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Original Research Confirmation of preeclampsia-like syndrome induced by severe COVID-19: an observational study Berta Serrano, MD; Erika Bonacina, MD; Itziar Garcia-Ruiz, MD; Manel Mendoza, MD, PhD; Pablo Garcia-Manau, MD; Paula Garcia-Aguilar, MD; Judit Gil, MD; Mireia Armengol-Alsina, MD; ndez-Hidalgo, MD, PhD; Elena Sulleiro, MD, PhD; Laura Castillo-Ribelles, MD; Nuria Ferna Nerea Maiz, MD, PhD; Elena Carreras, MD, PhD; Anna Suy, MD, PhD BACKGROUND: Since the outbreak of the COVID-19 pandemic, some preeclampsia and remained pregnant after pneumonia (non-preeclamp- studies have reported an increased preeclampsia incidence in pregnant sia); 7 (6.6%) met the diagnostic criteria for preeclampsia, had abnormal women with SARS-CoV-2 infection. Several explanations for this associa- (>38) soluble fms-like tyrosine kinase 1−to−placental growth factor ratio tion have been proposed, including a preeclampsia-like syndrome induced (preeclampsia), and delivered during severe pneumonia, and 8 (7.5%) by severe COVID-19. This syndrome was described in a small case series met the diagnostic criteria for preeclampsia, had normal (≤38) soluble and has not been confirmed in larger studies, and its effect on perinatal fms-like tyrosine kinase 1−to−placental growth factor ratio (preeclampsia outcomes has not been studied. like), and did not deliver during pneumonia. Despite not having delivered, OBJECTIVE: This study aimed to confirm the preeclampsia-like syn- most preeclampsia-related features improved after severe pneumonia in drome because of COVID-19 and to investigate its implications on preg- women with preeclampsia-like syndrome. Women with preeclampsia had nancy outcomes and prognosis. significantly poorer outcomes than women with preeclampsia-like syn- STUDY DESIGN: This was a prospective, observational study con- drome or without preeclampsia. ducted in a tertiary referral hospital. The inclusion criteria were pregnant CONCLUSION: More than 50% of women with severe COVID-19 and women admitted to the intensive care unit for severe pneumonia because diagnostic criteria for preeclampsia may not be preeclampsia but a pre- of COVID-19. They were classified into 3 groups based on clinical and lab- eclampsia-like syndrome, which may affect up to 7.5% of women with oratory findings: preeclampsia, preeclampsia-like syndrome, and women severe COVID-19. Preeclampsia-like syndrome might have similar perina- without preeclampsia features. The 3 cohorts were analyzed and com- tal outcomes to those of normotensive women with severe pneumonia pared at 3 different times: before, during, and after severe pneumonia. because of COVID-19. For these reasons, preeclampsia-like syndrome The main outcomes were incidence of adverse perinatal outcomes and should be excluded by using soluble fms-like tyrosine kinase 1−to−pla- signs and symptoms of PE, such as hypertension, proteinuria, thrombocy- cental growth factor ratio in future research and before making clinical topenia, elevated liver enzymes, and increased angiogenic factors (soluble decisions. fms-like tyrosine kinase 1−to−placental growth factor ratio). RESULTS: A total of 106 women were admitted to the intensive care Key words: angiogenic factors, COVID-19, preeclampsia, preeclamp- unit because of severe pneumonia, and 68 women were included in the sia-like syndrome, pregnancy, SARS-CoV-2, soluble fms-like tyrosine study. Of those, 53 (50.0%) did not meet the diagnostic criteria for kinase-1−to−placental growth factor ratio T he etiology and pathogenesis of preeclampsia (PE) are not completely understood; however, defi- imbalance in maternal serum, with increased antiangiogenic factors, such as soluble fms-like tyrosine kinase 1 (sFlt- findings with PE, and its diagnostic cri- teria may overlap; therefore, to provide adequate care, a differential diagnosis, cient trophoblast invasion seems to play 1), and decreased proangiogenic factors, although challenging, is necessary. a leading role.1 The resulting placental such as placental growth factor (PlGF).2 Some studies have shown that the sFlt-1 ischemia leads to an angiogenic Some studies have shown that this −to−PlGF ratio is a highly specific angiogenic status might induce endothe- marker for placental dysfunction and a Berta Serrano and Erika Bonacina contrib- lial cell dysfunction, which contributes may help to accurately discriminate PE uted equally to this work (co-first authors). to the development of PE with its signs from some of its imitators.6,8,9 Since the b Elena Carreras and Anna Suy contributed and symptoms (hypertension, protein- outbreak of the COVID-19 pandemic, equally to this work (co-last authors). uria, thrombocytopenia, elevated liver some studies have reported an increased enzymes, and neurologic disturbances).3 PE incidence in pregnant women with Cite this article as: Serrano B, Bonacina E, Garcia-Ruiz Several disorders have previously SARS-CoV-2 infection, and several I, et al. Confirmation of preeclampsia-like syndrome been demonstrated to mimic the clinical explanations for this association have induced by severe COVID-19: an observational study. Am features of PE, including acute fatty been proposed.10−13 On May 2020, a J Obstet Gynecol MFM 2023;5:100760. liver, thrombotic thrombocytopenic small case series published by Mendoza 2589-9333/$36.00 purpura, hemolytic uremic syndrome, et al7 described a PE-like syndrome © 2022 The Author(s). Published by Elsevier Inc. This is acute exacerbation of lupus erythemato- induced by severe COVID-19 during an open access article under the CC BY license (http:// sus, and COVID-19.4−7 These condi- pregnancy. That study showed that up creativecommons.org/licenses/by/4.0/) http://dx.doi.org/10.1016/j.ajogmf.2022.100760 tions share some clinical and laboratory to 62.5% of pregnant women with January 2023 AJOG MFM 1 Original Research AJOG MFM at a Glance women with true PE (met the PE criteria and had an sFlt-1−to−PlGF ratio of Why was this study conducted? >38) and women who did not meet the The preeclampsia (PE)-like syndrome has not yet been confirmed in larger stud- PE criteria and did not deliver during ies, and its effect on perinatal outcomes has not been studied. the ICU stay (non-PE group). As com- Key findings paring women with PE-like syndrome Despite not having delivered, most PE-related features in women with severe with women without PE and electively COVID-19 improved after severe pneumonia in women with PE-like syndrome. delivered because of pneumonia during Women with PE had significantly poorer outcomes than women with PE-like the ICU stay did not provide additional syndrome or without PE. Angiogenic factors are useful to discriminate PE-like information on the prognosis of patients from true PE. with PE-like syndrome, these women were excluded from this study (Figure). What does this add to what is known? Gestational age was confirmed by PE-like syndrome may be accurately identified by angiogenic factors. Correct fetal crown-rump length measurement identification of cases with PE-like syndrome may improve pregnancy outcomes at the first-trimester scan.14 Participants by reducing iatrogenic complications. were examined at 3 different times: before severe pneumonia, during severe pneumonia (at the time of ICU stay), and after recovery from severe severe pneumonia because of SARS- inclusion criteria were pregnant women pneumonia. Demographic characteris- CoV-2 infection may go on to develop admitted to the intensive care unit tics, obstetrical and maternal history, features of PE. Nevertheless, among the (ICU) for severe pneumonia because and biophysical and biochemical 5 cases with signs and symptoms of PE, of SARS-CoV-2 infection during preg- markers were collected. Biophysical and only 1 case had abnormal angiogenic nancy. SARS-CoV-2 infection was con- biochemical data included systolic status, suggesting that the remaining 4 firmed by a real-time polymerase chain blood pressure (SBP; mm Hg), diastolic cases probably did not have PE. Of reaction of nasal and pharyngeal swabs. blood pressure (DBP; mm Hg), hyper- these 4 cases, only 1 patient was still Participants who met the PE diagnostic tension (SBP of >140 mm Hg and/or pregnant after recovering from pneu- criteria and had normal sFlt-1−to DBP of >90 mm Hg), mean uterine monia, and all signs and symptoms of −PlGF ratio (≤38) were not delivered artery pulsatility index (PI) percentile PE had disappeared. Given that PE does for PE and were classified as patients by transabdominal Doppler ultra- not resolve spontaneously, and delivery with PE-like syndrome. To establish sound,15 proteinuria (in 24-hour urine is the only definitive treatment, severe whether the prognosis of women with samples, spot urine protein-to-creati- COVID-19-induced PE-like syndrome PE-like syndrome was more similar to nine ratio, and/or dipstick urinalysis), was the most plausible explanation for that of women with PE or to that of nor- platelet count (mL), aspartate amino- this case. motensive women, pregnancy outcomes transferase (AST; U/L), alanine amino- Therefore, only 1 confirmed case of were compared with 2 reference groups: transferase (ALT; U/L), lactate PE-like syndrome was described in that study at the beginning of the COVID- 19 pandemic; this syndrome has not been confirmed in larger studies, and its FIGURE effect on perinatal outcomes has not Inclusion flowchart been studied. Therefore, this study aimed to confirm the existence of a PE- like syndrome in a larger cohort of women with severe COVID-19 and to investigate its implications for preg- nancy outcomes and prognosis. Materials and Methods This was a prospective cohort study conducted at Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain, from February 2020 to September 2021. Our site was a referral hospital for PlGF, placental growth factor ratio; sFlt-1, soluble fms-like tyrosine kinase 1. severe COVID-19 pneumonia, espe- Serrano. Preeclampsia-like syndrome in severe COVID-19. Am J Obstet Gynecol MFM 2022. cially among pregnant patients. The 2 AJOG MFM January 2023 Original Research dehydrogenase (LDH; U/L), and creati- included in the study gave their oral or COVID-19 were admitted to the ICU. Of nine level (mg/dL). In women with sus- written consent according to the criteria those, 38 (35.8%) did not meet the inclu- pected PE, maternal serum PlGF and of our ethics committee. sion criteria for needing elective delivery sFlt-1 (pg/mL) were determined using during the ICU stay because of clinical the fully automated Elecsys assays for Statistical analysis worsening of pneumonia and not having sFlt-1 and PlGF on an electrochemilumi- Categorical data were reported as fre- clinical suspicion of PE. Therefore, 68 nescence immunoassay platform (cobas quency and percentage, and compari- women (64.2%) were included in the e analyzers; Roche Diagnostics, Rotk- sons among the groups were estimated study: 7 (6.6%) with PE, 8 (7.6%) with reuz, Switzerland). The sFlt-1−to−PlGF by the chi-square or fisher tests, as PE-like syndrome, and 53 (50.0%) with- ratio was calculated, with ≤38 values appropriate. Continuous variables were out PE features and not needing delivery considered normal and unlikely to be reported as median (interquartile range during severe pneumonia (non-PE associated with an underlying placental [IQR]). The Mann-Whitney U test was group). All 7 cases with PE required elec- dysfunction.16 used to assess differences among the tive delivery during severe pneumonia (4 PE was defined as new-onset high groups. The Wilcoxon signed-rank test [57.1%] because of PE, 2 [28.6%] because blood pressure (SBP of >140 mm Hg was used to assess differences of of COVID-19 worsening, and 1 [14.3%] and/or DBP of >90 mm Hg), worsening repeated measurements on a single because of nonreassuring cardiotocogra- of previous high blood pressure in addi- sample. The statistical significance level phy). In contrast, none of the cases in the tion to new-onset proteinuria (protein- was set at P<.05, and the Bonferroni PE-like syndrome group or the non-PE to-creatinine ratio of >300), worsening correction was applied to compensate group required elective delivery during of previous proteinuria, or at least 1 of for multiple comparisons. The Stata sta- severe pneumonia. The median (IQR) the following signs and symptoms of tistical software package was used for gestational age at the time of admission severe PE: cerebral or visual symptoms, data analysis (StataCorp 2019; Stata Sta- to the ICU was significantly higher in the elevation of liver enzymes to twice the tistical Software: Release 16; StataCorp PE group (35.4 [30.3−36.6]) than in the normal concentration, platelet count of LLC, College Station, TX). PE-like syndrome group (25.6 [21.3 <100.000/mL, serum creatinine level of −30]) and non-PE group (27.7 [24.5 >1.1 mg/dL, or pulmonary edema.17 Results −31.3]) (P=.01). No other pregnancy Here, to diagnose hypertension, at least During the study period, 106 patients baseline characteristic differed among the 5 of 6 consecutive measurements had to with severe pneumonia because of groups (Table 1). be abnormal for a 6-hour period. Hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome) TABLE 1 is considered a variant of PE. The diag- Demographic characteristics of the study population nostic criteria for the HELLP syndrome Characteristics PE like (n=8) PE (n=7) Non-PE (n=53) were hemolysis with increased LDH (>600 U/L), AST or ALT (≥70 U/L), Age (y) 31.9 (25.3−33.6) 33.8 (30−42.4) 33.6 (31.0−37.2) and platelet counts of <100 000/mL.18 BMI (kg/m2) 32.2 (24.8−36.1) 28.7 (24.3−29.9) 28.7 (26.4−32.3) Elective delivery was recommended at Chronic hypertension (%) 0/8 (0) 0/7 (0) 1/52 (1.9) ≥37 weeks of gestation in women with PE without severe features and ≥34 Smoking (%) 0/8 (0) 0/7 (0) 2/52 (3.9) weeks of gestation in women with Diabetes mellitus (%) 0/8 (0) 0/7 (0) 1/53 (1.9) severe PE and/or HELLP syndrome. In Nulliparous 4/8 (50.0) 5/7 (71.4) 11/53 (20.8) COVID-19 cases that met the PE diag- ART 1/8 (12.5) 1/7 (14.3) 3/45 (6.7) nostic criteria and had an sFlt-1−to −PlGF ratio of ≤38, elective delivery Race (%) because of PE was not recommended; White 6/8 (75.0) 7/7 (100.0) 46/53 (86.8) alternatively, these cases were managed South-Asian 0/8 (0) 0/7 (0) 3/53 (5.7) according to the clinical evolution of Asian 1/8 (12.5) 0/7 (0) 1/53 (1.9) COVID-19. Elective delivery because of severe pneumonia was indicated at ≥36 Afro-descendant 1/8 (12.5) 0/7 (0) 1/53 (1.9) to 38 weeks of gestation and ≥33 to 35 Mixt 0/8 (0) 0/7 (0) 2/53 (3.8) weeks of gestation if invasive respiratory Gestational age at ICU admission 25.6 (21.3−30.0)a 35.4 (30.3−36.6) 27.7 (24.5−31.3) support was required. Continuous data are presented as median (interquartile range). Categorical data presented as frequency (percentage). This study was approved by the Vall ART, assisted reproductive treatment; BMI, body mass index; ICU, intensive care unit; PE, preeclampsia. d’Hebron Barcelona Hospital Campus a Statistically significant difference compared to the PE group. Ethics Committee (PR[AMI]181/2020) Serrano. Preeclampsia-like syndrome in severe COVID-19. Am J Obstet Gynecol MFM 2022. on March 13, 2020. All patients January 2023 AJOG MFM 3 4 AJOG MFM January 2023 Original Research TABLE 2 PE-related findings during and after severe pneumonia PE like (n=8) PE (n=7) Non-PE (n=53) Variable During severe After severe During severe After severe During severe After severe pneumonia pneumonia P value pneumonia pneumonia P value pneumonia pneumonia P value SBP (mm Hg) 153.0 (147.3 115.0 (112.3 .012 154.0 (145.0 128.0 (123.0 .018 108.0 (103.5 104.0 (98.0 <.001 −160.8) −125.8) −156.0) −137.0) −119.0) −112.0) DBP (mm Hg) 95.5 (90.8 76.0 (63.8−77.5) .012 100.0 (97.0 83.0 (81.0−90.0) .018 69.0 (64.5−76.5) 65.0 (60.0−71.0) .005 −104.5) −109.0) Hypertension 8/8 (100.0) 0/8 (0) .005 7/7 (100.0) 2/7 (28.5) .025 0/53 (0) 1/53 (1.9) .320 Proteinuria 6/6 (100.0) 0/2 (0) .16 5/7 (71.4) — — 8/14 (57.1) 3/9 (33.3) .160 Platelet count per mL 245,000 273,500 .21 197,000 371,000 .06 259,000 290,000 (240,000 .045 (191,500 (224,800 (137,000 (307,000 (187,000 −352,000) −328,300) −384,500) −309,000) −406,000) −323,000) Thrombopenia<100,000/mL 0/8 (0) 0/8 (0) 1.0 0/7 (0) 0/7 (0) 1.0 0/51 (0) 0/51 (0) 1.0 AST (U/L) 99 (28.3−160.8) 18 (16−25) .028 104 (42−164) 29 (24−31) .022 74 (44−144.5) 23 (17−43) <.001 ALT (U/L) 114.5 (32.8 15.0 (9.0−33.0) .043 85.0 (39.0 30.0 (20.0−45.0) .028 58.8 (35.5 25.0 (14.0−37.0) <.001 −290.3) −150.0) −136.5) Transaminitis more than 5/8 (62.5) 1/7 (14.3) .083 6/7 (85.7) 0/7 (0) .014 32/52 (62.5) 6/47 (12.8) <.001 twice the normal values LDH (U/L) 282.0 (203.8 223.0 (167.0 .07 497.5 (347.3 328.5 (239.0 .68 280.5 (234.0 203.0 (173.0 .005 −360.3) −246.3) −538.3) −367.8) −320.5) −202.5) LDH>600 U/L 0/8 (0) 0/8 (0) 1.0 0/7 (0) 0/7 (0) 1.0 2/52 (3.9) 0/53 (0) .160 Creatinine level (mg/dL) 0.32 (0.25−0.41) 0.41 (0.39−0.42) .036 0.49 (0.47−0.64) 0.43 (0.38−0.49) .45 0.35 (0.31−0.44) 0.4 (0.34−0.51) .029 Creatinine level>1 mg/dL 0/8 (0) 0/8 (0) 1.0 0/7 (0) 0/7 (0) 1.0 0/51 (0) 0/53 (0) 1.0 Mean uterine artery PI >95th 1/5 (20.0) 1/6 (14.3) 1.0 — — — 2/13 (15.4) 4/29 (13.8) .320 percentile sFlT-1−to−PlGF ratio 4.60 (2.56 11.30 (7.30 .068 122.90 (49.40 15.20 (8.50 .18 6.70 (2.30 5.91 (3.40−10.40) .790 −12.80) −23.30) −225.50) −21.90) −10.90) Fulfill PE criteria 8/8 (100.0) 0/8 (0) .005 7/7 (100.0) 0/7 (0) .008 0/53 (0) 1/53 (1.9) 0.310 Fulfill HELLP criteria 0/8 (0) 0/8 (0) 1.0 0/7 (0) 0/7 (0) 1.0 0/53 (0) 0/53 (0) 1.0 Continuous data are presented as median (interquartile range). Categorical data are presented as frequency (percentage). The Wilcoxon signed-rank test was used to assess differences of repeated measurements on a single sample. ALT, alanine aminotransferase; AST, aspartate aminotransferase; DBP, diastolic blood pressure; HELLP, hemolysis, elevated liver enzymes, and low platelet count; LDH, lactate dehydrogenase; PE, preeclampsia; PI, pulsatility index; PlGF, placental growth factor; SBP, systolic blood pressure; sFlt-1, soluble fms-like tyrosine kinase 1. Serrano. Preeclampsia-like syndrome in severe COVID-19. Am J Obstet Gynecol MFM 2022. Original Research We found that some PE-related related features. When comparing the Regarding perinatal and neonatal features worsened similarly during PE-like syndrome and PE groups dur- outcomes, the PE-like syndrome group severe pneumonia across all 3 groups; ing pneumonia, the sFlt-1−to PlGF had significantly fewer cesarean deliver- however, most of these features ratios (4.6 [2.6−12.8] vs 122.9 [49.4 ies (37% vs 100%; P=.015), higher gesta- improved significantly after recovery −225.5]; P=.008) and creatinine val- tional age at delivery (39.1 [38.2−40.7] from severe pneumonia, without requir- ues (0.32 [0.25−0.41] mg/dL vs 0.49 weeks vs 36.3 [32−36.8] weeks; ing elective delivery in most cases [0.47−0.64] mg/dL; P=.015) differed P=.001), and higher birthweight (2737.5 (Tables 2 and 3). Among the 68 women significantly, although creatinine val- [2637.3−3037.5] g vs 2412.5 [1683.8 included in this study, there were 15 ues were within the normal range in −2580] g; P=.004) than the PE group. cases (22.1%) of hypertension, 19 cases both groups. In contrast, when com- No difference was found between the (27.9%) of proteinuria, and 43 cases paring the PE-like syndrome and PE-like syndrome and non-PE groups. (63.2%) of elevated liver enzymes. There non-PE groups, no significant differ- More information can be found in was no case of thrombocytopenia or ence was found, except for hyperten- Table 5. abnormal LDH or creatinine. Moreover, sion (8/8 (100%) vs 0/53 (0%); 15 women (22.1%) met the PE diagnos- P<.001), SBP (153 [147.3−160.8] mm Discussion tic criteria during severe pneumonia. Hg vs 108 [103.5−119] mm Hg; Principal findings When comparing the incidence of PE- P<.001), and DBP (95.5 [90.8−104.5] During severe pneumonia, up to 14.2% related features among groups, hyper- mm Hg vs 69 [64.5−76.5] mm Hg; (15/106) of women met the PE diagnos- tension was present in the PE and PE- P<.001). tic criteria; however, 8 of 15 cases like syndrome groups (100%) and not When we compared the groups after (53.3%) improved after pneumonia in the non-PE group (0%). In addition, the resolution of severe pneumonia without elective delivery. These 8 cases the sFlt-1−to−PlGF ratios were higher because of COVID-19, only blood pres- had normal sFlt-1−to−PlGF ratios, bet- in the PE group than in the PE-like syn- sure was significantly different among ter outcomes than the 7 women with drome and non-PE groups (Table 3). groups, being higher in the PE group, PE, and similar pregnancy outcomes to No other significant difference was although always within the normal those of normotensive women with observed across groups regarding PE- range (Table 4). severe COVID-19 who did not deliver TABLE 3 PE-related features during severe pneumonia in the PE-like group vs the PE and non-PE groups Variable PE like (n=8) PE (n=7) Non-PE (n=53) a SBP (mm Hg) 153 (147.3−160.8) 154 (145.0−156.0) 108 (103.5−119.0) DBP (mm Hg) 95.5 (90.8−104.5)a 100.0 (97.0−109.0) 69.0 (64.5−76.5) Hypertension 8/8 (100.0)a 7/7 (100.0) 0/53 (0) Proteinuria 6/6 (100.0) 5/7 (71.4) 8/14 (57.1) Platelet count per mL 245 (191.5−328.3) 197 (137.0−309.0) 259 (187.0−323.0) Thrombopenia<100,000/mL 0/8 (0) 0/7 (0) 0/51 (0) AST (U/L) 99 (28.3−160.8) 104 (42.0−164.0) 74 (44.0−144.5) ALT (U/L) 114.5 (32.8−290.3) 85.0 (39.0−150.0) 58.8 (35.5−136.5) Transaminitis more than twice the normal values 5/8 (62.5) 6/7 (85.7) 32/52 (62.5) LDH (U/L) 282 (203.8−360.3) 497.5 (347.3−538.3) 280.5 (234−320.5) LDH>600 U/L 0/8 (0) 0/7 (0) 2/52 (3.9) Creatinine (mg/dL) 0.32 (0.25−0.41)b 0.49 (0.47−0.64) 0.35 (0.31−0.44) Creatinine level>1 mg/dL 0/8 (0) 0/7 (0) 0/51 (0) Mean uterine artery PI >95th percentile 1/5 (20.0) — 2/13 (15.4) sFlT-1−to−PlGF ratio 4.6 (2.6−12.8)b 122.9 (49.4−225.5) 6.7 (2.3−10.9) Continuous data are presented as median (interquartile range). Categorical data presented as frequency (percentage). ALT, alanine aminotransferase; AST, aspartate aminotransferase; DBP, diastolic blood pressure; LDH, lactate dehydrogenase; PE, preeclampsia; PI, pulsatility index; PlGF, placental growth factor; SBP, systolic blood pressure; sFlt-1, soluble fms-like tyrosine kinase 1. a Statistically significant difference compared to the non-PE group;; b Statistically significant difference compared to the PE group. Serrano. Preeclampsia-like syndrome in severe COVID-19. Am J Obstet Gynecol MFM 2022. January 2023 AJOG MFM 5 Original Research TABLE 4 PE-related features after severe pneumonia in the PE-like group vs the PE and non-PE groups Variables PE like (n=8) PE (n=7) Non-PE (n=53) a,b SBP (mm Hg) 115 (112.3−125.8) 128 (123.0−137.0) 104 (98.0−112.0) DBP (mm Hg) 76 (63.8−77.5)a 83 (81.0−90.0) 65 (60.0−71.0) Hypertension 0/8 (0) 2/7 (28.5) 1/53 (1.9) Proteinuria 0/2 (0) — 3/9 (33.3) Platelet count per mL 273,500 (224,800−384,500) 371,000 (307,000−406,000) 290,000 (240,000−352,000) Thrombopenia<100,000/mL 0/8 (0) 0/7 (0) 0/51 (0) AST (U/L) 18 (16−25) 29 (24−31) 23 (17−43) ALT (U/L) 15 (9−33) 30 (20−45) 25 (14−37) Transaminitis more than twice the normal values 1/7 (14.3) 0/7 (0) 6/47 (12.8) LDH (U/L) 223 (167.0−246.3) 328.5 (239.0−367.8) 203 (173.0−202.5) LDH>600 U/L 0/8 (0) 0/7 (0) 0/53 (0) Creatinine (mg/dL) 0.41 (0.39−0.42) 0.43 (0.38−0.49) 0.40 (0.34−0.51) Creatinine level>1 mg/dL 0/8 (0) 0/7 (0) 0/53 (0) Mean uterine artery PI >95th percentile 1/7 (14.3) — 4/29 (13.8) sFLT-1−to−PlGF 11.3 (7.3−23.3) 15.2 (8.5−21.9) 5.91 (3.4−10.4) Continuous data are presented as median (interquartile range). Categorical data are presented as frequency (percentage). ALT, alanine aminotransferase; AST, aspartate aminotransferase; DBP, diastolic blood pressure; LDH, lactate dehydrogenase; PE, preeclampsia; PI, pulsatility index; PlGF, placental growth factor; SBP, systolic blood pressure; sFlt-1, soluble fms-like tyrosine kinase 1. a Statistically significant difference compared to the PE group;; b Statistically significant difference compared to the non-PE group. Serrano. Preeclampsia-like syndrome in severe COVID-19. Am J Obstet Gynecol MFM 2022. during severe pneumonia. This suggests enzymes) were observed during severe and increased sFlt-1−to−PlGF ratio, that the sFlt-1−to−PlGF ratio may be a pneumonia but improved after recov- improved similarly across all groups, useful marker to identify a subset of ery. This suggests that even in normo- with the remarkable difference that all patients with PE-like syndrome that tensive patients, severe pneumonia cases in the PE-like syndrome and non- otherwise may be misdiagnosed with because of COVID-19 can induce tran- PE groups recovered without elective PE and who would benefit from a more sient systemic effects that mimic PE and delivery. This confirms that PE-related conservative management. that resolve completely after the resolu- features in these 2 groups were due to In Table 2, we confirm that in both tion of pneumonia. the systemic effects of COVID-19. the PE-like syndrome group and the PE During severe pneumonia (Table 3), Regarding perinatal outcomes group, most PE features observed dur- the PE-like and PE groups were identi- (Table 5), the rate of cesarean deliveries ing severe pneumonia improved after cal, except for sFlt-1−to−PlGF and cre- was significantly higher and the birth- recovery, especially hypertension and atinine values that were significantly weight and gestational age at delivery transaminitis. Improvement in the PE lower, although within the normal were significantly lower in the PE group group can be attributed to the fact that range, in all patients with PE-like syn- than in the PE-like and non-PE groups. all women delivered because of drome. However, creatinine values were No difference was found between the COVID-19 and/or PE during ICU stay. also normal in the PE group, making PE-like and non-PE groups for perina- In contrast, in the PE-like group, PE- this finding clinically irrelevant for dif- tal outcomes. related features improved without deliv- ferential diagnosis. Therefore, the sFlt-1 ery. Given that PE does not resolve −to−PlGF ratio seems to be the only Results spontaneously, but only after delivery, parameter that allows to accurately dis- Several studies have reported an associ- the most plausible explanation for this criminate PE from PE-like syndrome. ation between PE and COVID-19 that outcome in the PE-like group is a PE- All women with PE were electively may be explained by several etiopatho- like syndrome induced by severe delivered during severe pneumonia. genic pathways.13,19−22 PE-like syn- COVID-19. After resolution of severe pneumonia drome was described at the beginning In the non-PE group, some PE- (Table 4), most PE-related features, of the pandemic in a small case series related features (such as increased liver such as hypertension, transaminitis, and could partly explain the higher PE 6 AJOG MFM January 2023 Original Research TABLE 5 Neonatal outcomes in the PE-like group vs the PE and non-PE groups Variables PE like (n=8) PE (n=7+1) Non-PE (n=53+2) Delivery Vaginal 3/8 (37.5)a 0/7 (0) 34/52 (65.4) a Vaginal assisted 2/8 (25.0) 0/7 (0) 3/52 (5.8) a Cesarean delivery 3/8 (37.5) 7/7 (100.0) 15/52 (28.9) a Gestational age at delivery 39.1 (38.2−40.7) 36.3 (32.0−36.8) 39 (37.9−40.0) Born alive 8/8 (100.0) 8/8 (100.0) 55/55 (100.0) Birthweight (g) 2737.5 (2637.3−3037.5)a 2412.5 (1683.8−2580.0) 3130.0 (2900.0−3540.0) Apgar score of <7 at 5 min 0/8 (0) 2/8 (25.0) 0/50 (0) Arterial pH<7 0/7 (0) 0/8 (0) 1/21 (4.8) Hypoglycemia 0/8 (0) 0/8 (0) 0/41 (0) Jaundice with phototherapy 0/8 (0) 1/8 (12.5) 1/41 (2.4) Intraventricular hemorrhage 0/8 (0) 0/8 (0) 0/49 (0) Necrotizing enterocolitis 0/8 (0) 0/8 (0) 0/49 (0) Sepsis 0/8 (0) 0/8 (0) 0/49 (0) Seizures 0/8 (0) 0/8 (0) 0/49 (0) Respiratory distress syndrome 0/8 (0) 3/8 (37.5) 1/48 (2.0) Periventricular leukomalacia 0/8 (0) 0/8 (0) 0/49 (0) Composite adverse neonatal outcomes 0/8 (0) 3/8 (37.50) 2/55 (3.64) Continuous data are presented as median (interquartile range). Categorical data are presented as frequency (percentage). PE, preeclampsia. a Statistically significant difference compared to the preeclampsia group. Serrano. Preeclampsia-like syndrome in severe COVID-19. Am J Obstet Gynecol MFM 2022. incidence in COVID-19 pregnancies.7 women with severe COVID-19 was pregnancy outcomes to those of normo- Unfortunately, none of the studies 50.0%, whereas the incidence was only tensive women with severe COVID-19. investigating the association between 7.5% in this study. This difference may Therefore, patients with PE-like both conditions have examined the be explained by the larger sample size in syndrome may benefit from a sFlt-1−to−PlGF ratio or excluded this study. Another plausible explana- more conservative management. Most women with PE-like syndrome from tion may be the longer study period (19 women with PE-like syndrome may be the analyses, making their results diffi- months) in this study compared with erroneously diagnosed with PE with cult to interpret. After that small case the case series (31 days). Both situations severity features because of the systemic series, PE-like syndrome was no further may offer a wider scope of the clinical effects of COVID-19 and, therefore, investigated in larger cohorts. For this characteristics of PE-like syndrome may be electively delivered at ≥34 weeks reason, the exact relationship between through different management proto- of gestation. In this context, the sFlt-1 PE and COVID-19 remains unknown, cols and different clinical manifesta- −to−PlGF ratio may help to discrimi- as some studies might have misdiag- tions because of the increasing vaccine nate true PE from PE-like syndrome, nosed some cases of PE. Here, we pro- administration rates and the evolving thus improving clinical management vided further evidence that PE-like SARS-CoV-2 variants. and pregnancy outcomes for cases with syndrome is an actual condition that PE-like syndrome by reducing the risk may affect 7.5% (8/106) of women with Clinical implications of iatrogenic complications and prema- severe COVID-19 and more than 50% This study has important clinical impli- turity. of women meeting the diagnostic crite- cations, as it shows that PE-like syn- ria for PE. According to the first case drome is a transient condition that Research implications series describing the PE-like syndrome, spontaneously resolves after recovery In addition, our results have important the incidence of this syndrome in from severe pneumonia and has similar research implications, as we show that January 2023 AJOG MFM 7 Original Research some cases classified as true PE in previ- Conclusions from preeclampsia by serum biomarkers. Kid- ous studies might instead be cases with More than 50% of women with severe ney Int 2013;83:177–81. 10. Villar J, Ariff S, Gunier RB, et al. Maternal PE-like syndrome. Therefore, to better COVID-19 that meet the diagnostic cri- and neonatal morbidity and mortality among assess the association between true PE teria for PE have PE-like syndrome. pregnant women with and without COVID-19 and COVID-19, in future studies, PE- Therefore, future research on COVID- infection: The INTERCOVID Multinational like syndrome should be excluded using 19 and PE should identify the cases Cohort Study. JAMA Pediatr 2021;175:817– the sFlt-1−to−PlGF ratio. with PE-like syndrome to better assess 26. the association of both conditions. PE- 11. Chen L, Li Q, Zheng D, et al. Clinical char- acteristics of pregnant women with Covid-19 in like syndrome is a transient condition Wuhan, China. N Engl J Med 2020;382:e100. Strengths and limitations with similar pregnancy outcomes to 12. Di Mascio D, Khalil A, Saccone G, et al. One of the main strengths of this study those of normotensive women with Outcome of coronavirus spectrum infections was the large number of pregnant severe COVID-19. Therefore, correct (SARS, MERS, COVID-19) during pregnancy: a women with severe pneumonia because identification of cases with PE-like systematic review and meta-analysis. Am J Obstet Gynecol MFM 2020;2:100107. of COVID-19. In addition, this study syndrome may improve pregnancy 13. Papageorghiou AT, Deruelle P, Gunier RB, confirmed the existence of a PE-like outcomes by reducing iatrogenic et al. Preeclampsia and COVID-19: results from syndrome induced by severe COVID- complications. & the INTERCOVID prospective longitudinal 19 by assessing the sFlt-1−to−PlGF in study. Am J Obstet Gynecol 2021;225:289.e1 −17. a relatively large cohort of pregnant ACKNOWLEDGMENTS 14. Robinson HP, Fleming JE. A critical evalua- women with suspicion of PE and severe tion of sonar “crown-rump length” measure- COVID-19. This study provided novel We thank all physicians who facilitated the ments. Br J Obstet Gynaecol 1975;82:702–10. recruitment at Hospital Universitari Vall d’He- evidence for the evolution and out- 15. Go mez O, Figueras F, Fernandez S, et al. bron and the participants who agreed to take comes of pregnancies with PE-like syn- Reference ranges for uterine artery mean pulsa- part in the study. drome induced by severe COVID-19. tility index at 11-41 weeks of gestation. Ultra- sound Obstet Gynecol 2008;32:128–32. Another strength of this study was that References 16. Schiettecatte J, Russcher H, Anckaert E, it further supports the clinical useful- 1. Magee LA, Nicolaides KH, von Dadelszen P. et al. Multicenter evaluation of the first auto- ness of the sFlt-1−to−PlGF ratio for Preeclampsia. N Engl J Med 2022;386:1817– mated Elecsys sFlt-1 and PlGF assays in nor- discriminating between placental dys- 32. mal pregnancies and preeclampsia. Clin 2. Erez O, Romero R, Jung E, et al. Preeclamp- Biochem 2010;43:768–70. function and other disorders.4 sia and eclampsia: the conceptual evolution of 17. Hypertension in pregnancy. Report of the The main limitation of this study was a syndrome. Am J Obstet Gynecol 2022;226: American College of Obstetricians and Gyne- the reduced number of cases with PE S786–803. cologists’ Task Force on Hypertension in Preg- and PE-like syndrome, which makes it 3. Turpin CA, Sakyi SA, Owiredu WK, Ephraim nancy. Obstet Gynecol 2013;122:1122–31. harder to identify differences across RK, Anto EO. Association between adverse 18. Haram K, Svendsen E, Abildgaard U. The groups for pregnancy outcomes. For pregnancy outcome and imbalance in angio- HELLP syndrome: clinical issues and manage- genic regulators and oxidative stress bio- ment. A Review. BMC Pregnancy Childbirth instance, the median birthweight in the markers in gestational hypertension and 2009;9:8. PE-like syndrome group tended to be preeclampsia. BMC Pregnancy Childbirth 19. Conde-Agudelo A, Romero R. SARS-CoV- lower than in the non-PE group 2015;15:189. 2 infection during pregnancy and risk of pre- (2737.5 g vs 3130 g, respectively), 4. Sibai BM. Imitators of severe pre-eclampsia. eclampsia: a systematic review and meta-anal- despite gestational age at delivery being Semin Perinatol 2009;33:196–205. ysis. Am J Obstet Gynecol 2022;226:68–89. 5. Inversetti A, Serafini A, Manzoni MF, Dolcetta e3. the same. However, this difference was Capuzzo A, Valsecchi L, Candiani M. Severe 20. Conde-Agudelo A, Romero R. Mecha- not statistically significant (P=.09), hypothyroidism causing pre-eclampsia-like nisms that may underlie a causal association probably because of the reduced sample syndrome. Case Rep Endocrinol 2012; between SARS-COV-2 infection and pre- size in the PE-like syndrome group. 2012:586056. eclampsia. Am J Obstet Gynecol 2022; 6. Verlohren S, Herraiz I, Lapaire O, et al. The 226:280–1. Therefore, it is plausible that patients sFlt-1/PlGF ratio in different types of hyperten- 21. Khalil A, Samara A, Chowdhury T, O’Brien who are hypertensive with severe sive pregnancy disorders and its prognostic P. Does COVID-19 cause pre-eclampsia? COVID-19 and normal sFlt-1−to potential in preeclamptic patients. Am J Obstet Ultrasound Obstet Gynecol 2022;59:146–52. −PlGF ratio (PE-like group) may have Gynecol 2012;206. 58.e1−8. 22. Giorgione V, Thilaganathan B. SARS-CoV- poorer perinatal outcomes than normo- 7. Mendoza M, Garcia-Ruiz I, Maiz N, et al. Pre- 2 related myocardial injury might explain the tensive patients with severe COVID-19 eclampsia-like syndrome induced by severe predisposition to preeclampsia with maternal COVID-19: a prospective observational study. SARS-CoV-2 infection. Am J Obstet Gynecol (non-PE group). However, this hypoth- BJOG 2020;127:1374–80. 2022;226:279–80. esis could not be confirmed in this 8. Hirashima C, Ogoyama M, Abe M, et al. Clin- study. Another limitation was that ical usefulness of serum levels of soluble fms- mean uterine artery PI was not recorded like tyrosine kinase 1/placental growth factor ratio to rule out preeclampsia in women with Author and article information in any women in the PE group; for this From the Maternal-Fetal Medicine Unit, Department of new-onset lupus nephritis during pregnancy. reason, we could not investigate its role CEN Case Rep 2019;8:95–100. Obstetrics, Vall d’Hebron Barcelona Hospital Campus, in distinguishing PE from PE-like syn- 9. Rolfo A, Attini R, Nuzzo AM, et al. Chronic Barcelona, Spain (Drs Serrano, Bonacina, Garcia-Ruiz, drome. kidney disease may be differentially diagnosed Mendoza, Garcia-Manau, Garcia-Aguilar, Gil, Armengol- 8 AJOG MFM January 2023 Original Research Alsina, Maiz, Carreras, and Suy); Universitat Autonoma Biochemistry, Vall d’Hebron Barcelona Hospital Campus, This study was approved by the Vall d’Hebron Univer- de Barcelona, Bellaterra, Spain (Drs Serrano, Bonacina, Barcelona, Spain (Dr Castillo-Ribelles). sity Hospital Ethics Committee (PR[AMI]181/2020) on Garcia-Ruiz, Mendoza, Garcia-Manau, Garcia-Aguilar, Received Aug. 19, 2022; revised Sept. 28, 2022; March 13, 2020. Written informed consent was waived Gil, Fernandez-Hidalgo, Sulleiro, Castillo-Ribelles, Maiz, accepted Sept. 28, 2022. because of the rapid emergence of this infectious dis- Carreras, and Suy); Department of Infectious Diseases, Nerea Maiz is a member of the European Reference ease. However, verbal informed consent was obtained Vall d’Hebron Barcelona Hospital Campus, Barcelona, Network on Rare Congenital Malformations and Rare Intel- from all patients, which was included in the patient’s Spain (Drs Fernandez-Hidalgo); Department of Microbiol- lectual Disability (European framework partnership agree- medical records. ogy, Vall d’Hebron Barcelona Hospital Campus, Barce- ment identification: 3HP-HP-FPA ERN-01-2016/739516). Corresponding author: Manel Mendoza, MD, PhD. lona, Spain (Dr Sulleiro); CIBERINFEC, ISCIII - CIBER de M.M. and I.G.R. received lecture fees from Roche manel.mendoza@vallhebron.cat Enfermedades Infecciosas, Instituto de Salud Carlos III, Diagnostics. The remaining authors report no conflict of Majadahonda, Spain (Dr Sulleiro); Department of interest. January 2023 AJOG MFM 9