Associations Between Phenotypes of Preeclampsia and Thrombophilia

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Associations Between Phenotypes of Preeclampsia and Thrombophilia European Journal of Obstetrics & Gynecology and Reproductive Biology 194 (2015) 199–205 Contents lists available at ScienceDirect European Journal of Obstetrics & Gynecology and Reproductive Biology jou rnal homepage: www.elsevier.com/locate/ejogrb Associations between phenotypes of preeclampsia and thrombophilia a, a a b Durk Berks *, Johannes J. Duvekot , Hillal Basalan , Moniek P.M. De MAAT , a a Eric A.P. Steegers , Willy Visser a Department of Obstetrics and Gynecology, Division of Obstetrics and Prenatal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands b Department of Hematology, Erasmus MC, University Medical Center Rotterdam, The Netherlands A R T I C L E I N F O A B S T R A C T Article history: Objectives: Preeclampsia complicates 2–8% of all pregnancies. Studies on the association of preeclampsia Received 29 July 2015 with thrombophilia are conflicting. Clinical heterogeneity of the disease may be one of the explanations. Received in revised form 4 September 2015 The present study addresses the question whether different phenotypes of preeclampsia are Accepted 17 September 2015 associated with thrombophilia factors. Study design We planned a retrospective cohort study. From 1985 until 2010 women with Keywords: preeclampsia were offered postpartum screening for the following thrombophilia factors: anti- Fetal growth restriction phospholipid antibodies, APC-resistance, protein C deficiency and protein S deficiency, hyperhomo- HELLP syndrome cysteineamia, factor V Leiden and Prothrombin gene mutation. Hospital records were used to obtain Pre-eclampsia information on phenotypes of the preeclampsia and placental histology. Retrospective study Thrombophilia Results: We identified 844 women with singleton pregnancies who were screened for thrombophilia factors. HELLP complicated 49% of pregnancies; Fetal growth restriction complicated 61% of pregnancies. Early delivery (<34th week) occurred in 71% of pregnancies. Any thrombophilia factor was present in 29% of the women. Severe preeclampsia was associated with protein S deficiency (p = 0.01). Fetal growth restriction was associated with anti-phospholipid antibodies (p < 0.01). Early onset preeclampsia was associated with anti-phospholipid antibodies (p = 0.01). Extensive placental infarction (>10%) was associated with anti-phospholipid antibodies (p < 0.01). Low placental weight (<5th percentile) was associated with hyperhomocysteineamia (p = 0.03). No other associations were observed. Conclusions: Early onset preeclampsia, especially if complicated by fetal growth restriction, are associated with anti-phospholipid antibodies. Other phenotypes of preeclampsia, especially HELLP syndrome, were not associated with thrombophilia. We advise only to test for anti-phospholipid antibodies after early onset preeclampsia, especially if complicated by fetal growth restriction. We suggest enough evidence is presented to justify no further studies are needed. ß 2015 Elsevier Ireland Ltd. All rights reserved. Introduction seems to be associated with preeclampsia in cohort studies. However, these results cannot be reproduced in larger prospective Preeclampsia complicates 2–8% of all pregnancies [1]. The cause studies [1]. of preeclampsia has not yet been elucidated and is most probably An explanation of these conflicting results might be that heterogenic [1]. One possible cause is a maternal pro-thrombo- preeclampsia is a heterogenic disease with different phenotypes. genic state, leading to mal-adaptation of the spiral arteries in early Not only can preeclampsia be classified as mild or severe, it may pregnancy and placental thrombosis and infarction in mid- and also be complicated by hemolysis, elevated liver enzymes or low late pregnancy [1]. A pro-thrombogenic state can be caused by platelets (HELLP-syndrome) and/or intrauterine growth restriction inherited or acquired thrombophilia [2–4]. Maternal thrombophilia (IUGR) and/or early onset preeclampsia. Histological examination of placentas of pregnancies complicated by preeclampsia may show extensive infarction, but also no abnormal findings at all [5]. Some authors suggest that early preeclampsia has another * Corresponding author at: Department of Obstetrics and Gynecology, Division of pathophysiological basis than late preeclampsia [6]. It might be Obstetric and Prenatal Medicine, Erasmus MC, Dr. Molewaterplein 50, 3015 GE that these different phenotypes of preeclampsia are differently Rotterdam, The Netherlands. Tel.: +31 10 7036686; fax: +31 10 7036815. E-mail address: [email protected] (D. Berks). associated with thrombophilia. If this is true, future research http://dx.doi.org/10.1016/j.ejogrb.2015.09.021 0301-2115/ß 2015 Elsevier Ireland Ltd. All rights reserved. 200 D. Berks et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 194 (2015) 199–205 should be focused on the pathophysiology, prediction and Patients with an abnormal test result, except for factor V Leiden, ultimately prevention of preeclampsia in combination with these Prothrombin gene mutation, and serum homocysteine concentra- thrombophilia factors. tions were retested at least six weeks after the initial test. Only if This retrospective cohort study addresses the question which the same abnormality was confirmed a patient was considered phenotypes of preeclampsia are associated with thrombophilia. positive for this coagulation abnormality. If a patient with an initial abnormal test result was not retested, the presence or absence of Material and methods this coagulation abnormality was reported as missing. The percentage of placental infarction was estimated by From 1985 until 2010 all patients with a singleton pregnancy combining macroscopy and microscopy of the placenta. Placental who were admitted for mild or severe preeclampsia to the weight was measured without umbilical cord and membranes. The department of obstetrics of the Erasmus Medical Centre, University percentile was calculated according to a previous study [7]. Medical Centre Rotterdam, were offered to be postpartum The thrombophilia factors were tested for associations. If more screened for thrombophilia factors. Preeclampsia was diagnosed than one thrombophilia measurements were missing, the category according to the definition of the International Society for the ‘one or more thrombophilia’ was also marked as missing. The Study of Hypertension (ISSHP). Severe preeclampsia was diag- phenotypes of preeclampsia tested for associations were: HELLP nosed if one or more of the following criteria were present: a syndrome, IUGR, early (<34 weeks) or late onset (34 weeks), blood pressure of 160 mmHg systolic or higher or 110 mmHg minimal (<10%) versus extensive (10%) placental infarction and diastolic or higher; proteinuria of 5 gram or more in a 24-h urine normal (>5th centile) versus low (5th centile) placental weight. specimen or dipstick urinalysis of 3+ or greater in two random Furthermore we did a factor analysis with a fixed 2-axis model. urine samples collected at least 4 h apart; cerebral or visual For this we defined 4 different subgroups with the 2 most disturbances; elevated liver enzymes; thrombocytopenia; fetal important phenotypes of preeclampsia: IUGR and HELLP. The 4 growth restriction. HELLP was defined as a combination of subgroups were defined as IUGRÀ/HELLPÀ, IUGR+/HELLPÀ, 9 platelet count <100 Â 10 /L, serum aspartate aminotransferase IUGRÀ/HELLP+, IUGR+/HELLP+. For the above mentioned (ASAT) 30 U/L and serum alanine aminotransferase (ALAT) 11 thrombophilia factors we used the continuous data for the 30 U/L (2 SD above the mean in our hospital). Intrauterine analysis. If more than one sample was available, we used the result growth restriction (IUGR) was defined as a birth weight below that was least abnormal. the 10th centile. Associations of thrombophilia factors with the different At least six weeks postpartum, patients were tested for: anti- phenotypes of preeclampsia and the factor analysis were done cardiolipin antibodies, lupus anticoagulans, APC-ratio, levels of with the statistical software package IBM SPSS Statistics Version 20 2 protein C and S, homocysteine and heterozygosity for factor V (IBM Corporation, 2011) using X -tests with continuity correction. Leiden and Prothrombin gene mutation. None of the patients were Missing values were excluded for the analysis. A two-sided p-value using vitamin supplements during the period of testing. of less than 0.05 was considered statistical significant. The reference values for the coagulation assays were ascer- tained in a population of at least 40 normal male volunteers. Anti- Results cardiolipin antibodies were determined by enzyme-linked immu- noassay (ELISA) according to the directives of Harris (normal A total of 844 women were tested for thrombophilia. The values IgG and IgM <31 units GPL and <12 units MPL, respective- general characteristics of these patients are summarized in Table 1. ly). The presence of lupus anticoagulant was determined with the Placental histology was available for 545 women. diluted Prothrombin time (Recombiplastin, Instrumentation Lab- Table 2 shows the preeclampsia phenotypes and the preva- oratories, Italy, normal ratio < 1.20) and the activated partial lence of the thrombophilia. Overall 29% of the women had one or thromboplastin time assay (Platelin, Organon Teknika, USA, more abnormal thrombophilia results. Severe preeclampsia was normal value < 40 s). Effect of factor deficiency was eliminated significantly associated with a higher presence of one or
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