Combined heterozygosity for methylenetetrahydrofolate reductase MTHFR) mutations C677T and A1298C is associated with abruptio placentae but not with intrauterine growth restriction Gabrie Èl S. Gebhardt a,* , Charlotte L. Scholtz b , Renate Hillermann a , Hein J. Odendaal a a Department of Obstetrics and Gynaecology, Faculty of Medicine, PO Box 19125, Tygerberg 7505, South Africa b Division of Human Genetics, Faculty of Medicine, Tygerberg Hospital, Stellenbosch University and MRC Research Unit for Perinatal Mortality, Tygerberg 7505, South Africa Received 14 June 2000; received in revised form 4 October 2000; accepted 14 November 2000 Abstract Objective: This study was undertaken to investigate the involvement of MTHFR gene mutations C677T and A1298C implicated in vascular disease, in patients with abruptio placentae and intrauterine growth restriction IUGR). Study Design: DNA was extracted from blood samples of 54 patients with placental vasculopathy 18 patients with abruptio placentae and 36 with IUGR) and 114 control patients and ampli®ed by the polymerase chain reaction PCR). The resulting fragments were subjected to restriction enzyme analysis and resolved by gel electrophoresis. Results: A signi®cant association could be demonstrated between mutation A1298C and both abruptio placentae and IUGR. Combined heterozygosity for mutations C677T and A1298C was detected in 22.2% of abruptio placentae cases. Conclusions: Combined heterozygosity for MTHFR mutations C677T and A1298C may represent a genetic marker for abruptio placentae. # 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: MTHFR combined heterozygosity; Abruptio placentae 1. Introduction Abruptio placentae is the most common cause of intrau- terine death at our institution and the second most frequent cause of perinatal death after preterm labour [1]. It is the primary cause of fetal distress in patients where early onset severe pre-eclampsia is treated expectantly [2]. Within this population, at least 36% of patients with severe pre-eclamp- sia also present with IUGR [3]. Abruptio placentae was associated with biochemical hyperhomocysteinaemia in the population served by our institution [4]. Elevated homocysteine levels have been shown to damage the vascular endothelium [5] and result in placental vasculopathy [6]. There are several documented mutations in the gene encoding methylenetetrahydrofolate reductase MTHFR) which is involved in the remethylation of homocysteine to methionine. Homozygosity for a mutated MTHFR gene was found to be a risk factor for placental vasculopathy [7] while the A1298C mutation has been associated with decreased MTHFR activity and neural- tube defects NTDs) [8]. This study was designed to determine the prevalence of the MTHFR enzyme defects in the local population and to investigate their role in abruptio placentae and IUGR. 2. Subjects and methods 2.1. Clinical The ®rst study group n  18) comprised patients who delivered at our institution in the period 1 January±31 December 1996 with the pregnancy complicated by abruptio placentae. Only patients from the immediate catchment area were approached and requested to participate. Abruptio placentae were diagnosed clinically and subsequently con- ®rmed when more than 15% of the placental surface was covered with blood clots. After informed consent European Journal of Obstetrics & Gynecology and Reproductive Biology 97 2001) 174±177 * Corresponding author. Tel.: 27-21938-4661; fax: 27-21933-3084. E-mail address: gsg@mweb.co.za G.S. Gebhardt). 0301-2115/01/$ ± see front matter # 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0301-211500)00540-6