Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study

Contexte Il n'est pas clair si le lien suggéré entre la COVID-19 pendant la grossesse et la prééclampsie est une association indépendante ou si ceux-ci sont causés par des facteurs de risque communs.  Objectif Cette étude visait à quantifier toute association indépendante entre la COVID-19 pendant la grossesse et la prééclampsie et à déterminer l'effet de ces variables sur la morbidité et la mortalité maternelles et néonatales.  Plan de l'étude Il s'agissait d'une vaste étude observationnelle longitudinale, prospective, non appariée, diagnostiquée et non diagnostiquée, évaluant l'effet de la COVID-19 pendant la grossesse sur les mères et les nouveau-nés. Deux femmes consécutives non diagnostiquées ont été recrutées de manière concomitante immédiatement après l'identification de chaque femme diagnostiquée, à n'importe quel stade de la grossesse ou de l'accouchement, et au même niveau de soins pour minimiser les biais. Les femmes et les nouveau-nés ont été suivis jusqu'à leur sortie de l'hôpital en utilisant les protocoles standardisés INTERGROWTH-21 et le système électronique de gestion des données. Au total, 43 institutions dans 18 pays ont contribué à l'échantillon de l'étude. L'association indépendante entre les 2 entités a été quantifiée avec les facteurs de risque connus pour être associés à la prééclampsie analysés dans chaque groupe. Les résultats ont été comparés chez les femmes atteintes de COVID-19 seul, de prééclampsie seule, des deux affections, et celles sans l'une ou l'autre des deux affections.  Résultats Nous avons recruté 2 184 femmes enceintes ; parmi celles-ci, 725 (33,2 %) ont été recrutées dans les groupes diagnostiqués COVID-19 et 1 459 (66,8 %) dans les groupes non diagnostiqués COVID-19. Parmi ces femmes, 123 présentaient une prééclampsie, dont 59 sur 725 (8,1 %) appartenaient au groupe diagnostiqué COVID-19 et 64 sur 1459 (4,4 %) appartenaient au groupe non diagnostiqué (risque relatif, 1,86 ; intervalle de confiance à 95 %, 1,32-2,61). Après ajustement pour tenir compte des facteurs sociodémographiques et des conditions associées à la COVID-19 et à la prééclampsie, le ratio de risque de prééclampsie est resté significatif chez toutes les femmes (ratio de risque : 1,77 ; intervalle de confiance à 95 % : 1,25-2,52) et chez les femmes nullipares en particulier (ratio de risque : 1,89 ; intervalle de confiance à 95 % : 1,17-3,05). Il y avait une tendance mais aucune signification statistique chez les femmes parentes (rapport de risque, 1,64 ; intervalle de confiance à 95 %, 0,99-2,73). Le ratio de risque de naissance prématurée pour toutes les femmes diagnostiquées avec COVID-19 et prééclampsie était de 4,05 (intervalle de confiance à 95 %, 2,99-5,49) et de 6,26 (intervalle de confiance à 95 %, 4,35-9,00) pour les femmes nullipares. Par rapport aux femmes sans diagnostic de maladie, l'issue périnatale défavorable composite a montré une augmentation progressive du rapport de risque pour la COVID-19 sans prééclampsie, la prééclampsie sans COVID-19 et la COVID-19 avec prééclampsie (rapport de risque, 2,16 ; intervalle de confiance à 95 %, 1,63-2,86 ; rapport de risque, 2,53 ; intervalle de confiance à 95 %, 1,44-4,45 ; et rapport de risque, 2,84 ; intervalle de confiance à 95 %, 1,67-4,82, respectivement). Des résultats similaires ont été trouvés pour les résultats maternels défavorables composites avec des rapports de risque de 1,76 (intervalle de confiance à 95 %, 1,32-2,35), 2,07 (intervalle de confiance à 95 %, 1,20-3,57) et 2,77 (intervalle de confiance à 95 %, 1,66-4,63). L'association entre la COVID-19 et l'hypertension gestationnelle et la direction des effets sur les naissances prématurées et les issues périnatales et maternelles défavorables était similaire à la prééclampsie, mais limitée aux femmes nullipares présentant des ratios de risque plus faibles.  Conclusion La COVID-19 pendant la grossesse est fortement associée à la prééclampsie, en particulier chez les femmes nullipares. Cette association est indépendante de tout facteur de risque et des conditions préexistantes. La gravité de la COVID-19 ne semble pas être un facteur dans cette association. Les deux affections sont associées indépendamment et de manière additive à une naissance prématurée, à une morbidité et une mortalité périnatales graves et à des résultats maternels défavorables. Les femmes atteintes de prééclampsie doivent être considérées comme un groupe particulièrement vulnérable en ce qui concerne les risques posés par la COVID-19.

section_content: COVID-19, which is primarily a respiratory infection, can have marked multiorgan, vascular effects leading to hypertension, renal disease, thrombocytopenia, and hepatic injury. SARS-CoV-2 can produce direct endothelial damage, thromboinflammation, dysregulation of immune responses, and alterations in angiotensin-converting enzyme 2e related pathways. 1 Preeclampsia, but not gestational hypertension (GH), causes endothelial damage, placental oxidative stress, and an antiangiogenic state leading to hypertension and proteinuria, 2 and similar multiorgan effects as seen in severe cases of COVID-19. 3 ecause COVID-19 has been shown to increase the risk for adverse pregnancy outcomes, including preeclampsia, 4e6 the concept of a COVID-19eassociated preeclampsia-like syndrome, which includes similar placental pathology, has been proposed. 7e9 However, it is important to note that COVID-19 during pregnancy and preeclampsia share the same set of risk factors, namely preexisting hypertension, obesity, and diabetes. 10e12 Thus, the association between COVID-19 and preeclampsia could be confounded by common underlying risk factors. 

A genuine association could manifest in the following 3 ways: (1) COVID-19 could cause symptoms and signs that meet the diagnostic criteria for preeclampsia, although these are separate conditions; (2) preeclampsia, which has pathophysiological changes already apparent early in pregnancy, 13e15 could constitute an additional risk factor for COVID-19, or (3) COVID-19 could be on an etiologic pathway toward preeclampsia, which in itself has been related etiologically to infectious diseases. 16e18 In this secondary analysis of the INTERCOVID multinational study, 19 we explored these possibilities including the independent association between the 2 conditions with severe adverse maternal and neonatal outcomes.
section_name: Introduction

section_content: INTERCOVID was a large, longitudinal, prospective, multinational observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. 19, 20 A total of 43 institutions in Argentina, Brazil, Egypt, France, Ghana, India, Indonesia, Italy, Japan, Mexico, Nigeria, North Macedonia, Pakistan, Russia, Spain, Switzerland, the United Kingdom, and the United States contributed to the study. 

Between March 2, 2020, and February 2, 2021, we enrolled women aged !18 years with a diagnosis of COVID-19 at any stage during their current pregnancy (diagnosed group) based on (1) a laboratory confirmation of COVID-19 or radiological pulmonary findings suggestive of COVID-19 21 or (2) !2 predefined COVID-19 symptoms. Of note, 2 immediately concomitant pregnant women aged !18 years without any of these diagnostic criteria (not-diagnosed group) were enrolled for each diagnosed woman to create an unbiased sample representative of all not-diagnosed pregnant women in these institutions. Women in the diagnosed and notdiagnosed samples were followed until hospital discharge of the newborn. 

When a woman was diagnosed antenatally, 2 not-diagnosed women of a similar gestational age (AE2 weeks), receiving standard antenatal care, were enrolled that day. If not possible or if those not-diagnosed women were lost to follow-up, we enrolled 2 not-diagnosed women who delivered immediately after the diagnosed woman. The same selection strategy was employed when a diagnosed woman was identified at hospital admission and delivery was likely to occur during that admission. If a not-diagnosed woman declined participation, the next woman was approached until 2 not-diagnosed women were enrolled for each diagnosed case. We sought confirmation from a biweekly, random 10% sample that the 2 notdiagnosed women were appropriately chosen; we excluded 5 diagnosed women and the corresponding not-diagnosed women without such confirmation. Live and stillborn and singleton and multiple gestation pregnancies in addition to those with congenital anomalies were included. 

For the secondary analysis, we considered preeclampsia as a primary co-exposure in addition to COVID-19 status; GH was considered a secondary co-exposure. Preeclampsia was defined by (1) blood pressure of 140/90 mm Hg or greater or an increase of 30 mm Hg systolic or 15 mm Hg diastolic above baseline values on at least 2 occasions 6 hours or more apart with proteinuria that developed after 20 weeks' gestation in a previously normotensive pregnancy; or (2) blood pressures of !160 mm Hg systolic or !110 mm Hg diastolic on 2 occasions, at least 4 hours but not more than 168 hours apart, or if the first measurement was immediately followed by treatment with an antihypertensive, either of these scenarios being associated with the presence of proteinuria; (3) eclampsia, defined as the occurrence of AJOG at a Glance Why was this study conducted? It is unclear whether the suggested association between COVID-19 during pregnancy and preeclampsia is independent of common risk factors. This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine key related pregnancy outcomes and maternal and neonatal morbidity and mortality.
section_name: Materials and Methods

section_name: Key findings

section_content: Women with preeclampsia should be considered a particularly vulnerable group for COVID-19. 

convulsions or coma unrelated to cerebral conditions in a woman with symptoms and signs of preeclampsia; or (4) evidence of hemolysis, elevated liver enzymes, and low platelet count syndrome. GH was defined as blood pressure of >140/90 mm Hg without proteinuria after 20 weeks' gestation in a previously normotensive woman.
section_name: What does this add to what is known?

section_content: The neonatal outcomes of interest were preterm birth (<37 weeks' gestation), frequency of small for gestational age (SGA) neonates (birthweight below the 10th percentile for gestational age and sex according to the INTERGROWTH-21 st Newborn Size Standards), 22 and an unweighted index, namely the severe perinatal morbidity and mortality index, which includes (1) fetal death; or (2) at least 1 of the following severe complications: bronchopulmonary dysplasia, hypoxic-ischemic encephalopathy, sepsis, anemia requiring transfusion, patent ductus arteriosus requiring treatment or surgery, intraventricular hemorrhage, necrotizing enterocolitis or retinopathy of prematurity diagnosed before hospital discharge; or (3) admission to the neonatal intensive care unit for !7 days; or (4) neonatal death before hospital discharge. We also examined a composite adverse maternal outcome, defined as the presence of (1) at least 1 of the following pregnancy-related morbidities: vaginal bleeding during pregnancy, preterm labor, and infection requiring antibiotics; or (2) any other pregnancyrelated conditions requiring treatment or referral; or (3) maternal admission to the intensive care unit (ICU) or referral to a higher level of care; or (4) death. 

Gestational age at delivery was estimated based on the earliest ultrasound scan (<14 weeks' gestation using the international INTERGROWTH-21 st standards). 23 If early ultrasound dating was not carried out, the best obstetrical estimate was used based on all clinical and ultrasound data available. 24
section_name: Outcomes

section_content: We used the same centrally coordinated data management system developed for the INTERGROWTH-21 st Project (MedSciNet, London, United Kingdom). 25 All data were entered locally into the on-line system with its extensive, built-in quality control facility. Queries can be dispatched immediately to the study sites, which provides continuously clean datasets for intermediate analysis.
section_name: Data management and analysis

section_content: We first compared the baseline demographic characteristics, and gynecologic, obstetrical, and medical histories of the 4 study groups, namely COVID-19 diagnosis without preeclampsia, preeclampsia without COVID-19, COVID-19 diagnosis with preeclampsia, and neither condition diagnosed. Second, we explored the association between preeclampsia and COVID-19 by adjusting for potential confounders that were selected a priori to be on the casual pathway using a directed acyclic graph. We further considered effect modification by parity or aspirin use during pregnancy and performed sensitivity analyses of multiple pregnancies and age of <20 years and, for the main outcome of COVID-19 and preeclampsia, adjustment by study site as a covariate and using mixed-effects models with random slopes by site. 

Associations of preeclampsia and COVID-19 with the binary outcomes were assessed using generalized linear models with a Poisson distribution and log link function. Estimates are expressed as risk ratios (RRs) and 95% confidence intervals (CIs). We used robust standard errors (SEs) to account for model misspecification and a clustered estimator of variance in models with perinatal outcomes to account for the lack of independence of multiple births. We assessed the joint effects of COVID-19 and preeclampsia on neonatal outcomes using an interaction term in the models. 

In all regression models, we adjusted first for potential sociodemographic confounders, such as maternal age, parity, and tobacco use during pregnancy, and second for a set of risk factors know to be associated with both COVID-19 and preeclampsia such as overweight and obesity, a history of diabetes, cardiac disease, hypertension, or renal disease. 

Finally, we adjusted for pregnancy history that included a preterm birth, miscarriage, or low birthweight neonate. 

We plotted Kaplan-Meier curves with the percentage of women who remained pregnant according to the gestational age to compare the distributions among the 4 groups. We also plotted Kaplan-Meier curves with the gestational age at the time of COVID-19 diagnosis as the dependent variable and the diagnosis of preeclampsia as the independent binary variable. Hazard ratios with 95% CIs were estimated using a Cox proportional hazards model. 26 thics approval was obtained from the Oxford Tropical Research Ethics Committee (OxTREC), reference 526-20, and all participating medical institutions obtained local approval from their corresponding ethics committees or institutional review boards. Written or verbal consent was obtained according to local practices. The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization-Good Clinical Practice guidelines and did not interfere with the clinical management of the women enrolled. The protocol was published on the study website before starting the study. 20
section_name: Statistical methodology

section_content: We enrolled a total of 2184 pregnant women. Of these, 725 were diagnosed with COVID-19 during pregnancy on the basis of a laboratory confirmation (realtime polymerase chain reaction [RT-PCR) test, n¼672, 92. 7%), radiological confirmation (n¼4, 0. 6%), or !2 predefined COVID-19 symptoms (n¼49, 6. 8%) if no laboratory results were available. The remaining 1459 pregnant women constituted the not-diagnosed COVID-19 group enrolled concomitantly using the rigorous methodology described above. In the not-diagnosed COVID-19 group, 730 of 1459 (50. 0%) women were tested; of these, 698 had a negative RT-PCR test and 32 had a negative COVID-19 antibody test. 

The contribution to the total study population ranged from 19. 9% (Italy, n¼434) to 0. 1% (Macedonia, n¼3). The other sites contributed to the ajog. org OBSTETRICS Original Research study data as follows: Argentina contributed 10. 6% (n¼231), the United States contributed 10. 2% ( n¼222), Pakistan contributed 9. 6% (n¼210), Mexico contributed 8. 0% (n¼ 174), France contributed 6. 7% (n¼147), India contributed 6. 7% (n¼147), the United Kingdom contributed 5. 3% (n¼116), Russia contributed 5. 0% (n¼108), Spain contributed 4. 7% (n¼102), Brazil contributed 4. 3% (n¼93), Nigeria contributed 3. 6% (n¼ 78), Indonesia contributed 2. 6% (n¼57), Ghana contributed 1. 7% (n¼36), Japan contributed 0. 6% (n¼12), Egypt contributed 0. 4% (n¼9), and Switzerland contributed 0. 2% (n¼5). 

Overall, 123 women had preeclampsia; of these, 8. 1% (59 of 725) of the women were in the COVID-19 diagnosed group and 4. 4% (64 of 1459) were in the COVID-19 not-diagnosed group, (RR, 1. 77; 95% CI, 1. 25e2. 52). There were 143 women with GH; 8. 4% (61 of 725) of the women were in the COVID-19 diagnosed group and 5. 6% (82 of 1459) were in the COVID-19 notdiagnosed group (RR, 1. 53; 95% CI, 1. 11e2. 11). Of the 725 women with COVID-19, 292 (40. 3%) were
section_name: Results

section_content: Table 2 presents the preeclampsia risk for the COVID-19 diagnosed and notdiagnosed groups. After initial adjustment for maternal age, parity (nulliparous vs parous), tobacco use, and history of adverse pregnancy outcomes, the RR for preeclampsia remained statistically significant for nulliparous (RR, 2. 14; 95% CI, 1. 33e3. 44) and parous women (RR, 1. 75; 95% CI, 1. 06e2. 88), however, the interaction was not significant (P¼. 60). Further adjustment for conditions known to be associated with preeclampsia (overweight and obesity, history of diabetes, cardiac disease, hypertension, or renal disease) led to a relatively small reduction in the RR, which remained statistically significant for nulliparous women (RR, 1. 89; 95% CI, 1. 17e3. 05) (Table 2 ). These results strongly suggest that the association between COVID-19 and preeclampsia is independent of the main confounding variables. The results were also very similar after adjusting for study site (Supplemental Table 3 ). 

Aspirin was used by 9. 6% of women, but no evidence of effect modification by aspirin use was seen (P value for interaction,. 42 for the model adjusting for demographic and risk factors). Sensitivity analyses excluding subgroups of women with maternal age <20 years and those with multiple pregnancy did not change the results. Similarly, a sensitivity analysis that excluded women diagnosed early in the pandemic based on 2 or more symptoms (n¼54), led to a small reduction in the association (for all women: from RR, 1. 77; 95% CI, 1. 25e2. 52; to RR, 1. 57; 95% CI, 1. 08e2. 28 and for nulliparous women from RR, 1. 89; 95% CI, 1. 17e3. 05; to RR, 1. 76; 95% CI, 1. 06e2. 90). 

We explored 5 characteristics to better understand the association. First, as described above, the effect was mostly 2 ). Hence, COVID-19 severity was not a factor in the observed association (Table 2 ) when assuming that symptom occurrence is indicative of worse disease. 

Third, there was no association among women (32. 5%) in whom COVID-19 was diagnosed >7 days from delivery (RR, 0. 99; 95% CI, 0. 55e1. 79) (Table 3 ), suggesting that the independent association mostly relates to women who may have developed preeclampsia already by the time of their COVID-19 diagnosis (RR, 2. 12; 95% CI, 1. 44e3. 11), particularly among nulliparous women (RR, 2. 36; 95% CI, 1. 40e3. 98) (Table 3 ). 

Fourth, as seen in Figure 1, there was a gradual and constant increase in COVID-19 diagnoses across gestational age among women without preeclampsia, whereas women with preeclampsia were mostly diagnosed with COVID-19 from 33 to 37 weeks' gestation; thereafter, both curves remained parallel (Cox model hazard ratio, 1. 49; 95% CI, 1. 12e1. 97 for COVID-19 among women with preeclampsia). 

Finally (Table 4 ), there was a statistically significant association between COVID-19 and GH (RR, 1. 53; 95%CI, 1. 11e2. 11) mostly seen among
section_name: Association between COVID-19 and preeclampsia

section_name: Association between COVID-19 and preeclampsia according to time elapsed between COVID-19 diagnosis and birth

section_content: For gestational age at diagnosis of COVID-19, stratified by preeclampsia status during pregnancy. Blue represents no preeclampsia; red represents preeclampsia. Cox model hazard ratio, 1. 49 (95% CI, 1. 12e1. 97). One woman was diagnosed with COVID-19 at 13 weeks' gestation; 34 were diagnosed from >13 to 26 weeks' gestation; 636 were diagnosed at >26 weeks' gestation; for 35 women the information about the gestational age at diagnosis was not available. 4 ).
section_name: Kaplan-Meier curves

section_content: As we have previously shown, 19 the COVID-19 group had an almost 2-fold higher risk for preterm birth, even after adjusting for a previous preterm birth. In Figure 2, A, we show that there was an additional negative effect of preeclampsia, namely women with both conditions had a RR for preterm birth of more than 4 (above 6 for nulliparous women) (Table 5 ). In women with COVID-19 and preeclampsia, 97% of the preterm births were medically indicated, similar to the 93% in those with preeclampsia without COVID-19. However, 80% were medically indicated in those with COVID-19 without preeclampsia and 61% were medically indicated in those with neither condition (Figure 2, B ). 

The SGA rate was 29. 3% in women with COVID-19 and preeclampsia with an RR of 2. 32 (95% CI, 1. 50e3. 58) when compared with the group with neither condition. The rate in those with preeclampsia without COVID-19 was 17. 5%; however, COVID-19 without preeclampsia was not associated with SGA (11. 6%), suggesting that preeclampsia was affecting fetal growth before COVID-19 infection. 

The RR for the severe perinatal morbidity and mortality index increased stepwise, particularly among nulliparous women; the RRs were 2. 41 (95% CI, 1. 54e3. 77), 3. 22 (95% CI, 1. 51e6. 88), and 3. 88 (95% CI, 1. 89e7. 96) for women with COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia, respectively (Table 5 ; unadjusted results are given in Supplemental Table 1 ). Similar results were observed in those 3 groups for the composite adverse maternal outcome; the RRs were 1. 76 (95% CI, 1. 32e2. 35), 2. 07 (95% CI, 1. 20e3. 57), and 2. 77 (95% CI, 1. 66e4. 63), respectively. However, we did not observe a significant interaction between COVID-19 exposure and preeclampsia on these neonatal outcomes. 

Overall, the direction of the effects of GH on preterm birth (Supplemental Figure ), SGA, the severe perinatal morbidity and mortality index, and composite adverse maternal outcome (Table 6 ; unadjusted results are given in Supplemental Table 2 ) were similar to what was observed for preeclampsia and were confined to nulliparous women, albeit with lower RRs. There was also a stepwise increase in the risk for preterm birth among women with COVID-19 without GH, women with GH without COVID-19, and women with both conditions.
section_name: Impact of COVID-19 and preeclampsia on the outcomes

section_content: Principal findings COVID-19 during pregnancy and preeclampsia are strongly associated with each other, especially among nulliparous women. This association is independent of risk factors and preexisting conditions. COVID-19 severity does not affect the association. In an additive fashion, these conditions increase the risks for preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. An effect on SGA frequency was seen only among women with preeclampsia.
section_name: Comment

section_content: COVID-19 and preeclampsia share many common risk factors such as obesity and underlying hypertension. Is it possible that these explain the observed association by a process of
section_name: Hypothesized mechanism of action and further research

section_name: ajog.org

section_content: There is certainly evidence emerging in support of a biological explanation. COVID-19 causes endothelial dysfunction either directly or indirectly, leading to hyperinflammation and aberrant antiviral responses. 27, 28 In addition, coagulopathy and disseminated intravascular coagulationelike massive intravascular clot formation are seen in the most severely ill, nonpregnant patients. 29 During pregnancy, COVID-19 induces specific vascular pathology that is similar to the changes seen in preeclampsia. In fact, Mendoza et al 7 have introduced the concept of a "preeclampsia-like syndrome" associated with COVID-19. In other words, it may be difficult to clinically distinguish this syndrome from "true" preeclampsia because they both share characteristics of the severe endothelial dysfunction seen in nonpregnant patients. 7, 30 owever, 2 observations from our study discourage this line of thinking. The first is that the severity of COVID-19 symptoms did not increase the association with preeclampsia, although we acknowledge that, in a recent cohort study, hypertensive disorders in pregnancy were more frequent in those women with severe COVID-19. 31 Secondly, the association was also present with GH, a hypertensive condition that does not present with the "preeclampsialike syndrome. "

We believe that the most likely explanation for the observed association is that preeclampsia and GH are vascular conditions, preceding infection with SARS-CoV-2, which increase the risk for COVID-19 in the same way essential hypertension does. This is supported by the relationship being mostly seen in nulliparous women; if COVID-19 led to preeclampsia (rather than the other way round), the association should also have been seen in parous women. Furthermore, the risk was highest when COVID-19 was diagnosed in the last 7 days of pregnancy; if COVID-19 were on the etiologic pathway, an earlier diagnosis would likely have had a stronger association with preeclampsia. The same conclusion emerges from Figure 1, namely there was a sharp increase in COVID-19 diagnoses among women with preeclampsia between 33 to 37 weeks' gestation when the condition typically manifests itself clinically. Conversely, in women without preeclampsia, COVID-19 diagnoses were proportionally distributed throughout pregnancy. Lastly, the excess risk for preeclampsia in women with COVID-19 persisted (RR, 1. 77; 95% CI, 1. 25e2. 52) even when we controlled for maternal sociodemographic and risk factors for preeclampsia.
section_name: OBSTETRICS Original Research confounding instead of a biological interaction or causal relationship?

section_content: COVID-19 during pregnancy is known to increase severe maternal morbidity and death, particularly respiratory dysfunction requiring invasive mechanical ventilation or admission to the ICU. 32 Our data provide additional information about the additive negative effects of COVID-19 and preeclampsia during pregnancy. Women who are at high risk for preeclampsia should also be considered at higher risk for COVID-19 and should be included in all preventive strategies during the pandemic. Whether aspirin administration reduces this risk further is not known, but effect modification by aspirin treatment in our study did not show any changes to the strength of the association. Original Research OBSTETRICS ajog. org
section_name: Clinical implications

section_content: We used data from a large-scale, prospective, multinational study that was specifically conducted to assess the symptoms and effects of COVID-19 during pregnancy on maternal and neonatal outcomes when compared with pregnant women not-diagnosed with COVID-19 who were carefully enrolled concomitantly to minimize selection bias. Rigorous data monitoring was applied to record severe morbidity markers including preeclampsia and GH. 

Our study has expected limitations. The circumstances for the diagnosis of maternal infection changed over time, from testing for severe symptoms of COVID-19 only to screening on admission. Hence, we cannot exclude the possibility that women admitted to hospital with a diagnosis of preeclampsia, or those with risk factors, were more likely to be tested for, or diagnosed with COVID-19. Nor did we examine the placentas of the women enrolled, which might have helped to determine whether the severity of infection correlates with the extent of vasculitis or whether different patterns of inflammation are seen in the 3 diagnostic groups. 33 However, this should not reduce the impact of our results because preeclampsia is a purely clinical diagnosis. We assessed the association between COVID-19 and preeclampsia in symptomatic and asymptomatic women; however, we could not conduct stratified analyses according to the COVID-19 disease severity classification proposed by the National Institutes of Health, because we did not have the complete information required by these relatively recent criteria. 31 Because this was an observational study, the clinical management of pregnancy complications, such as COVID-19 and preeclampsia, was based on local practice and therefore not standardized. Finally, it is also possible
section_name: Strengths and limitations of the study

section_content: OBSTETRICS Original Research that the not-diagnosed COVID-19 cohort may have included a small number of asymptomatic infected women who were not identified, either because routine testing was not available at that stage of the pandemic or because they became infected after they were included in the not-diagnosed cohort. We do not consider this a strong source of bias because it would have led to more conservative estimates from the analyses using that group as reference.
section_name: ajog.org

section_content: Preeclampsia (and to a lesser degree GH) is independently associated with COVID-19 during pregnancy; both conditions are associated independently of and in an additive fashion with increased risks for preterm birth, the severe perinatal morbidity and mortality index, and composite adverse maternal outcome. Hence, preeclampsia (and GH) seem to be a strong risk factor for SARS-CoV-2 infection and its related complications. There was no evidence to support that COVID-19 is etiologically associated with preeclampsia or GH. Clinicians caring for women with preeclampsia should be aware of the additional risks that COVID-19 poses. n
section_name: Conclusions

section_name: Acknowledgments

section_content: We are very grateful to the contributing institutions and local researchers involved in the study. The Appendix contains their details and the details of the study committees. tive Health, University of Oxford, Women 's Centre, John Radcliffe Hospital, Oxford, United Kingdom ( Drs Papageorghiou and Deantoni, Ms Craik, and Drs Winsey, Kennedy, and Villar); Oxford Maternal and Perinatal Health Institute, Green Templeton College, University of Oxford, Oxford, United Kingdom ( Drs Papageorghiou, Deantoni, Kennedy, and Villar); Department of Obstetrics and Gynaecology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom ( Dr Papageorghiou and Dr Liu ); Department of Obstetrics and Gynecology, Hoˆpitaux Universitaires de Strasbourg, Strasbourg, France ( Dr Deruelle ); Center for Environmental Research and Community Health (CERCH), School of Public Health, University of California, Berkeley, CA ( Dr Gunier, Mr Rauch, and Dr Eskenazi ); Hospital Regional Lic. Adolfo Lo´pez Mateos ISSSTE, Mexico City, Mexico ( Dr Garcı ´a-May ); Tufts Medical Center, Boston, MA ( Dr Mhatre ); Department of Obstetrics and Gynaecology, Muhammad Abdullahi Wase Teaching Hospital, Kano State, Nigeria (Mr Usman) ; Tropical Medicine and Infectious Diseases Department, Tanta University, Tanta, Egypt ( Dr Abd-Elsalam ); University of Calabar Teaching Hospital, Calabar, Nigeria ( Dr Etuk ); Department of Obstetrics and Gynecology, University of Washington, Seattle, WA (Dr Simmons ); Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom ( Dr Napolitano ); Fetal Medicine Unit, University College London Hospitals NHS Foundation Trust, London, United Kingdom ( Dr Napolitano ); Neonatal Care Unit, Department of Public Health and Pediatrics, School of Medicine, University of Turin, Italy ( Dr Deantoni ); Division of Obstetrics and Gynecology, zienda Socio Sanitaria Territoriale Spedali Civili di Brescia, Brescia, Italy ( Dr Prefumo ); Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy ( Dr Prefumo ); Department of BioMedical and Clinical Sciences, Ospedale Luigi Sacco University Hospital, University of Milan, Milan, Italy ( Dr Savasi ); Universidade Federal do Maranha ˜o, Sa ˜o Luı ´s, Brazil (Dr do Vale) ; Holy Family Hospital, Nkawkaw, Ghana ( Dr Baafi ); Department of Obstetrics and Gynaecology, the Aga Khan University, Karachi, Pakistan ( Dr Zainab ); Division Neonatologı ´a, Hospital Materno Infantil Ramo ´n Sarda, Buenos Aires Argentina ( Drs Nieto and Soto Conti ); Obstetrics Department, Hospital Universitari Vall d'Hebron, Barcelona Hospital Campus, Barcelona, Spain ( Dr Maiz ); Department of Obstetrics and Gynaecology, Abubakar Tafawa Balewa University Teaching Hospital, Bauchi, Nigeria (Dr Aminu) ; Instituto Nacional de Perinatologı ´a Isidro Espinosa de los Reyes, Mexico City, Mexico ( Dr Cardona-Perez ); Department of Pediatrics, General Hospital Borka Taleski, Prilep, Republic of North Macedonia (Ms Tavchioska ); Department of Obstetrics and Gynaecology, Faculty of Clinical Sciences, College of Medical Sciences, Gombe State University, Gombe, Nigeria ( Dr Bako ); ajog. orgOBSTETRICS Original Research SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 289. e11Obstetrics Department, Aragon Institute of Health Research, Hospital Clı ´nico Universitario Lozano Blesa Zaragoza, Zaragoza, Spain ( Dr Oros ); Department of Pediatrics, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil (Dr Rego); De ´partement de la Femme, de l'Enfant et de l'Adolescent, Hoˆpitaux Universitaires de Gene`ve, Geneva, Switzerland ( Dr Benski ); Bayero University Kano, Nigeria ( Dr Hassan-Hanga ); Aminu Kano Teaching Hospital, Kano State, Nigeria ( Dr Hassan-Hanga ); Hospital de Moron, Moron, Provincia de Buenos Aires, Argentina ( Dr Savorani ); Neonatal Special Care Unit, Regina Margherita Children Hospital, Citta `della Salute e della Scienza di Torino, Turin, Italy ( Dr Giuliani ); Department of Obstetrics and Gynecology Bordeaux University Hospital, Bordeaux, France ( Dr Sentilhes ); Servicio de Neonatologia del Departamento Materno Infantil del Hospital Universitario Austral, Pilar, Provincia de Buenos Aires, Argentina ( Dr Risso ); Department of Obstetrics and Gynecology, the Jikei University School of Medicine, Tokyo, Japan ( Dr Takahashi ); Sanatorio Otamendi, Ciudad de Buenos Aires, Argentina ( Dr Vecchiarelli ); Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan ( Dr Ikenoue ); Translational Health Science and Technology Institute, Faridabad, India ( Dr Thiruvengadam ); Department of Woman, Child and Neonate, Fondazione IRCCS Ca `Granda Ospedale Maggiore Policlinico, Milan, Italy ( Dr Ferrazzi ); Department of BioMedical and Clinical Sciences, Ospedale Vittore Buzzi Children's Hospital, University of Milan, Milan, Italy ( Dr Cetin ); Fr. Thomas Alan Rooney Memorial Hospital, Asankragwa, Ghana ( Dr Nachinab ); Department of Obstetrics and Gynecology, Medical Faculty, Universitas Airlangga, Surabaya, Indonesia ( Dr Ernawati ); Soetomo General Academic Hospital, Surabaya, Indonesia ( Dr Ernawati ); Universidad de Buenos Aires, Buenos Aires, Argentina ( Dr Duro ); Universidad de Moron, Moron, Argentina ( Dr Duro ); National Medical Research Center for Obstetrics, Gynecology & Perinatology, Moscow, Russia ( Dr Kholin ); Department of Obstetrics and Gynecology, University of Illinois Hospital and Health Science System, Chicago, IL ( Dr Firlit ); Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Harvard Medical School, Boston, MA ( Dr Easter ); Division of Critical Care Medicine, Department of Anesthesia, Perioperative, and Pain Medicine, Harvard Medical School, Boston, MA ( Dr Easter ); Hoˆpital Universitaire Necker-Enfants Malades, AP-HP, Universite ´de Paris, France ( Dr Sichitiu ); Mainland Hospital Yaba, Lagos, Nigeria ( Dr Bowale ); Maternal and Child Department, Hospital Nacional Profesor Alejandro Posadas, Buenos Aires, Argentina (Dr Casale); Neonatal Unit and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy ( Dr Cerbo ); Department of Obstetrics and Gynaecology, IRCCS San Raffaele Hospital and University, Milan, Italy ( Dr Cavoretto ); Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, United Kingdom ( Dr Guzman, Hernan Jensen, Fernando Tami, and Federico Crispin. Hospital Materno Infantil Ramón Sarda, Buenos Aires, Argentina: R. N. and C. P. S. C. (co-principal investigators), Eugenia Luque, Jimena Melisa Vargas, Marta Isabel Lopez, and Karen Zelada. Hospital Universitario Austral, Buenos Aires, Argentina: Maria Carola Capelli and M. R. (co-Principal Investigators), and Josefina Maria Bran. Hospital Magdalena V de Martinez, Buenos Aires, Argentina: E. A. D. (principal investigator). Hospital Nacional Profesor Alejandro Posadas, Buenos Aires, Argentina: R. Ca. (principal investigator), Silvia Garcia, Alberto Ferreiros, Lucio Ribola, Grethelm Ferrufino, Karell Rojas, Dafne Sidiropulos, and Silvana Varela. Hospital Municipal O. B de Lavignole, Buenos Aires, Argentina: M. S. (principal investigator), Silvana Aguirre, and Maria Rocio Tozzini. Hospital Universitário da Universidade Federal do Maranhão, São Luís, Brazil: M. S. D. V. (principal investigator), Ana Claudia Garcia Marques, Patricia Franco Marques, and Rebeca Aranha Arrais Santos Almeida. Tanta University Hospital, Tanta, Egypt: S. A. E. (principal investigator), Mohamed Elbahnasawy, Mai Khalaf, Mohamed Samir Abd El Ghafar, and Eslam Saber Esmail. Bordeaux University Hospital, Bordeaux, France: L. S. (principal investigator), Amaury Brot, Aurélien Mattuizzi, and Clémence Houssin. Hôpital Necker-Enfants Malades (Hôpital AP-HP ), Paris, France: Laurent J. Salomon (principal investigator), J. S., and Laurence Bussières. Hôpitaux Universitaires de Strasbourg, Strasbourg, France: P. D. (principal investigator), Fanny De Marcillac, Mary Pontvianne, Georges-Emmanuel Roth, Charlotte Jouffrieau, Sylvain Hufschmitt-Henry, Valentine Bergthold, Mathilde Airoldi, Olivier Behra, Julie Delplanque, and Coraline Schutz. Fr. Thomas Alan Rooney Memorial Hospital, Asankragua, Ghana: V. B. N. (principal investigator), Bright Sandow, Priscilla Baffour Kyeremeh, Rita Akpene Kumi, Thomas Asechaab, and Grace Hanson National Catholic Health Service, Directorate, Ghana : George Adjei, Anita Appiah, Roberta Ama Asiedu, and Ivan Essegbey. Holy Family Hospital, Nkawkaw, Ghana: E. B. (principal investigator) and Genevieve Insaidoo. Translational Health Science and Technology Institute, Faridabad, India, Employee's State Insurance Corporation Medical College and Hospital, Faridabad, India, and affiliated Badshah Khan Civil Hospital, Haryana, India: R. T. and Shinjini Bhatnagar (co-principal investigators), Vandita Bhartia, Mudita Gosain, Anil K. Pandey, Jagadish Chandra Sharma, Rajesh Dhiman, and GARBH-Ini-Department of Biotechnology India Consortium for COVID-19 Research Collaboration. Medical Faculty, Universitas Airlangga, Dr Soetomo General Academic Hospital, Surabaya, Indonesia: E. E. (principal investigator), Hendy Hendarto, Erry Gumilar, and Aditiawarman. Spedali Civili and University of Brescia, Brescia, Italy: F. P. (principal investigator), Roberta Castellani, and Marta Papaccio. Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy: Paola Roggero and Enrico Ferrazzi (coprincipal investigators), Camilla Menis, Michela Perrone, and Enrico Iurlaro. Ospedale Luigi Sacco, Milan, Italy: V. S. (principal investigator), Silvia Corti, and Francesca Rana. IRCCS San Raffaele Hospital and University, Milan, Italy: P. I. C. (principal investigator), Massimo Candiani, and Giulia Bonavina. Ospedale Vittore Buzzi, Milan, Italy: I. C. (principal investigator), Alice Zavatta, and Stefania Livio. University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy: Hellas Cena and R. M. C. (co-principal investigators), Debora Porri, Rachele De Giuseppe, Arsenio Spinillo, Annachiara Licia Scatigno, Francesca Perotti, and Marco Zecca. Ospedale Infantile Regina Margherita-Sant'Anna, Città della Salute e ajog. orgOBSTETRICS Original Research SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 289. e13 della Scienza di Torino, Turin, Italy: F. G. and Manuela Oberto (co-principal investigators), Enrico Bertino, Pietro Gaglioti, Cristian Romolo Macchione, and Francesca Carpano Maglioli. The Jikei University School of Medicine, Tokyo, Japan : K. T. (principal investigator) and Osamu Samura. Keio University School of Medicine, Tokyo, Japan : Mamoru Tanaka and S. I. (co-principal investigators), Daigo Ochiai, Yoshifumi Kasuga, and Miho Iida. General Hospital Borka Taleski, Prilep, North Macedonia: G. T. (principal investigator). General Hospital Kumanovo, Kumanovo, North Macedonia: Aleksandra Hristova (principal investigator). Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City, Mexico: J. A. C. P. (principal investigator), Sandra Acevedo-Gallegos, Irma Alejandra Coronado-Zarco, Brenda Ivette Frías, Addy Cecilia Helguera-Repetto, Maria José Rodriguez Sibaja, Isabel Villegas-Mota, and Maria Yolotzin Valdespino. Lic. Adolfo López Mateos ISSSTE, Mexico City, Mexico: P. K. G. M. (principal investigator), Alberto Almanza Aguilar, Sanjuanita Gonzalez Garza, Lorena Gomez Aldape, Alejandra Loera Olvera, and Paulina Soriano Cabelo. Abubakar Tafawa Balewa University Teaching Hospital, Bauchi, Nigeria: M. B. A. (principal investigator) and Tiamiyu Ismail. University of Calabar Teaching Hospital, Calabar, Nigeria: S. E. (principal investigator), Chinyere Akpanika, Komommo Okpebri, Etim Ekanem, and Ubong Akpan. Federal Teaching Hospital Gombe, Gombe, Nigeria: B. B. (principal investigator) and Yahaya Musa Suleiman. University College Hospital, Ibadan, Nigeria: Adejumoke Idowu Ayede and Yetunde John-Akinola (co-principal investigators), Oladapo OlayemI, and Olufisayo Christopher Ologunore. Mainland Hospital Yaba, Lagos, Nigeria : A. B. (principal investigator) and Tope Ogunniyan. Aminu Kano Teaching Hospital, Kano State, Nigeria: Hadiza Galadanci and F. H. H. (co-principal investigators) and Mahmoud Magashi. Muhammad Abdullahi Wase Teaching Hospital, Kano State, Nigeria: M. A. U. (principal investigator), Iman Haruna, Maryam Sulaiman, Rahila Garba, Badiyya Sayyidi, Hanifa Datti, Frank Akabudu, Abdurrahman Ali Bunawa, and Amira Aminu. The Aga Khan University Hospital, Karachi, Pakistan: Shabina Ariff (principal investigator), G. Z., Lumaan Shaikh, and Khalil Ahmed. National Medical Research Center for Obstetrics, Gynecology & Perinatology, Moscow, Russia: A. K. (principal investigator), Irina Yakovleva, Aleksander Gus, Alexander Sencha, Roman Shmakov, and Gennady Sukhikh. Hospital Universitari Vall d'Hebron, Barcelona, Spain: N. M. (principal investigator), Berta Serrano, Ester del Baco, Marta Miguez, Ana Perestelo, Lidia Barberán, Cristina Tusquets, Montserrat Capell, Clementina de Antonio, and Judit Gil. Hospital Clínico Universitario Lozano Blesa Zaragoza, Zaragoza, Spain: D. O. (principal investigator), Sara Ruiz-Martinez, Marta Fabre, and Cristina Paules. Hôpitaux Universitaires de Genève, Geneva, Switzerland: A. C. B. (principal investigator), Martinez de Tejada Weber, Véronique Othenin-Girard, Monia Moreau, Dominique Deletraz, and David Baud. St George's University Hospitals NHS Foundation Trust, London, United Kingdom: A. T. P. (principal investigator), B. L., Matthew Cauldwell, Yaa Acheampong, Danielle Hake, Sophie Robinson, and Rosemary Nyamboya. University College Hospitals NHS Foundation Trust, London, United Kingdom: R. N. (principal investigator), Laura Salazar, Rohit Atre, Alex Fry, and Hilary Hewitt. Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom: J. V., S. H. K., S. D. (co-principal investigators), Angelika Capp, Lotoyah Carty, Kate Dixon, Yvonne Nsiah, and Fenella Roseman. 

Brigham and Women's Hospital, Boston, Massachusetts: S. R. E. (principal investigator). 

Tufts Medical Center, Boston, Massachusetts: M. M. (principal investigator), Jenny Koenig, and Arome Obende. 

Mercy Hospital and Medical Center, Chicago, Illinois : Jagjit Singh Teji (principal investigator) and M. L. F. 

University of Washington, Seattle, Washington: Michael Gravett (principal investigator) and L. E. S. 

Original Research OBSTETRICS ajog. org
section_name: Acknowledgments

section_name: Author and article information

section_content: From the Nuffield Department of Women's & Reproduc-Thornton); Center for Global Child Health, Hospital for Sick Children, Toronto, Canada (Dr Bhutta); and Center of Excellence in Women & Child Health, The Aga Khan University, Karachi, Pakistan (Dr Bhutta). 

Received March 18, 2021; revised May 5, 2021; accepted May 11, 2021. 

A. T. P. and P. D. contributed equally. S. H. K. and J. V. contributed equally. 

The authors report no conflict of interest. 

The study was supported by the COVID-19 Research Response Fund from the University of Oxford (Ref 0009083). A. T. P. is supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the National Institute for Health Research (NIHR) Biomedical Research Centre funding scheme. The funding organization had no involvement in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication. 

The opinions expressed in this article are those of the authors and not necessarily reflect the views of the National Health Service, NIHR, Department of Health, or any of the other funders. 

J. V. and A. T. P. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. 

Corresponding author: Aris T.
section_name: Author and article information