Exploring the association between Preeclampsia and antiphospholipid antibodies. New insights on the clinical criteria of APS. A prospective study

Exploring the association between Preeclampsia and antiphospholipid antibodies. New insights on the clinical criteria of APS. 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New insights on the clinical criteria of APS. A prospective study Beatriz Grand, Sebastián Udry, Andrea Avigliano, Mónica González Alcántara, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5684910/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives: to study prospectively the presence aPL on pregnant women at time of preeclampsia (PE) diagnosis in comparison with normal pregnant controls (I), to determine the association between aPL and diagnosis of severe preeclampsia and (II) to evaluate the association between the presence of aPL and severe preeclampsia before and after 34 weeks of gestations. Study Design: This prospective, interventional, and analytical study included one hundred forty women who were tested for aPL during pregnancy and separated in 2 groups based on their diagnostic status of PE. Group 1: forty normal pregnant women studied for aPL beyond 20 weeks of pregnancy, followed until the birth of a full-term new-born baby and Group 2: one hundred women studied for aPL at the time of PE onset/diagnosis. We evaluated and compared rates of aPL positivity between Group 1 and 2. Results: We compared the presence of aPL between group 1 10,0% (4/40) and group 2 34,0% (34/100). We found an association between severe PE and aPL positivity [OR= 4.63 (95% CI: 1.523 – 14.107), p =0.005]. We also found an association between LA and severe PE [OR= 6.0 (95% CI: 1.3466 – 26.7335), p =0.01]. We confirmed an association between early severe PE and the presence of aPL positivity [OR= 4,384 (95% CI: 1.3615 – 14.1206), p = 0.01]. We also found an association between late severe PE and the presence of aPL positivity [OR= 5.0 (95% CI: 1.4901 – 16.777), p = 0.008]. We compared the presence of aPL between patients with early severe PE 25,9% (19/58) and patients with late severe PE 23,8% (15/42). No significant association was found between the 2 groups. These results suggest that the positivity of aPL and gestational age are independent, and both related to their severity. Conclusion : These results suggest that the presence of aPL is associated to the severe PE. The positivity of aPL is associated to the severity of PE, independently from gestational age. We suggest including the study aPL in women with severe PE independently of prematurity. High risk Hypertension Obstetric antiphospholipid syndrome Preeclampsia 1. Introduction Antiphospholipid syndrome (APS) is a rare multisystemic autoimmune disorder characterized by the presence of persistent antiphospholipid antibodies (aPL) and thrombosis and/or pregnancy morbidity [ 1 ]. According to the International consensus statement the pregnancy clinical criteria is defined by recurrent early pregnancy loss (three or more unexplained), fetal death (one or more unexplained) or one or more premature birth due to preeclampsia (PE), intrauterine growth restriction and other consequences of placental insufficiency. The laboratory criteria are defined by the presence of anti-cardiolipin (aCL) antibodies and/or anti–β2-glycoprotein I (aβ2-GPI) antibodies and/or lupus anticoagulant (LA), respectively [ 2 ]. The APS is currently classified based on a combination of laboratory and clinical criteria. Recently, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) updated the antiphospholipid syndrome classification criteria [ 3 ]. In this new diagnostic criteria, severe PE is classified as the most relevant obstetric clinical criteria [ 3 ]. Obstetric APS remains a clinical challenge for physicians, with several controversial points that have not been answered so far. Severe PE is one of the obstetric criteria of the APS [ 2 , 3 ] but the association between antiphospholipid antibodies (aPL) and severe PE remains unclear and controversial[ 4 ]. This controversy is due to a lack of high quality prospective studies [ 4 ]. We study prospectively the presence aPL on pregnant women at time of PE diagnosis in comparison with normal pregnant controls (I), to determine the association between aPL and diagnosis of severe PE and (II) to evaluate the association between the presence of aPL and severe PE before and after 34 weeks of gestations. 2. Materials and Methods 2.1 Study Population We carefully and prospectively selected one hundred forty women who were tested for aPL during pregnancy. All the included patients were recruited from one medical centre in Argentina: Hospital General de Agudos “Juan A. Fernández”. This institution is a renowned referral tertiary-level and University Centre for the management of high-risk pregnancies that includes women with APS and PE. This prospective, interventional, and analytical study included women who were tested for aPL during pregnancy and stratified in 2 groups based on their diagnostic status of PE. Group 1: normotensive pregnant women (control Group) and Group 2: women with diagnosis of severe PE. Patients of group 1 were followed prospectively until the birth of a full-term new-born baby, carrying out strict control of blood pressure during this follow-up. Patients in Group 2 were treated with the standard of care (SC) for PE, based our institutional guidelines. No additional treatment related to aPL positivity was indicated. To evaluate the association between the onset of severe PE and aPL, we compare the aPL positivity between these 2 groups. We stratified patients of Group 2, according to gestational age of diagnosis of severe PE. We separated these patients into two groups: early severe PE and late severe PE. We compare the frequency of aPL between early and late severe PE, to evaluate if there is an association between weeks of gestation and PE. We also compare each of these subgroups with Group 1 to evaluate the association between aPL and severe PE in each subgroup separately. 2.2 Definitions According to the Sydney classification criteria of APS, premature births were defined as morphologically normal neonate births before the 34 th week of gestation because of eclampsia or severe PE, defined according to standard definitions, or recognized features of placental insufficiency [2]. PE was defined as diastolic blood pressure ≥90 mm Hg or systolic blood pressure ≥140 mm Hg on 2 occasions at least 4 hours apart after 20 weeks of gestation, in a previously normotensive or hypertensive patient with significant proteinuria (0.3 grams in a 24-hour urine sample)[5]. Severe PE was defined as PE + one or more of the following features: Severe blood pressure elevation, renal dysfunction, impaired liver function, thrombocytopenia, and central nervous system dysfunction. Severe blood pressure elevation: systolic blood pressure ≥160mm Hg or diastolic blood pressure ≥110mm Hg on 2 occasions at least 4 hours apart while the patient is on bed rest. Central nervous system dysfunction: New-onset headache unresponsive to medication and not accounted for by alternative diagnosis. Impaired liver function: Abnormally elevated blood concentrations of liver enzymes (more than twice the upper limit of normal concentrations), or severe persistent right upper quadrant or epigastric pain unresponsive to medications, not accounted by alternative diagnosis. Renal dysfunction: Serum creatinine concentration >1.1mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease. Thrombocytopenia: platelet count of <100.000 PE was classified as early when it was diagnosed at 34 weeks. 2.3 Inclusion criteria: Group 1 and Group 2 inclusion criteria: Pregnant women with >20 weeks of gestation Signing the informed consent Group 1 (control group) inclusion criteria: Normotensive patients (in all control among pregnancy) and no history of hypertension Delivering a newborn at term with adequate birth weight for gestational age and without complications among pregnancy. Determination of aPL antibodies (during pregnancy, approximately 20-30 weeks of gestation) Group 2 inclusion criteria Women with severe PE. Determination of aPL antibodies at onset/ diagnosis of severe PE. 2.4 Exclusion criteria: Group 1 and Group 2 exclusion criteria: Lost to follow up (weekly follow-up until birth) Withdrawal of consent Infection diseases Other autoimmune diseases Use of antithrombotic drugs Other Thromboembolic diseases. Other clinical conditions that might negatively affect the pregnancy outcome (cardiovascular disease, chronic renal failure, etc) 2.5 Laboratory tests: Blood samples Blood was obtained by clean venipuncture (after an 8 hour fast) and was collected into plastic tubes containing sodium citrate (ratio 9:1). After two centrifugation steps at 2500 × g for 15 minutes, the platelet-poor plasma was immediately assayed for LA and then stored at -40 °C. The blood was collected into tubes, allowed to clot at 37 °C and then centrifuged at 1500 × g for serum preparation. The serum was stored at -40 °C until ready for use. Blood samples were taken at the time of PE onset and in normal group after 20 weeks of gestation. Laboratory tests Lupus Anticoagulant (LA): the profile includes dilute Russell viper venom time (dRVVT) and two different activated partial thromboplastin time (aPTT) reagents. Laboratory studies: Screening tests: aPTT was performed using PTT-LA (Stago) and an aPTT homemade reagent with diluted cephalin. dRVVT was performed using Russel viper venom RVV (Stago) and diluted cephalin. The negative control plasma was prepared according to ISTH LA recommendations for the mixing tests [ 6 ] . Confirmatory tests: We performed a homemade reagent for platelet neutralization procedure (PNP)-aPTT and dRVVT; Rosner Index and % of Correction as criteria for mixing and confirmatory tests interpretation. In our experience, in pregnancy, we found that the most sensitive screening test to detect LA was the Diluted Russell Viper Venom time [7]. ELISA tests Anti-β2 glycoprotein I (aβ2GPI) antibody IgG and/or IgM (Louisville) and APhL Ig G and IgM (Louisville APL Diagnostics) antibodies were measured using standardized enzyme immunoassays of IgG and IgM isotypes. The APhL ELISA Kit follows the same procedure as the standard published method for performance of the anticardiolipin assay[8]. We classified the patients into negative and positive groups according to the serum levels of aCL IgG and IgM or ab2GPI IgG and IgM. A negative titer was defined as less than 39 GPL or MPL or less than 39 UG or UM; a positive titer was defined as >40 MPL or as >40 UM. Women were classified according to aPL positivity in the laboratory categories as follows: triple-positive for aPL (LA+, aCL+ and aβ2GPI+), double-positive for aPL (LA+ and aCL+ or LA+ and aβ2GPI+, or aCL+ and aβ2GPI+) and single-positive for aPL (LA+ or aCL+, or aβ2GPI+). Triple and double positivity corresponded with laboratory category I and single positivity with category II (IIa, IIb and IIC, respectively) according to the Sydney recommendations[2]. 2.6 Ethics This study was approved by the ethics committee of the Hospital General de Agudos “Juan A. Fernández” and was performed according to the principles of the Declaration of Helsinki and current national laws. Informed consent was obtained from all the participants. 2.7 Statistical analysis Statistical analysis was performed using the SPSS statistical software package (version 23.0 for Windows, SPSS, Chicago, IL, USA). Categorical variables were described as counts and percentages, and continuous variables were presented as medians (interquartile ranges) or means (standard deviations). A nonparametric test (Mann-Whitney U) was used to compare quantitative data, and the chi-square test or Fisher’s exact test was used to compare proportions. Chi-square and/or Fisher test was performed to evaluate the association among aPL and PE (Group 1 vs Group 2). Chi-square and/or Fisher test was performed compare the association among aPL and PE according to gestational age (Group 2). Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated to assess the strength of the association between treatment and pregnancy outcomes. P <0.05 was considered to indicate statistical significance. 3. Results This study included 140 pregnant women who were prospectively tested for aPL during pregnancy, separated in two groups according to inclusion criteria. Group 1 included 40 pregnant women (median age: 29,2 years; interquartile range: 20-41 years) and Group 2 included 100 women (median age: 28,3 years; interquartile range: 18-42 years). pregnancy and laboratory characteristics are described at Table 1. TABLE 1 We compared the presence of aPL between group 1 10,0% (4/40) and group 2 34,0% (34/100). We found an association between severe PE and aPL positivity [OR= 4.63 (95% CI: 1.523 – 14.107), p =0.005]. We also found an association between LA and severe PE [OR= 6.0 (95% CI: 1.3466 – 26.7335), p =0.01] We compared Group 1 vs early severe PE; and we found association between early severe PE and the presence of aPL positivity [OR= 4,384 (95% CI: 1.3615 – 14.1206), p = 0.01]. When we compared Group 1 vs late severe PE, we also found an association between late severe PE and the presence of aPL positivity [OR= 5.0 (95% CI: 1.4901 – 16.777), p = 0.008]. We compared the presence of aPL between patients with early severe PE 25,9% (19/58) and patients with late severe PE 23,8% (15/42). No significant association was found between the 2 groups (Table 2). TABLE 2 Discussion This is one of the largest cohort’s series evaluating the association between aPL and severe PE. What makes this evidence more valuable is the prospective nature of the study, the severity of PE and the time of aPL determination. Several animal models have provided insights into the direct relationship between the presence of aPL and obstetric manifestation of APS [ 9 ]. This evidence leads us to think that antibodies have a direct effect at placenta, which justifies their determination at the time of diagnosis of severe PE. When the association between aPL and severe PE was assessed, we found that patients with diagnosis of severe PE had a strong correlation with the presence of positive results of aPL, especially with LA [ 10 , 11 ]. We also evaluated the relationship between aPL and severe PE, stratified according to gestational age. We found an homogeneous distribution of aPL regardless of the time of diagnosis. These results suggest that the positivity of aPL is associated to the severity of PE, independently from gestational age of onset. Severity is the most relevant clinical feature to request antiphospholipid antibodies associated with PE. Taking into account the strict clinical criteria of APS, PE should be considered a manifestation of “classic” obstetric APS, only if it`s associated with Prematurity[ 2 ]. These association is reinforced with some retrospective studies and a recent prospective study that informed an increased frequency of aPL in women with PE [ 11 – 15 ]. Many of these studies are limited, as they are mostly retrospective, and some do not evaluate the entire antibody profile[ 16 , 17 ]. Cervera et al, found that the most frequent complication in patients with aPL was PE (13.9%). This study, however, lacks data such as the time of onset of PE[ 18 ]. Some authors found this same correlation between severity and aPL (Roni Zemet, Heilmann,Gibbins)[ 11 , 19 , 20 ]. Our results are also supported by Marchetti et al; who compare plasma samples from 199 women with “non-severe” PE and 143 women with “severe” PE, as well as from 195 control women[ 21 ]. The authors found an association between PE and aPLs only in the “sever” Group[ 21 ]. In accordance with our results, other groups like the APS Alliance for Clinical Trials and International Networking (APS ACTION) defines the aPL related composite pregnancy morbidity as a preterm delivery at or before 37 week due to PE [ 22 ]. It is remarkable that the 34-week cut-off point for the clinical criteria of APS is the same cut-off point for the iatrogenic premature ending of a pregnancy with severe PE [ 2 , 23 ]. Added to this, PE after 34th weeks is usually not severe[ 11 ]. This data could have been misinterpreted when the clinical criteria was defined. Thus, our data suggest that aPL should be considered always on severe PE severity independently from Prematurity. These results suggest the need to re-evaluate the diagnostic criteria for antiphospholipid syndrome, not only for PE, but also for other causes involving placental vascular alterations. Our study has numerous strengths. Prospective design. We included patients at time of severe PE onset. Control pregnant women were studied from 20 weeks of gestations and follow up until the end of pregnancy, achieving a full-term newborn with adequate weight for gestational age (high specific control group). With access to a single laboratory techniques, reagents and cutoff values. We measured all aPL that are considered for the classification of APS. Taking into account all these considerations, we considered this study a high-quality study. We must consider that according to the Obstetric task forces at the 14th and 15th there is a lack of high quality studies regarding this topic[ 11 ]. Our study adds the importance of studying all pregnancies that develop severe hypertension by confirming the frequency of aPL in a prospective cohort of women studied at time of PE onset and our analysis was not limited by preterm birth before 34th weeks. However, a limitation of our study is the small sample size. Nevertheless, it is important to note that this limitation is a common and crucial concern among all the studies on APS. Conclusions These results suggest that the presence of aPL is associated to the severe PE. The positivity of aPL is associated to the severity of PE, independently from gestational age. We suggest including the study aPL in women with severe PE independently of prematurity. Declarations Funding The author(s) received no financial support for the research, authorship, and/or publication of this article. Conflict of interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Author Contribution Authors’ contributionsBG and LV were involved in the study conception and design. All the authors were involved in drafting the article. BG, SU and JOL 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. Data analysis and interpretation were performed by SU. Final revision was performed by BG and SU. References Palomo I, Segovia F, Ortega C, Pierangeli S. Antiphospholipid syndrome: a comprehensive review of a complex and multisystemic disease. Clinical and experimental rheumatology. 2009;27(4):668-77. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). Journal of thrombosis and haemostasis : JTH. 2006;4(2):295-306. doi: 10.1111/j.1538-7836.2006.01753.x. Barbhaiya M, Zuily S, Naden R, Hendry A, Manneville F, Amigo MC, et al. 2023 ACR/EULAR antiphospholipid syndrome classification criteria. Annals of the rheumatic diseases. 2023;82(10):1258-70. doi: 10.1136/ard-2023-224609. Abalos E, Cuesta C, Grosso AL, Chou D, Say L. Global and regional estimates of preeclampsia and eclampsia: a systematic review. 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Tables Table 1: Pregnancy and laboratory characteristics Variables Group 1 (n=40) Group 2 (n=100) Age 29,2 (20-41) 28,3 (18-42) Delivery > 34.0 weeks Delivery < 33.6 weeks Delivery /Weeks of gestation Cesarean section Vaginal delivery 100,0% (40/40) 0,0% (0/40) 39,2 ± 1,32 42,5% (17/40) 57,5% (23/40) 42,0% (42/100) 58,0% (58/100) 34,21 ± 5,28 82,0% (82/100) 18,0% (18/100) aβ2GPI positive aβ2GPI IgG positive aβ2GPI IgM positive aCL positive aCL IgG positive aCL IgM positive LA positive 2,5% (1/40) 0,0% (0/40) 2,5% (1/40) 2,5% (1/40) 2,5% (1/40) 0,0% (0/40) 5,0% (2/40) 16,0% (16/100) 0,0% (0/100) 16,0% (16/100) 3,0% (3/100) 3,0% (3/100) 2,0% (2/100) 24,0% (24/100) aPL positive 10,0% (4/40) 34,0% (34/100) aPL profile aPL profile I aPL profile IIa aPL profile IIb aPL profile IIc 0,0% (0/40) 5,0% (2/40) 2,5% (1/40) 2,5% (1/40) 9,0% (9/100) 15,0% (15/100) 1,0% (1/100) 9,0% (9/100) aPL: antiphospholipid antibodies; aCL: anticardiolipin antibodies; aβ2GPI: anti-β2 glycoprotein I; LA: lupus anticoagulant. Table 2: Distribution of aPL according to weeks of gestation. Group 2 – Variables Early severe Preeclampsia x34.0 weeks (n=42) p aPL positive 32,7% (19/58) 35,7 % (15/42) NS aPL doble positivity aPL simple positivity 6,9 % (4/58) 25,9 % (15/58) 11,9% (5/42) 23,8 % (10/42) NS NS LA positive aβ2GPI positive aCL positive 25,9% (15/58) 8,6 % (8/58) 0,0 % (0/58) 21,4 % (9/42) 19,0 % (8/42) 7,1 % (3/42) NS NS NS aPL: antiphospholipid antibodies; aCL: anticardiolipin antibodies; aβ2GPI: anti-β2 glycoprotein I; LA: lupus anticoagulant. NS: non-significant Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5684910","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":395481411,"identity":"5f935d5f-c112-4d78-8b75-79d1ed33000b","order_by":0,"name":"Beatriz Grand","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYLACHoYDDAzsjQ0HJCqAPGbmBiK18Bw+eMDiDEgLI7FaJNKSD1S2gbgEtMhHH3724A3DHTn+hhyDAzfn1UbztwO1/KjYhlOL4bk0c8M5DM+MJQ6cMTg4c9vx3BmHGRsYe87cxq2lh8FMmofhcGLDwR6Dw5LbjuU2ALUwM7bh08L+DaSlfv5hHoPDf+ccy51PSIs8Dw/YlgSDY2wJByQbanI3ENJiwMNTJjnH4JnhxjPMBw5IHDuQuxGo5SA+v8j3sG+TeFNxR17u/sPmDxI1dbnzzh8++OBHBR5bDoBJOP8wmDyAUz3IlgZUfh0+xaNgFIyCUTBCAQDnN2Luft8yRQAAAABJRU5ErkJggg==","orcid":"","institution":"Department of Maternal and Perinatal Medicine, Obstetric and Hematology Division Hospital General de Agudos “Juan A Fernández”.","correspondingAuthor":true,"prefix":"","firstName":"Beatriz","middleName":"","lastName":"Grand","suffix":""},{"id":395481412,"identity":"183e55f8-5da6-4c04-bc50-111107111d09","order_by":1,"name":"Sebastián Udry","email":"","orcid":"","institution":"Research Center \"Fundación Respirar\"","correspondingAuthor":false,"prefix":"","firstName":"Sebastián","middleName":"","lastName":"Udry","suffix":""},{"id":395481413,"identity":"48bf6cb5-7623-417c-a824-5071c957533d","order_by":2,"name":"Andrea Avigliano","email":"","orcid":"","institution":"Department of Maternal and Perinatal Medicine, Obstetric and Hematology Division Hospital General de Agudos “Juan A Fernández”.","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Avigliano","suffix":""},{"id":395481414,"identity":"fa3ea334-0765-4468-b961-150736e46913","order_by":3,"name":"Mónica González Alcántara","email":"","orcid":"","institution":"Department of Maternal and Perinatal Medicine, Obstetric and Hematology Division Hospital General de Agudos “Juan A Fernández”.","correspondingAuthor":false,"prefix":"","firstName":"Mónica","middleName":"González","lastName":"Alcántara","suffix":""},{"id":395481415,"identity":"6488e4db-1436-4c8e-9c55-6d518a96a793","order_by":4,"name":"José Omar Latino","email":"","orcid":"","institution":"Autoimmune, Thrombophilic Diseases and Pregnancy Section, Acute Hospital \"Dr. Carlos G. Durand\"","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"Omar","lastName":"Latino","suffix":""},{"id":395481416,"identity":"0f8d4665-4f48-43bd-9a65-67a4e0cafcc3","order_by":5,"name":"Liliana S. Voto","email":"","orcid":"","institution":"Department of Maternal and Perinatal Medicine, Obstetric and Hematology Division Hospital General de Agudos “Juan A Fernández”.","correspondingAuthor":false,"prefix":"","firstName":"Liliana","middleName":"S.","lastName":"Voto","suffix":""}],"badges":[],"createdAt":"2024-12-20 14:38:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5684910/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5684910/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85365909,"identity":"30b5b067-7575-4c5f-b4a2-3280f519bef7","added_by":"auto","created_at":"2025-06-25 06:47:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":679078,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5684910/v1/a400b63f-dcbf-4ad6-b027-ad9832acc0ce.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eExploring the association between Preeclampsia and antiphospholipid antibodies. New insights on the clinical criteria of APS. A prospective study\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAntiphospholipid syndrome (APS) is a rare multisystemic autoimmune disorder characterized by the presence of persistent antiphospholipid antibodies (aPL) and thrombosis and/or pregnancy morbidity [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAccording to the International consensus statement the pregnancy clinical criteria is defined by recurrent early pregnancy loss (three or more unexplained), fetal death (one or more unexplained) or one or more premature birth due to preeclampsia (PE), intrauterine growth restriction and other consequences of placental insufficiency. The laboratory criteria are defined by the presence of anti-cardiolipin (aCL) antibodies and/or anti\u0026ndash;β2-glycoprotein I (aβ2-GPI) antibodies and/or lupus anticoagulant (LA), respectively [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The APS is currently classified based on a combination of laboratory and clinical criteria. Recently, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) updated the antiphospholipid syndrome classification criteria [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In this new diagnostic criteria, severe PE is classified as the most relevant obstetric clinical criteria [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eObstetric APS remains a clinical challenge for physicians, with several controversial points that have not been answered so far. Severe PE is one of the obstetric criteria of the APS [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] but the association between antiphospholipid antibodies (aPL) and severe PE remains unclear and controversial[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This controversy is due to a lack of high quality prospective studies [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe study prospectively the presence aPL on pregnant women at time of PE diagnosis in comparison with normal pregnant controls (I), to determine the association between aPL and diagnosis of severe PE and (II) to evaluate the association between the presence of aPL and severe PE before and after 34 weeks of gestations.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1 Study Population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe carefully and prospectively selected one hundred forty women who were tested for aPL during pregnancy. All the included patients were recruited from one medical centre in Argentina: Hospital General de Agudos \u0026ldquo;Juan A. Fern\u0026aacute;ndez\u0026rdquo;.\u003c/p\u003e\n\u003cp\u003eThis institution is a renowned referral tertiary-level and University Centre for the management of high-risk pregnancies that includes women with APS and PE.\u003c/p\u003e\n\u003cp\u003eThis prospective, interventional, and analytical study included women who were tested for aPL during pregnancy and stratified in 2 groups based on their diagnostic status of PE. Group 1: normotensive pregnant women (control Group) and Group 2: women with diagnosis of severe PE. Patients of group 1 were followed prospectively until the birth of a full-term new-born baby, carrying out strict control of blood pressure during this follow-up. Patients in Group 2 were treated with the standard of care (SC) for PE, based our institutional guidelines. No additional treatment related to aPL positivity was indicated.\u003c/p\u003e\n\u003cp\u003eTo evaluate the association between the onset of severe PE and aPL, we compare the aPL positivity between these 2 groups.\u003c/p\u003e\n\u003cp\u003eWe stratified patients of Group 2, according to gestational age of diagnosis of severe PE. We separated these patients into two groups: early severe PE and late severe PE. We compare the frequency of aPL between early and late severe PE, to evaluate if there is an association between weeks of gestation and PE. We also compare each of these subgroups with Group 1 to evaluate the association between aPL and severe PE in each subgroup separately.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Definitions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the Sydney classification criteria of APS, premature births were defined as morphologically normal neonate births before the 34\u003csup\u003eth\u003c/sup\u003e week of gestation because of eclampsia or severe PE, defined according to standard definitions, or recognized features of placental insufficiency [2].\u003c/p\u003e\n\u003cp\u003ePE was defined as diastolic blood pressure \u0026ge;90 mm Hg or systolic blood pressure \u0026ge;140 mm Hg on 2 occasions at least 4 hours apart after 20 weeks of gestation, in a previously normotensive or hypertensive patient with significant proteinuria (0.3 grams in a 24-hour urine sample)[5].\u003c/p\u003e\n\u003cp\u003eSevere PE was defined as PE + one or more of the following features: Severe blood pressure elevation, renal dysfunction, impaired liver function, thrombocytopenia, and central nervous system dysfunction.\u003c/p\u003e\n\u003cp\u003eSevere blood pressure elevation: systolic blood pressure \u0026ge;160mm Hg or diastolic blood pressure \u0026ge;110mm Hg on 2 occasions at least 4 hours apart while the patient is on bed rest.\u003c/p\u003e\n\u003cp\u003eCentral nervous system dysfunction: New-onset headache unresponsive to medication and not accounted for by alternative diagnosis.\u003c/p\u003e\n\u003cp\u003eImpaired liver function: Abnormally elevated blood concentrations of liver enzymes (more than twice the upper limit of normal concentrations), or severe persistent right upper quadrant or epigastric pain unresponsive to medications, not accounted by alternative diagnosis.\u003c/p\u003e\n\u003cp\u003eRenal dysfunction: Serum creatinine concentration \u0026gt;1.1mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease.\u003c/p\u003e\n\u003cp\u003eThrombocytopenia: platelet count of \u0026lt;100.000\u003c/p\u003e\n\u003cp\u003ePE was classified as early when it was diagnosed at \u0026lt;33.6 weeks or late when it was diagnosed at \u0026gt;34 weeks.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Inclusion criteria:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGroup 1 and Group 2 inclusion criteria:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cem\u003ePregnant women with \u0026gt;20 weeks of gestation\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eSigning the informed consent\u003c/em\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eGroup 1 (control group) inclusion criteria:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cem\u003eNormotensive patients (in all control among pregnancy) and no history of hypertension\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eDelivering a newborn at term with adequate birth weight for gestational age and without complications among pregnancy.\u0026nbsp;\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eDetermination of aPL antibodies (during pregnancy, approximately 20-30 weeks of gestation)\u0026nbsp;\u003c/em\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cem\u003eGroup 2 inclusion criteria\u003c/em\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cem\u003eWomen with severe PE.\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eDetermination of aPL antibodies at onset/ diagnosis of severe PE.\u0026nbsp;\u003c/em\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Exclusion criteria:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGroup 1 and Group 2 exclusion criteria:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cem\u003eLost to follow up (weekly follow-up until birth)\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eWithdrawal of consent\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eInfection diseases\u0026nbsp;\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eOther autoimmune diseases\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eUse of antithrombotic drugs\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eOther Thromboembolic diseases.\u0026nbsp;\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eOther clinical conditions that might negatively affect the pregnancy outcome (cardiovascular disease, chronic renal failure, etc)\u003c/em\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003e2.5 Laboratory tests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBlood samples\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBlood was obtained by clean venipuncture (after an 8 hour fast) and was collected into plastic tubes containing sodium citrate (ratio 9:1). After two centrifugation steps at 2500 \u0026times; g for 15 minutes, the platelet-poor plasma was immediately assayed for LA and then stored at -40 \u0026deg;C. The blood was collected into tubes, allowed to clot at 37 \u0026deg;C and then centrifuged at 1500 \u0026times; g for serum preparation. The serum was stored at -40 \u0026deg;C until ready for use. Blood samples were taken at the time of PE onset and in normal group after 20 weeks of gestation.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLaboratory tests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eLupus Anticoagulant (LA): the profile includes dilute Russell viper venom time (dRVVT) and two different activated partial thromboplastin time (aPTT) reagents. Laboratory studies: Screening tests: aPTT was performed using PTT-LA (Stago) and an aPTT homemade reagent with diluted cephalin. dRVVT was performed using Russel viper venom RVV (Stago) and diluted cephalin. The negative control plasma was prepared according to ISTH LA recommendations for the mixing tests \u003csup\u003e[\u003c/sup\u003e\u003csup\u003e6\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e. Confirmatory tests: We performed a homemade reagent for platelet neutralization procedure (PNP)-aPTT and dRVVT; Rosner Index and % of Correction as criteria for mixing and confirmatory tests interpretation.\u003c/p\u003e\n\u003cp\u003eIn our experience, in pregnancy, we found that the most sensitive screening test to detect LA was the Diluted Russell Viper Venom time [7].\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eELISA tests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAnti-\u0026beta;2 glycoprotein I (a\u0026beta;2GPI) antibody IgG and/or IgM (Louisville) and APhL Ig G and IgM (Louisville APL Diagnostics) antibodies were measured using standardized enzyme immunoassays of IgG and IgM isotypes. The APhL ELISA Kit follows the same procedure as the standard published method for performance of the anticardiolipin assay[8].\u003c/p\u003e\n\u003cp\u003eWe classified the patients into negative and positive groups according to the serum levels of aCL IgG and IgM or ab2GPI IgG and IgM. A negative titer was defined as less than 39 GPL or MPL or less than 39 UG or UM; a positive titer was defined as \u0026gt;40 MPL or as \u0026gt;40 UM.\u003c/p\u003e\n\u003cp\u003eWomen were classified according to aPL positivity in the laboratory categories as follows: triple-positive for aPL (LA+, aCL+ and a\u0026beta;2GPI+), double-positive for aPL (LA+ and aCL+ or LA+ and a\u0026beta;2GPI+, or aCL+ and a\u0026beta;2GPI+) and single-positive for aPL (LA+ or aCL+, or a\u0026beta;2GPI+). Triple and double positivity corresponded with laboratory category I and single positivity with category II (IIa, IIb and IIC, respectively) according to the Sydney recommendations[2].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.6 Ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the ethics committee of the Hospital General de Agudos \u0026ldquo;Juan A. Fern\u0026aacute;ndez\u0026rdquo; and was performed according to the principles of the Declaration of Helsinki and current national laws. Informed consent was obtained from all the participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.7 Statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis was performed using the SPSS statistical software package (version 23.0 for Windows, SPSS, Chicago, IL, USA). Categorical variables were described as counts and percentages, and continuous variables were presented as medians (interquartile ranges) or means (standard deviations). A nonparametric test (Mann-Whitney U) was used to compare quantitative data, and the chi-square test or Fisher\u0026rsquo;s exact test was used to compare proportions. Chi-square and/or Fisher test was performed to evaluate the association among aPL and PE (Group 1 vs Group 2). Chi-square and/or Fisher test was performed compare the association among aPL and PE according to gestational age (Group 2). Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated to assess the strength of the association between treatment and pregnancy outcomes. \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05 was considered to indicate statistical significance.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eThis study included 140 pregnant women who were prospectively tested for aPL during pregnancy, separated in two groups according to inclusion criteria. Group 1 included 40 pregnant women (median age: 29,2 years; interquartile range: 20-41 years) and Group 2 included 100 women (median age: 28,3 years; interquartile range: 18-42 years). pregnancy and laboratory characteristics are described at Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTABLE 1\u003c/p\u003e\n\u003cp\u003eWe compared the presence of aPL between group 1 10,0% (4/40) and group 2 34,0% (34/100). \u0026nbsp;We found an association between severe PE and aPL positivity [OR= 4.63 (95% CI: 1.523 \u0026ndash; 14.107), \u003cem\u003ep\u003c/em\u003e=0.005]. We also found an association between LA and severe PE [OR= 6.0 (95% CI: 1.3466 \u0026ndash; 26.7335), \u003cem\u003ep\u003c/em\u003e=0.01]\u003c/p\u003e\n\u003cp\u003eWe compared Group 1 vs early severe PE; and we found association between early severe PE and the presence of aPL positivity [OR= 4,384 (95% CI: 1.3615 \u0026ndash; 14.1206), \u003cem\u003ep\u003c/em\u003e= 0.01].\u0026nbsp;When we compared Group 1 vs late severe PE, we also found an association between late severe PE and the presence of aPL positivity [OR= 5.0 (95% CI: 1.4901 \u0026ndash; 16.777), \u003cem\u003ep\u003c/em\u003e= 0.008].\u003c/p\u003e\n\u003cp\u003eWe compared the presence of aPL between patients with early severe PE 25,9% (19/58) and patients with late severe PE 23,8% (15/42). No significant association was found between the 2 groups (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTABLE 2\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is one of the largest cohort\u0026rsquo;s series evaluating the association between aPL and severe PE. What makes this evidence more valuable is the prospective nature of the study, the severity of PE and the time of aPL determination. Several animal models have provided insights into the direct relationship between the presence of aPL and obstetric manifestation of APS [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This evidence leads us to think that antibodies have a direct effect at placenta, which justifies their determination at the time of diagnosis of severe PE.\u003c/p\u003e \u003cp\u003eWhen the association between aPL and severe PE was assessed, we found that patients with diagnosis of severe PE had a strong correlation with the presence of positive results of aPL, especially with LA [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe also evaluated the relationship between aPL and severe PE, stratified according to gestational age. We found an homogeneous distribution of aPL regardless of the time of diagnosis. These results suggest that the positivity of aPL is associated to the severity of PE, independently from gestational age of onset. Severity is the most relevant clinical feature to request antiphospholipid antibodies associated with PE. Taking into account the strict clinical criteria of APS, PE should be considered a manifestation of \u0026ldquo;classic\u0026rdquo; obstetric APS, only if it`s associated with Prematurity[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThese association is reinforced with some retrospective studies and a recent prospective study that informed an increased frequency of aPL in women with PE [\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Many of these studies are limited, as they are mostly retrospective, and some do not evaluate the entire antibody profile[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCervera et al, found that the most frequent complication in patients with aPL was PE (13.9%). This study, however, lacks data such as the time of onset of PE[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSome authors found this same correlation between severity and aPL (Roni Zemet, Heilmann,Gibbins)[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Our results are also supported by Marchetti et al; who compare plasma samples from 199 women with \u0026ldquo;non-severe\u0026rdquo; PE and 143 women with \u0026ldquo;severe\u0026rdquo; PE, as well as from 195 control women[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The authors found an association between PE and aPLs only in the \u0026ldquo;sever\u0026rdquo; Group[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn accordance with our results, other groups like the APS Alliance for Clinical Trials and International Networking (APS ACTION) defines the aPL related composite pregnancy morbidity as a preterm delivery at or before 37 week due to PE [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt is remarkable that the 34-week cut-off point for the clinical criteria of APS is the same cut-off point for the iatrogenic premature ending of a pregnancy with severe PE [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Added to this, PE after 34th weeks is usually not severe[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This data could have been misinterpreted when the clinical criteria was defined.\u003c/p\u003e \u003cp\u003eThus, our data suggest that aPL should be considered always on severe PE severity independently from Prematurity.\u003c/p\u003e \u003cp\u003eThese results suggest the need to re-evaluate the diagnostic criteria for antiphospholipid syndrome, not only for PE, but also for other causes involving placental vascular alterations.\u003c/p\u003e \u003cp\u003eOur study has numerous strengths. Prospective design. We included patients at time of severe PE onset. Control pregnant women were studied from 20 weeks of gestations and follow up until the end of pregnancy, achieving a full-term newborn with adequate weight for gestational age (high specific control group). With access to a single laboratory techniques, reagents and cutoff values. We measured all aPL that are considered for the classification of APS. Taking into account all these considerations, we considered this study a high-quality study. We must consider that according to the Obstetric task forces at the 14th and 15th there is a lack of high quality studies regarding this topic[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study adds the importance of studying all pregnancies that develop severe hypertension by confirming the frequency of aPL in a prospective cohort of women studied at time of PE onset and our analysis was not limited by preterm birth before 34th weeks.\u003c/p\u003e \u003cp\u003eHowever, a limitation of our study is the small sample size. Nevertheless, it is important to note that this limitation is a common and crucial concern among all the studies on APS.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThese results suggest that the presence of aPL is associated to the severe PE. The positivity of aPL is associated to the severity of PE, independently from gestational age. We suggest including the study aPL in women with severe PE independently of prematurity.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe author(s) received no financial support for the research, authorship, and/or publication of this article.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConflict of interest\u003c/strong\u003e \u003cp\u003eThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthors\u0026rsquo; contributionsBG and LV were involved in the study conception and design. All the authors were involved in drafting the article. BG, SU and JOL 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. Data analysis and interpretation were performed by SU. Final revision was performed by BG and SU.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePalomo I, Segovia F, Ortega C, Pierangeli S. Antiphospholipid syndrome: a comprehensive review of a complex and multisystemic disease. Clinical and experimental rheumatology. 2009;27(4):668-77. \u003c/li\u003e\n\u003cli\u003eMiyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). Journal of thrombosis and haemostasis : JTH. 2006;4(2):295-306. doi: 10.1111/j.1538-7836.2006.01753.x.\u003c/li\u003e\n\u003cli\u003eBarbhaiya M, Zuily S, Naden R, Hendry A, Manneville F, Amigo MC, et al. 2023 ACR/EULAR antiphospholipid syndrome classification criteria. Annals of the rheumatic diseases. 2023;82(10):1258-70. doi: 10.1136/ard-2023-224609.\u003c/li\u003e\n\u003cli\u003eAbalos E, Cuesta C, Grosso AL, Chou D, Say L. Global and regional estimates of preeclampsia and eclampsia: a systematic review. European journal of obstetrics, gynecology, and reproductive biology. 2013;170(1):1-7. doi: 10.1016/j.ejogrb.2013.05.005.\u003c/li\u003e\n\u003cli\u003eNewman C, Petruzzi V, Ramirez PT, Hobday C. Hypertensive Disorders of Pregnancy. Methodist DeBakey cardiovascular journal. 2024;20(2):4-12. doi: 10.14797/mdcvj.1305.\u003c/li\u003e\n\u003cli\u003eDevreese KMJ, de Groot PG, de Laat B, Erkan D, Favaloro EJ, Mackie I, et al. Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis: Update of the guidelines for lupus anticoagulant detection and interpretation. Journal of thrombosis and haemostasis : JTH. 2020;18(11):2828-39. doi: 10.1111/jth.15047.\u003c/li\u003e\n\u003cli\u003eRiveros DA, Grand BE, Blanco AN, Pieroni G, Lazzari M, Voto LS. Laboratory identification of the lupus anticoagulant in normal pregnancy and pregnancy-induced hypertension. American journal of obstetrics and gynecology. 1990;163(2):704-5. doi: 10.1016/0002-9378(90)91276-i.\u003c/li\u003e\n\u003cli\u003eMerkel PA, Chang Y, Pierangeli SS, Harris EN, Polisson RP. Comparison between the standard anticardiolipin antibody test and a new phospholipid test in patients with connective tissue diseases. The Journal of rheumatology. 1999;26(3):591-6. \u003c/li\u003e\n\u003cli\u003eRadway-Bright EL, Inanc M, Isenberg DA. Animal models of the antiphospholipid syndrome. Rheumatology. 1999;38(7):591-601. doi: 10.1093/rheumatology/38.7.591.\u003c/li\u003e\n\u003cli\u003eGebhart J, Posch F, Koder S, Quehenberger P, Perkmann T, Kuessel L, et al. High risk of adverse pregnancy outcomes in women with a persistent lupus anticoagulant. Blood advances. 2019;3(5):769-76. doi: 10.1182/bloodadvances.2018026948.\u003c/li\u003e\n\u003cli\u003eGibbins KJ, Tebo AE, Nielsen SK, Branch DW. Antiphospholipid antibodies in women with severe preeclampsia and placental insufficiency: a case-control study. Lupus. 2018;27(12):1903-10. doi: 10.1177/0961203318787035.\u003c/li\u003e\n\u003cli\u003eYasuda M, Takakuwa K, Tokunaga A, Tanaka K. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy. Obstetrics and gynecology. 1995;86(4 Pt 1):555-9. doi: 10.1016/0029-7844(95)00247-o.\u003c/li\u003e\n\u003cli\u003eBranch DW, Andres R, Digre KB, Rote NS, Scott JR. The association of antiphospholipid antibodies with severe preeclampsia. Obstetrics and gynecology. 1989;73(4):541-5. \u003c/li\u003e\n\u003cli\u003eDekker GA, de Vries JI, Doelitzsch PM, Huijgens PC, von Blomberg BM, Jakobs C, et al. Underlying disorders associated with severe early-onset preeclampsia. American journal of obstetrics and gynecology. 1995;173(4):1042-8. doi: 10.1016/0002-9378(95)91324-6.\u003c/li\u003e\n\u003cli\u003eSletnes KE, Wisloff F, Moe N, Dale PO. Antiphospholipid antibodies in pre-eclamptic women: relation to growth retardation and neonatal outcome. Acta obstetricia et gynecologica Scandinavica. 1992;71(2):112-7. doi: 10.3109/00016349209007966.\u003c/li\u003e\n\u003cli\u003eMello G, Parretti E, Marozio L, Pizzi C, Lojacono A, Frusca T, et al. Thrombophilia is significantly associated with severe preeclampsia: results of a large-scale, case-controlled study. Hypertension. 2005;46(6):1270-4. doi: 10.1161/01.HYP.0000188979.74172.4d.\u003c/li\u003e\n\u003cli\u003evan Pampus MG, Dekker GA, Wolf H, Huijgens PC, Koopman MM, von Blomberg BM, et al. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia. American journal of obstetrics and gynecology. 1999;180(5):1146-50. doi: 10.1016/s0002-9378(99)70608-3.\u003c/li\u003e\n\u003cli\u003eCervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis and rheumatism. 2002;46(4):1019-27. doi: 10.1002/art.10187.\u003c/li\u003e\n\u003cli\u003eHeilmann L, Schorch M, Hahn T, Adasz G, Schilberz K, Adiguzel C, et al. Pregnancy outcome in women with antiphospholipid antibodies: report on a retrospective study. Seminars in thrombosis and hemostasis. 2008;34(8):794-802. doi: 10.1055/s-0029-1145261.\u003c/li\u003e\n\u003cli\u003eZemet R, Dulitzki M, Baum M, Ofer Friedman H, Morag I, Simchen MJ. Early-onset preeclampsia - The impact of antiphospholipid antibodies on disease severity. European journal of obstetrics, gynecology, and reproductive biology. 2021;263:79-84. doi: 10.1016/j.ejogrb.2021.06.006.\u003c/li\u003e\n\u003cli\u003eMarchetti T, de Moerloose P, Gris JC. Antiphospholipid antibodies and the risk of severe and non-severe pre-eclampsia: the NOHA case-control study. Journal of thrombosis and haemostasis : JTH. 2016;14(4):675-84. doi: 10.1111/jth.13257.\u003c/li\u003e\n\u003cli\u003eErton ZB, Sevim E, de Jesus GR, Cervera R, Ji L, Pengo V, et al. Pregnancy outcomes in antiphospholipid antibody positive patients: prospective results from the AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository (\u0026apos;Registry\u0026apos;). Lupus science \u0026amp; medicine. 2022;9(1). doi: 10.1136/lupus-2021-000633.\u003c/li\u003e\n\u003cli\u003eSibai BM, Barton JR. Expectant management of severe preeclampsia remote from term: patient selection, treatment, and delivery indications. American journal of obstetrics and gynecology. 2007;196(6):514 e1-9. doi: 10.1016/j.ajog.2007.02.021.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: Pregnancy and laboratory characteristics\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"520\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.7308%;\"\u003e\n \u003cp\u003e\u003cem\u003eVariables\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.9615%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eGroup 1 (n=40)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.3077%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eGroup 2 (n=100)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.7308%;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.9615%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e29,2 (20-41)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.3077%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e28,3 (18-42)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.7308%;\"\u003e\n \u003cp\u003eDelivery \u0026gt; 34.0 \u0026nbsp;weeks\u003c/p\u003e\n \u003cp\u003eDelivery \u0026lt; 33.6 \u0026nbsp;weeks\u003c/p\u003e\n \u003cp\u003eDelivery /Weeks of gestation \u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCesarean section\u003c/p\u003e\n \u003cp\u003eVaginal delivery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.9615%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e100,0% (40/40)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0,0% (0/40)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e39,2 \u0026plusmn; 1,32\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e42,5% (17/40)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e57,5% (23/40)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.3077%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e42,0% (42/100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e58,0% (58/100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e34,21 \u0026plusmn; 5,28\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e82,0% (82/100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e18,0% (18/100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.7308%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ea\u0026beta;2GPI positive\u003c/p\u003e\n \u003cp\u003ea\u0026beta;2GPI IgG positive\u003c/p\u003e\n \u003cp\u003ea\u0026beta;2GPI IgM positive\u003c/p\u003e\n \u003cp\u003eaCL positive\u003c/p\u003e\n \u003cp\u003eaCL IgG positive\u003c/p\u003e\n \u003cp\u003eaCL IgM positive\u003c/p\u003e\n \u003cp\u003eLA positive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.9615%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2,5% (1/40)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0,0% (0/40)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2,5% (1/40)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2,5% (1/40)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2,5% (1/40)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0,0% (0/40)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5,0% (2/40)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.3077%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e16,0% (16/100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0,0% (0/100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e16,0% (16/100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e3,0% (3/100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e3,0% (3/100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2,0% (2/100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e24,0% (24/100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.7308%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eaPL positive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.9615%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10,0% (4/40)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.3077%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e34,0% (34/100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.7308%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eaPL profile\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eaPL profile I\u003c/p\u003e\n \u003cp\u003eaPL profile IIa\u003c/p\u003e\n \u003cp\u003eaPL profile IIb\u003c/p\u003e\n \u003cp\u003eaPL profile IIc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25.9615%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0,0% (0/40)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5,0% (2/40)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2,5% (1/40)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2,5% (1/40)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27.3077%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e9,0% (9/100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e15,0% (15/100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1,0% (1/100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e9,0% (9/100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eaPL: antiphospholipid antibodies; aCL: anticardiolipin antibodies; a\u0026beta;2GPI: anti-\u0026beta;2 glycoprotein I; LA: lupus anticoagulant.\u003c/p\u003e\n\u003cp\u003eTable 2: Distribution of aPL according to weeks of gestation.\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"595\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.8571%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eGroup 2 \u0026ndash; Variables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.9916%;\"\u003e\n \u003cp\u003eEarly severe Preeclampsia x\u0026lt;33.6 weeks\u003c/p\u003e\n \u003cp\u003e(n=58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003eLate severe Preeclampsia x\u0026gt;34.0 weeks\u003c/p\u003e\n \u003cp\u003e(n=42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.8571%;\"\u003e\n \u003cp\u003eaPL positive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.9916%;\"\u003e\n \u003cp\u003e32,7% (19/58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e35,7 % (15/42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.8571%;\"\u003e\n \u003cp\u003eaPL doble positivity\u003c/p\u003e\n \u003cp\u003eaPL simple positivity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.9916%;\"\u003e\n \u003cp\u003e6,9 % (4/58)\u003c/p\u003e\n \u003cp\u003e25,9 % (15/58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e11,9% (5/42)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 23,8 % (10/42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.8571%;\"\u003e\n \u003cp\u003eLA positive\u003c/p\u003e\n \u003cp\u003ea\u0026beta;2GPI positive\u003c/p\u003e\n \u003cp\u003eaCL positive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.9916%;\"\u003e\n \u003cp\u003e25,9% (15/58)\u003c/p\u003e\n \u003cp\u003e8,6 % (8/58)\u003c/p\u003e\n \u003cp\u003e0,0 % (0/58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e21,4 % (9/42)\u003c/p\u003e\n \u003cp\u003e19,0 % (8/42)\u003c/p\u003e\n \u003cp\u003e7,1 % (3/42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eaPL: antiphospholipid antibodies; aCL: anticardiolipin antibodies; a\u0026beta;2GPI: anti-\u0026beta;2 glycoprotein I; LA: lupus anticoagulant. NS: non-significant\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"High risk, Hypertension, Obstetric antiphospholipid syndrome, Preeclampsia","lastPublishedDoi":"10.21203/rs.3.rs-5684910/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5684910/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives: \u003c/strong\u003eto study prospectively the presence aPL on pregnant women at time of preeclampsia (PE) diagnosis in comparison with normal pregnant controls (I), to determine the association between aPL and diagnosis of severe preeclampsia and (II) to evaluate the association between the presence of aPL and severe preeclampsia before and after 34 weeks of gestations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design: \u003c/strong\u003eThis prospective, interventional, and analytical study included one hundred forty women who were tested for aPL during pregnancy and separated in 2 groups based on their diagnostic status of PE. Group 1: forty normal pregnant women studied for aPL beyond 20 weeks of pregnancy, followed until the birth of a full-term new-born baby and Group 2: one hundred women studied for aPL at the time of PE onset/diagnosis. We evaluated and compared rates of aPL positivity between Group 1 and 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eWe compared the presence of aPL between group 1 10,0% (4/40) and group 2 34,0% (34/100). We found an association between severe PE and aPL positivity [OR= 4.63 (95% CI: 1.523 – 14.107), \u003cem\u003ep\u003c/em\u003e=0.005]. We also found an association between LA and severe PE [OR= 6.0 (95% CI: 1.3466 – 26.7335), \u003cem\u003ep\u003c/em\u003e=0.01].\u003c/p\u003e\n\u003cp\u003eWe confirmed an association between early severe PE and the presence of aPL positivity [OR= 4,384 (95% CI: 1.3615 – 14.1206), \u003cem\u003ep\u003c/em\u003e= 0.01]. We also found an association between late severe PE and the presence of aPL positivity [OR= 5.0 (95% CI: 1.4901 – 16.777), \u003cem\u003ep\u003c/em\u003e= 0.008].\u003c/p\u003e\n\u003cp\u003eWe compared the presence of aPL between patients with early severe PE 25,9% (19/58) and patients with late severe PE 23,8% (15/42). No significant association was found between the 2 groups. These results suggest that the positivity of aPL and gestational age are independent, and both related to their severity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: These results suggest that the presence of aPL is associated to the severe PE. The positivity of aPL is associated to the severity of PE, independently from gestational age. We suggest including the study aPL in women with severe PE independently of prematurity.\u003c/p\u003e","manuscriptTitle":"Exploring the association between Preeclampsia and antiphospholipid antibodies. New insights on the clinical criteria of APS. A prospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-30 04:31:32","doi":"10.21203/rs.3.rs-5684910/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b38f4514-79fd-4085-aa75-8d89f630a8ec","owner":[],"postedDate":"December 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-25T06:38:54+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-30 04:31:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5684910","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5684910","identity":"rs-5684910","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}