key: cord-0691769-xfol3c9l authors: Safadi, Marco A. P.; Spinardi, Julia; Swerdlow, David; Srivastava, Amit title: COVID‐19 disease and vaccination in pregnant and lactating women date: 2022-05-09 journal: Am J Reprod Immunol DOI: 10.1111/aji.13550 sha: 044196fa98edcf54a4e3580633df5305a7c95e59 doc_id: 691769 cord_uid: xfol3c9l BACKGROUND: More than 325,000 cases of coronavirus disease 2019 (COVID‐19) have been reported among pregnant women in the Americas. AIMS: This review examines the impact of COVID‐19 in pregnant women and describes available evidence on the safety, effectiveness, and immune response(s) to vaccination among pregnant and lactating women. CONTENT: Multiple studies indicate that pregnant women are more susceptible to adverse COVID‐19 outcomes, including hospitalization, intensive care unit admission, and invasive ventilation than non‐pregnant women with COVID‐19. Furthermore, COVID‐19 in pregnancy is associated with adverse maternal and neonatal outcomes. Adverse COVID‐19 outcomes appear to disproportionately affect pregnant women from low‐ and middle‐income countries, likely reflecting inequities in access to quality healthcare. Despite the absence of safety and efficacy data from randomized clinical trials in this subpopulation, observational studies and data from pregnancy registries thus far have demonstrated that vaccination of pregnant or lactating women against COVID‐19 is safe, effective, and results in robust immune responses including transfer of antibodies to the newborn via the placenta and breast milk, respectively. IMPLICATIONS: These data support vaccination recommendations intending to help protect these vulnerable individuals against COVID‐19 and its sequelae. Randomized clinical studies will further evaluate the safety and immunogenicity of COVID‐19 vaccines in these populations. This review examines the impact of COVID‐19 in pregnant women and describes available evidence on the safety, effectiveness, and immune response(s) to vaccination among pregnant and lactating women. COVID-19 in pregnant women is likely underestimated and varies geographically; adverse pregnancy outcomes are generally more frequent in low-and middle-income countries (LMIC). [6] [7] [8] COVID-19 vaccines are authorized for general or emergency use globally, 9 with > 7 billion vaccine doses administered to date. 1 As with many early clinical trials, pregnant or lactating women were excluded from COVID-19 vaccine authorization studies 10, 11 ; randomized clinical trial data on COVID-19 vaccine safety and efficacy among these groups were thus lacking when vaccine use was first authorized. However, acknowledging the pandemic emergency and the imperative to ensure access of pregnant or lactating women to vaccine-mediated protection against COVID-19, various public health organizations recommend vaccination of these subpopulations. [10] [11] [12] Nevertheless, vaccination rates among pregnant women remain lower than among nonpregnant women, 13 As of October 28, 2021, a total of 325 344 SARS-CoV-2 infections and 3237 deaths were reported among pregnant women in 33 countries/territories with available information from the World Health Organization (WHO) Americas region. 14 14 Intercountry differences in COVID-19−related antepartum and postpartum mortality reflect discrepancies that existed previously, 16 with the pandemic and its burden on the healthcare system likely exacerbating underlying healthcare access disparities associated with differential health outcomes. In Brazil, 1031 maternal deaths occurred among the 11 247 cases of COVID-19 severe acute respiratory syndrome in pregnant/postpartum women during March 1, 2020-May 5, 2021 (9.2% case-fatality rate); case-fatality rates were highest during the second trimester (11.4%) and the postpartum period (18.9%). 16 Among those who died, 22 .5% and 33.5% did not have access to an ICU or invasive ventilator support, respectively. Alarmingly, maternal mortality among SARS-CoV-2−positive pregnant women rose dramatically in 2021 rel-ative to 2020 in many Latin American countries, including Brazil (from 9.0 to 36.4 per 100 000 live new births), Paraguay (from .7 to 60.1), and Colombia (from 7.7 to 24.4), among others. 14 The emergence and spread of highly transmissible SARS-CoV-2 variants will likely affect COVID-19 incidence and hospitalization rates. In particular, rapid increases in cases and hospitalizations associated with the Delta variant, including in countries with high vaccine coverage, is concerning. 17 The Delta variant was initially identified in July 2020 and by October 26, 2021 , was reported in 185 countries. 14 (Table S1 ). 3 Importantly, analyses that adjusted for age, comorbidity presence, and/or race/ethnicity supported these findings. 4, [24] [25] [26] Severe COVID-19 was also more frequent among pregnant women in several studies. [27] [28] [29] Studies not supporting this relationship defined "severe" disease inconsistently or based on symptoms rather than morbidity. 3, 30 Community-based studies can provide information regarding hospitalization risk among a larger group that may be more generalizable to the overall population (Table 1) Antepartum SARS-CoV-2 infection is associated with substantial morbidity and mortality risk in parents and infants compared with uninfected pregnant women (Tables 2 and 3) . 6 1.3, 6.5) among women with versus without COVID-19; differences in risk of Cesarean section (C-section) and neonatal death were not statistically significant. 2 A meta-analysis of pregnancy outcomes from 17 countries during January 2020-January 2021 also reported significant increases in maternal and fetal mortality, but not neonatal death, associated with COVID-19; subgroup analyses indicated statistical significance in LMIC but not HIC. 7 Similarly, a meta-analysis of data from 35 countries found that adverse pregnancy/neonatal COVID-19 outcomes were significantly more common in LMIC, likely due to limited access to healthcare, compared with HIC. 8 In Brazil, data from the System showed that the overall case fatality rate (CFR) for pregnant women admitted with severe acute respiratory syndrome due to COVID-19 was 6.3%. This rate was approximately ten times higher compared with that reported for the United States (.6%). Furthermore, when comparing CFR and mortality rates among White versus Black women in Brazil, a substantially higher burden and worse maternal outcomes were observed among Black women. Interestingly, these racial disparities were also observed in pregnant women in the United States, probably reflecting inequalities in access to quality health care. 47 The mechanisms underlying poor maternal and fetal outcomes associated with maternal SARS-CoV-2 infection are not fully understood. 48 angiotensin-converting enzyme 2 (ACE2), which is found in various parts of the body, via the spike protein. 49, 50 Age-dependent ACE2 expression may account for lower risk of COVID-19 among children relative to adults. 49 In the placentas of women without COVID-19, ACE2 is highly expressed in the first and second trimesters but is virtually absent at term, suggesting that ACE2-mediated risk of placental infection may peak earlier during pregnancy. 48 In addition to maternal-fetal antibody transfer, SARS-CoV-2reactive antibodies in breast milk may bolster passive immunity in infants. 57, 68, 69 Levels of antibodies to the SARS-CoV-2 spike and nucleocapsid proteins were significantly higher in human milk collected during versus before the COVID-19 pandemic. 69 A prospective cohort study observed equivalent antibody titers induced by BNT162b2 and mRNA-1273 vaccination in pregnant/lactating and nonpregnant women. 83 Notably, postvaccination titers across groups were significantly higher than those following antepartum SARS-CoV-2 infection (P < .001). Analysis of maternal and fetal (cord blood) samples indicates IgG antibody transfer to fetuses following COVID-19 mRNA vaccination of pregnant women. 67, 86, 87 An Israeli multicenter study identified robust humoral IgG responses in maternal and cord blood collected at delivery among women who received BNT162b2 (n = 86) or with con- The COVID-19 pandemic has profoundly affected pregnant women worldwide, particularly in LMIC. Data overwhelmingly suggest that pregnant versus nonpregnant women with COVID-19 more frequently require hospitalization, ICU admission, and invasive ventilation [2] [3] [4] [5] 26, 31 compared with uninfected pregnant women. COVID-19 is also associated with increased risk of poor maternal/fetal outcomes, including preeclampsia, preterm birth, maternal/infant ICU admission, invasive ventilation, maternal death, and stillbirth ( Figure 1 ). 2 respondents, and concern about side effects was the most common reason for vaccine hesitancy. 95 Health workers were considered the most trusted sources of information about COVID-19 vaccines. However, we have to acknowledge that LMICs face considerable challenges in both receiving and distributing vaccine doses. 96 Although most studies found no evidence of vertical SARS-CoV-2 transmission through breast milk to newborns from infected mothers, evidence exists that it may occur in a small proportion of cases ( Figure 1 ). [53] [54] [55] [56] [57] [58] 97 In among newborns. 88 In the real-world study conducted in the United States during Delta and Omicron circulation, maternal vaccination reduced the risk for COVID-19 hospitalization among infants aged < 6 months. Various organizations have issued guidance to address the unique burden affecting not only pregnant women but also recently pregnant and lactating women. In a recent study performed in Brazil, rates of death were higher among postpartum women with COVID-19 compared with pregnant women with COVID-19. 47 In a retrospective cohort study in the United States that included 14 104 patients, SARS-CoV-2 infection was associated with increased risk of a composite outcome of maternal mortality or serious morbidity from obstetric complications in pregnant as well as postpartum individuals. 98 Considering the relative rarity of serious COVID-19 in infants, the limited reports of vertical SARS-CoV-2 transmission, and protective benefits of breastfeeding, the WHO and the UK Health Security Agency 12,99 encourage breastfeeding among mothers with COVID-19 (Table 4 ). 99 Data are available from the cited references. 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