha t dat a on abor tion a nd its complications may be incomple te i n Brazil, since the 198 hospitaliz ations occur red du e to an ab ort ion is only one data sou rce to estima te t he tot al number of 199 aborti ons in the coun try. 31 200 When comparing t he differen t vaccines a dminister ed in this population in B razil , we found that 201 Sinovac/Butant an and Pfizer/BioNT ech vaccines had the low est IR of AE, which is in line with MoH 202 recommenda tions to only administer the m in pregnant and pos tpa rtum woman. 8,32 203 Our study has some limit ations . The AEFI notifications used in this study are subje ct to limita tions of 204 passive surveillance system. This means t hat each h ealth l evel rou tinely and pe rio dically sends 205 information ab out t he even ts subject to surveillance a t the immedi ately supe rior . In the same way, th e 206 classifications in the da tabas e might be s usceptible to th e inte rpr eta tion of th e pe rson filling out the 207 system, implying in the possibility of lack of uniformity in reporti ng the char acte ri stics of the event a nd 208 in the place whe re th e informat ion is filled in the form of the surveill ance system. Although t hese 209 systems genera te valuabl e informatio n r egarding th e descripti on of the occur ren ce of adverse events , 210 they usually do not all ow establishing ca usality betwe en th e occurre nce of AEFI a nd the vaccine. 11,33–35 In 211 that se nse, ou r study is unable t o evalua t e AE outcomes t hat might occur in associ ation with e xposur es 212 earlie r in pregna ncy or postpa rtum pe rio d. 213 Furthe rmore , th e definition of pos tpar tu m women varied in the da ta sourc es use d - which may 214 underes timat e th e incidence in th is popu lation . In th e same direc tion, the Br azilia n obstet ric 215 observato ry for COVID-19 has been showing that th ere are inconsis tencies in the vaccination 216 information fulfilling, since they found pr egnant and p ostpa rtum women of male sex, and AEF I notifie d 217 for COVID-19 vaccines administered prev ious to th e vaccination campaign st art an d over 55 years old. 4 218 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 10 Anoth er po ten tial limita tion of our an alyses is the unde rrep orting of AE. S IEAPV is a passive surveillance 219 system. Under rep orting can occur du e to difficulties in the conclusion of cases investigati ons and in 220 adher ence of the p opulat ion to no tify th e events . In tha t sense , mild to mode rat e events might be mor e 221 underr epor ted than sever e th at r equire d hospitaliza tion or mo re int ensive care . O n the oth er han d, 222 each of the four vaccines wer e available i n different momen ts (Sinovac/Butant an and Astr aZeneca since 223 Janua ry, Pfizer/BioNTech since May and Janssen since July 2021). 8 The Janssen vaccine was first 224 provided to the popu latio n when the re was already the recommend ation no t to vaccinate pregn ant and 225 postpar tum women with viral vecto r vaccines, which led to a small number of do ses administer ed in this 226 populati on, henc e, a low number of no tifications up to the cut-off perio d of this st udy. In the sam e 227 sense, Sinovac/But antan and Ast raZenec a vaccines were available in the beginni n g of the campaign, 228 when only women with comorbiditi es were bei ng vaccinated. 8 Also , some of the AE presen ted in t his 229 study might be still unde r investigati on d uring the study pe riod and might no t hav e a final classification. 230 Never thel ess, our study allows a be tt er u nderst and of COVID-19 vaccines safety p rofile under a 231 vaccination campaign placed du ring a pa ndemic setting in a LMIC as Br azil. W e found a similar pat tern of 232 AE as state d in oth er studi es, with even b ett er r esults for non-viral vecto r vaccines, corrobo rating t hat 233 vaccination of this groups should con tinu e as a priori ty. Fur ther s tudies app raising a longer time for a 234 bett er und erst anding adverse events inci dence in relation to second an d boost er doses and th e 235 component of vaccine int erchange ability are still ne eded to provide a broad er saf ety aspect for the 236 vaccines currently unde r use for this po p ulation . 237 238 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 11 Contributors 239 AJLA, YPQ and GS J conceptu alized the st udy. RGP, RVF, AJLA an d CZD analyzed the data . RGP and RVF 240 curated the da ta . AJLA , YPQ, CZD and GSJ wrote the first d raft of the manuscr ipt . YPQ, XM, WDY and 241 other autho rs reviewed a nd edit ed r evisions of the manuscript , had full access to all the da ta in th e 242 study, and had final resp onsibility for th e decision to submit for publica tion . 243 Declaration of interests 244 RGP, RVF, AJLA, GSJ a nd CZD are employees of IQVIA Br azil which was contract ed by Sinovac Life 245 Sciences to conduc t the s tudy. 246 YPQ, XM, WDY are employees of Sinovac Life Sciences. 247 248 Acknowledgments 249 250 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 12

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CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 16 Eventos Adversos Pós-Vacinação no Br asil, 2014 a 2016. Rev Panam Salud Pública [Inter net] 336 2018;1–8. Availabl e from: ht tp://iris.p ah o.org/xmlui/handl e/123456789/34861 337 338 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 17 Tables 1 Table 1. Sociodemographic characteristics of pregnant and postpartum women that notified adverse events after receiving vaccines against 2 COVID-19 3 Sinov ac/Butant an Pfizer /BioN Tech AstraZenec a¹ Janssen Total AE (n= 187) % AE (n= 572) % AE (n= 1712) % AE (n= 15) % AE (n= 2,486) % Age group (years old) <15 0 0.0% 6 1.05% 5 0.29% 0 0.0% 11,00 0.44% 16 to 20 18 9.63% 76 13.29% 180 10.51% 2 13.33% 276,00 11.1% 21 to 25 47 25.13% 127 22.2% 460 26.87% 7 46.67% 641,00 25.78% 26 to 30 47 25.13% 101 17.66% 438 25.58% 3 20.0% 589,00 23.69% 31 to 35 51 27.27% 159 27.8% 398 23.25% 0 0.0% 608,00 24.46% 36 to 40 15 8.02% 68 11.89% 184 10.75% 0 0.0% 267,00 10.74% 41 to 45 8 4.28% 29 5.07% 20 1.17% 3 20.0% 60,00 2.41% 46 to 50 1 0.53% 1 0.17% 0 0.0% 0 0.0% 2,00 0.08% >50 0 0.0% 5 0.87% 26 1.52% 0 0.0% 31,00 1.25% Inconsi sten t² 0 0.0% 0 0.0% 1 0.06% 0 0.0% 1,00 0.04% . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 18 Race/ethnicity White 70 37.43% 222 38.81% 770 44.98% 3 20.0% 1065 42.84% Black 12 6.42% 46 8.04% 80 4.67% 0 - 138 5.55% Yell ow 1 0.53% 2 0.35% 7 0.41% 0 - 10 0.4% Brown 79 42.25% 220 38.46% 608 35.51% 10 66.67% 917 36.89% Indigenous 1 0.53% 0 - 1 0.06% 0 - 2 0.08% Ignored 24 12.83% 82 14.34% 246 14.37% 2 13.33% 354 14.24% Region of notification South 76 40.64% 162 28.32% 612 35.75% 3 20.0% 853 34.31% South eas t 53 28.34% 260 45.45% 524 30.61% 3 20.0% 840 33.79% Nor th 14 7.49% 32 5.59% 70 4.09% 0 - 116 4.67% Nor thea st 21 11.23% 90 15.73% 347 20.27% 7 46.67% 465 18.7% Midwe st 23 12.3% 28 4.9% 159 9.29% 2 13.33% 212 8.53% Maternal situation 1st t ri me ste r 76 40.64% 173 30.24% 368 21.5% 13 86.67% 630 25.34% 2nd tri mes te r 43 22.99% 144 25.17% 557 32.54% 2 13.33% 746 30.01% 3rs tri me st er 45 24.06% 163 28.5% 608 35.51% 0 - 816 32.82% Pos tpa rtum 8 4.28% 12 2.1% 18 1.05% 0 - 38 1.53% Inconsi sten t³ 10 5.35% 72 12.59% 136 7.94% 0 - 218 8.77% . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 19 Ignored 4 5 2.67% 8 1.4% 25 1.46% 0 - 38 1.53% AE: Advers e Event; ¹As tr aZene ca inc ludes the vac cines ChAdOx1 nC o V-19 and BBV152; ²Ages unlike ly t o c once ive a p regnancy we re c on sider ed a s in cons ist ent; 4 ³Gest ati ona l ag es inc onsis tent wi th a pr egna ncy i.e.: 12 month s 4 S tat ed a s ign or ed in the notifi ca ti on. 5 * Due to la ck of n oti fic ati ons in th e Sta te of S ão Paul o, the S outhe ast r egi on wi ll include th e S tat es of Ri o de Jane ir o, Espír it o Sant o and Minas Ge rai s ; 6 7 Table 2. Incidence of adverse events notified by Brazilian pregnant and postpartum women by vaccine received 8 Over al l Preg nant Postpartu m AE N doses IR* 95% CI AE N doses IR* 95% CI AE N doses IR* 95% CI Sinov ac /Butant an 187 252430 74.08 (63.47, 84.69) 179 193517 92.5 (78.95, 106.04) 9 58913 15.28 (5.3, 25.26) Pfize r/Bi oNTe ch 572 484310 118.11 (108.43, 127.78) 560 372980 150.14 (137.72, 162.57) 12 111330 10.78 (4.68, 16.88) Astr aZene ca¹ 1712 65435 2616.34 (2494.04, 2738.64) 1694 37954 4463.3 (4255.55, 4671.04) 18 27481 65.5 (35.25, 95.75) Janssen 15 1388 1080.69 (536.76, 1624.62) 15 367 4087.19 (2061.54, 6112.85) 0 1021 0 (0.0, 0.0) Tota l 2486 803563 309.37 (297.23, 321.51) 2448 604818 404.75 (388.75, 420.75) 39 198745 19.62 (13.47, 25.78) AE: Advers e Event s; IR: incid ence r at e; CI: C o nfidence inte rval ; 9 * IR per 100,00 d ose s; ¹Ast raZen ec a in cludes the va cc ines ChAdOx1 nC oV-19 and BBV152; 10 N.B: Pr egnant w omen c an be bre astf eeding; hence, they will c ount in pr egnant and p ostp artu m c olumns.11 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 20 Table 3. Incidence of AE among pregnant women according to the type and severity 12 Sinov ac/Butant an Pfizer /BioN Tech AstraZenec a¹ Janssen Total IR* 95% CI IR* 95% CI IR* 95% CI IR* 95% CI IR* 95% CI Mat ern al 10.3 (6.34, 14.26) 9.7 (6.93, 12.48) 65.71 (46.08, 85.35) 72.05 (0.0, 213.2) 14.56 (11.92, 17.2) Syste mi c 50.31 (41.56, 59.06) 89.41 (80.99, 97.82) 2194.5 (2082.29, 2306.8) 864.55 (377.51, 1351.59) 249.88 (238.97, 260.8) Lo ca l 4.36 (1.78, 6.93) 15.49 (11.98, 18.99) 311.76 (269.05, 354.47) 144.09 (0.0, 343.65) 36.34 (32.17, 40.51) IR: inciden ce r ate; CI: c onfiden ce inte rva l; ¹A s traZ enec a includes the va ccin es ChAdOx1 nC oV-19 and BBV152; 13 *IR per 100,000 dos es adm inist er ed. 14 Table 4. Frequency of most common adverse events experienced by pregnant and postpartum women receiving COVID-19 vaccines and w ho 15 reported an AEFI 16 Sinov ac/Butant an Pfizer /BioN Tech AstraZenec a¹ Janssen Total AE (n= 187) % AE (n= 572) % AE (n= 1712) % AE (n= 15) % AE (n=2,486) % Maternal Spont aneou s ab o rti on 9 4.81% 28 4.9% 21 1.23% 1 0.066% 59 2.37% Pregnan cy ble eding 6 3.21% 3 0.52% 11 0.64% 0 0% 20 0.80% Neona tal dea th 3 1.6% 9 1.57% 1 0.06% 0 0% 13 0.52% . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 21 Pre ma tur e bi rth 1 0.53% 3 0.52% 3 0.18% 0 0% 7 0.28% Abdomina l pr egnancy 3 1.6% 0 0% 0 0% 0 0% 3 0.12% Non-maternal Heada che 20 10.7% 77 13.46% 360 21.03% 4 28.57% 461 18.54% Feve r 13 6.95% 46 8.04% 282 16.47% 2 14.29% 343 13.8% Myalgi a 12 6.42% 37 6.47% 206 12.03% 1 7.14% 256 10.3% Pain 3 1.6% 35 6.12% 149 8.7% 2 14.29% 189 7.6% Vo mit 2 1.07% 20 3.5% 67 3.91% 2 14.29% 91 3.66% Chills 4 2.14% 8 1.4% 77 4.5% 0 0% 89 3.58% Nausea 2 1.07% 19 3.32% 62 3.62% 1 7.14% 84 3.38% Abdomina l pain 9 4.81% 22 3.85% 44 2.57% 1 7.14% 76 3.06% Diar rhea 3 1.6% 20 3.5% 40 2.34% 0 0% 63 2.53% Arm Pa in 0 0% 26 4.55% 34 1.99% 0 0% 60 2.41% Asthenia 6 3.21% 15 2.62% 35 2.04% 0 0% 56 2.25% Fat igue 2 1.07% 14 2.45% 39 2.28% 0 0% 55 2.21% Cough 7 3.74% 28 4.9% 17 0.99% 0 0% 52 2.09% Dyspnea 5 2.67% 15 2.62% 31 1.81% 0 0% 51 2.05% Runny nose 7 3.74% 23 4.02% 16 0.93% 0 0% 46 1.85% So re thr o at 4 2.14% 11 1.92% 22 1.29% 0 0% 37 1.49% . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 22 Edema 4 2.14% 9 1.57% 14 0.82% 0 0% 27 1.09% AE: Advers e ev ent; ¹Ast raZ enec a in cludes the vac cines ChAdOx1 nC o V-19 and BBV152. 17 18 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint 23 Figures 1 2 Figure 1. Attrition diagram 3 . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint . CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 17, 2021. ; https://doi.org/10.1101/2021.12.14.21267777doi: medRxiv preprint