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Prothrombin Gene G20210A Mutation and Obstetric Complications

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Prothrombin Gene G20210A Mutation and Obstetric Complications Prothrombin Gene G20210A Mutation and Obstetric Complications Robert M. Silver, MD, Yuan Zhao, MS, Catherine Y. Spong, MD, Baha Sibai, MD, George Wendel Jr, MD, Katharine Wenstrom, MD, Philip Samuels, MD, Steve N. Caritis, MD, Yoram Sorokin, MD, Menachem Miodovnik, MD, Mary J. O’Sullivan, MD, Deborah Conway, MD, and Ronald J. Wapner, MD, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (NICHD MFMU) Network* OBJECTIVE: To estimate whether maternal carriage of Human Development factor V Leiden study, a multi- the prothrombin gene G20210A mutation is associated center, prospective, observational cohort of 5,188 uns- with pregnancy loss, preeclampsia, placental abruption, elected singleton gestations. A total of 4,167 first-trimes- or small for gestational age (SGA) neonates in a low-risk, ter samples were available for analysis and were tested prospective cohort. for the prothrombin G20210A mutation. Obstetric com- METHODS: This was a secondary analysis of the Eunice plications were compared between women with and Kennedy Shriver National Institute of Child Health and without the prothrombin G20210A mutation by univari- able and multivariable analysis. RESULTS: A total of 157 (3.8%) women had the pro- See related editorial on page 2. thrombin gene mutation (156 heterozygous and one homozygous). Carriers of the prothrombin G20210A mu- *For a list of other members of the Eunice Kennedy Shriver National Institute of tation had similar rates of pregnancy loss, preeclampsia, Child Health and Human Development Maternal-Fetal Medicine Units Net- work, see the Appendix available online at http://links.lww.com/AOG/A154. SGA neonates, and abruption compared with noncarri- ers. Results were similar in a multivariable analysis con- From the Departments of Obstetrics and Gynecology at the University of Alabama at Birmingham, Birmingham, Alabama; the University of Chicago, trolling for age, race, prior pregnancy loss, prior SGA Chicago, Illinois; the University of Cincinnati, Cincinnati, Ohio; the University neonates, and family history of thromboembolism. Three of Pittsburgh, Pittsburgh, Pennsylvania; the University of Miami, Miami, thromboembolic events occurred in women testing neg- Florida; The Ohio State University, Columbus, Ohio; the University of ative for the mutation. Tennessee, Memphis, Tennessee; the University of Texas at San Antonio, San Antonio, Texas; the University of Texas Southwestern Medical Center, Dallas, CONCLUSION: There was no association between the Texas; Thomas Jefferson University, Philadelphia, Pennsylvania; the University prothrombin G20210A mutation and pregnancy loss, pre- of Utah, Salt Lake City, Utah; Wake Forest University Health Sciences, eclampsia, abruption, or SGA neonates in a low-risk, Winston-Salem, North Carolina; and Wayne State University, Detroit, Mich- igan; the George Washington University Biostatistics Center, Washington, DC, prospective cohort. These data raise questions about the and the Eunice Kennedy Shriver National Institute of Child Health and Human practice of screening women without a history of throm- Development, Bethesda, MD. bosis or adverse pregnancy outcomes for this mutation. Supported by grants from the Eunice Kennedy Shriver National Institute of (Obstet Gynecol 2010;115:14–20) Child Health and Human Development (HD27860, HD36801, HD27917, HD21414, HD27861, HD27869, HD27905, HD34208, HD34116, LEVEL OF EVIDENCE: II HD21410, HD27915, HD34136, HD34122, HD34210). The authors thank Margaret Cotroneo, RN, for central outcome review; Valerija nherited thrombophilias are a heterogeneous group Momirova, MS, and Elizabeth Thom, PhD, for data management and statistical analysis; and Michael Varner, MD, and Donna Dizon-Townson for protocol Iof coagulation disorders that predispose individuals development and oversight. to thromboembolic events. They are major risk fac- Corresponding author: Robert M. Silver, MD, Department of Obstetrics and tors for thromboembolism during pregnancy and the Gynecology, University of Utah School of Medicine, 30 North 1900 East, Room puerperium. In addition, thrombophilias have been 2B308, Salt Lake City, UT 84132; e-mail: [email protected]. implicated in a variety of adverse obstetric events, Financial Disclosure The authors did not report any potential conflicts of interest. including pregnancy loss (especially fetal death), pre- eclampsia, placental abruption, and small for gesta- © 2009 by The American College of Obstetricians and Gynecologists. Published 1 by Lippincott Williams & Wilkins. tional age (SGA) neonates. The pathophysiology is ISSN: 0029-7844/10 uncertain but is thought to involve thrombosis in the 14 VOL. 115, NO. 1, JANUARY 2010 OBSTETRICS & GYNECOLOGY uteroplacental circulation leading to infarction and centers as well as the Data Coordinating Center at the placental insufficiency.2 Thus, anticoagulant therapy George Washington University. has the potential to improve obstetric outcomes in For this secondary analysis, the outcome vari- women with heritable thrombophilias. This has lead ables of interest included preeclampsia, SGA neo- to widespread screening for and treatment of women nates, pregnancy loss, and placental abruption. Pre- with thrombophilias in hopes of improving obstetric eclampsia was defined as a diastolic blood pressure outcomes. However, efficacy remains uncertain.3 more than 90 mm Hg on two occasions 4 hours to 14 The vast majority of data linking thrombophilias, days apart occurring within 4 hours to 14 days of including the prothrombin G20210A mutation, to evident significant proteinuria (more than 300 mg adverse obstetric events are derived from case–con- protein in a 24-hour test, urinary protein/creatinine ϩ trol studies.4–11 Such studies are subject to bias and ratio more than 0.35, at least 2 proteinuria from a ϩ may overestimate the risk of adverse obstetric out- single dipstick evaluation or 1 proteinuria from two comes in women with thrombophilias.12,13 It is note- or more measurements obtained 4 hours to 14 days worthy that in two large cohorts of unselected preg- apart) in previously normotensive nonproteinuric pa- nant women, maternal carriage of the factor V Leiden tients. Women also were considered to have pre- mutation was not associated with an increased risk of eclampsia if they were diagnosed with eclampsia; any adverse pregnancy outcome.14,15 hemolysis, elevated liver enzymes, low platelets syn- Few prospective cohort studies have been per- drome; or if they met the blood pressure criteria and formed in unselected populations for the prothrombin had pulmonary edema or thrombocytopenia (less 3 G20210A mutation. This mutation is second only to than 100,000/mm ). Women with chronic hyperten- sion or proteinuria or both needed to meet strict, the factor V Leiden mutation with regard to fre- predefined criteria to be considered to have superim- quency in women with thromboembolism associated posed preeclampsia. For women with preexisting with pregnancy.16 It is present in about 2% to 3% of proteinuria, new-onset, pregnancy-associated hyper- Europeans and about 17% of women with thrombo- tension as well as superimposed proteinuria was embolism in pregnancy.17 Our objective was to esti- required for the diagnosis of preeclampsia.18 mate whether maternal heterozygosity of the pro- Small for gestational age was defined as a birth thrombin gene G20210A mutation is associated with weight less than the 10th percentile and less than the pregnancy loss, preeclampsia, or SGA neonates in a 5th percentile derived from sex- and race-specific prospective, low-risk cohort. growth curves.19 Pregnancy loss included first-trimes- ter spontaneous abortion, fetal death between 14 and MATERIALS AND METHODS 20 weeks of gestation, and stillbirth, defined as fetal This is a secondary analysis of a prospective, obser- demise after 20 weeks of gestation. Abruption was vational, multicenter, cohort study conducted by the considered present when there was clinical suspicion Maternal-Fetal Medicine Units Network of the Eunice that was supported by written documentation includ- Kennedy Shriver National Institute of Child Health and ing excessive antepartum bleeding, treatment with Human Development conducted from April 2000 blood products, and a description of delivery of the through August 2001. The methods have been de- placenta or when there was confirmation by patho- scribed previously.15 The cohort included women logic examination of the placenta. from 13 clinical centers who had uncomplicated Each participant had venous blood obtained and singleton pregnancies at 14 weeks of gestation or less submitted to the DNA diagnostic laboratory at the (best estimate based on clinical or ultrasonographic University of Utah School of Medicine. The DNA findings). Exclusion criteria included multiple gestation, was extracted from whole blood (Puregene DNA current or planned anticoagulation therapy, known fac- extraction kit, Gentra System, Minneapolis, MN). tor V Leiden status, antiphospholipid syndrome, previ- Genotype results were obtained using a Taqman ous thromboembolism, fetal demise, planned preg- Assay (Applied Biosystems, Inc., Foster City, CA) nancy termination, planned delivery at an institution not designed to detect the prothrombin G20210A muta- included in the Maternal-Fetal Medicine Units Network, tion. This allele discrimination assay used PCR am- and participation in another research study that might plification and a pair of fluorescent dye detectors
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