Women who had a previous pregnancy with antepartum complications occurring at a gestational age of 23 weeks or more were followed and tested for thrombophilia. Antepartum complications considered were unexplained intrauterine fetal death, neonates who were small for gestational age (SGA), severe pre-eclampsia and placental abruption. SGA was defined as birth weight below the 10
th percentile. Severe pre-eclampsia was defined as blood pressure measuring above 140/90 combined with proteinuria (300 mg/24 h) and accompanied with one or more of the following complications: worsening blood pressure to a level above 160/110, HELLP syndrome (hemolysis, low platelet count and elevated liver enzymes), persistent severe headache or visual disturbances, persistent severe epigastric pain, nausea and vomiting, eclampsia, pulmonary edema, oligouria (urine output less than 500 cc/24 h), proteinuria of 5 g or more per 24 h and fetal growth restriction (below the 5
th percentile). The study was conducted at a university teaching hospital on all women who were delivered, tested for thrombophilia after delivery, conceived and delivered again between January 2000 and January 2006. Women were tested for the mutation of guanine to adenine at nucleotide 1691 in the factor V gene (factor V Leiden), the mutation of cytosine to thymine at nucleotide 677 in the gene encoding methylenetetrahydrofolate reductase, and the mutation of guanine to adenine at nucleotide 20210 in the prothrombin gene. Women were also tested for protein C, protein S and antithrombin III deficiency; and the presence of antiphospholipid antibodies (lupus anticoagulant or anticardiolipin antibodies) and the results were confirmed in a second assay. Blood tests were done six weeks or more after the previous delivery. Women who had a previous pregnancy with antepartum complications that could be attributed to multiple gestations, having fetuses with major congenital anomalies or chromosomal abnormalities, fetal infection, chorioamnionitis, hydrops fetalis and diabetes mellitus were excluded. Only women found to have any thrombophilia (thrombophilic group) were treated for the first time, in the following pregnancy, with the low molecular weight heparin (LMWH), enoxaparin (Lovenox, Aventis, France). Enoxaparin was started after detection of fetal heart activity in the 1
st trimester throughout gestation, and six weeks into the post-partum period. The enoxaparin dose was 40 mg once daily in women with a solitary thrombophilia and 80 mg daily (40 mg every 12 h) in women with combined thrombophilia. This higher dose was used based upon the significantly higher risk for pregnancy loss and stillbirth in women with combined thrombophilia [
9]. Aspirin at a dose of 100 mg (Aspe'gic nourrissons, Sanofi-Synthe'labo, France) daily was given in addition to enoxaparin to women with antiphospholipid antibodies. Additionally, all women received 5 mg folic acid daily. Both the thrombophilic group and the non-thrombophilic group were managed and observed closely at our high-risk pregnancy clinic during the study period. Surveillance of both groups included weekly blood pressure measurements and sonographic estimates of fetal weight at 4 weeks intervals. When fetal growth restriction (below the 10
th percentile) was detected, sonographic fetal weight estimates were done every two weeks. In addition, non-stress testing (NST) twice weekly, umbilical artery Doppler and biophysical profile once weekly were also performed. Women detected to have fetal growth restriction with a reassuring fetal status were allowed to continue surveillance until term (37 weeks). At 37 – 38 weeks, induction of labor was considered. Women with a previous intrauterine fetal death had a weekly NST starting a week before the gestational age when fetal death was detected in the prior pregnancy. These women were induced between 38 – 39 weeks. Women who developed pre-eclampsia or placental abruption were managed according to the severity of the disease, fetal status and gestational age. Women were asked about bleeding episodes, signs of thrombosis, and symptoms of bone pain. Levels of platelets were followed monthly.
We compared perinatal outcomes within and between the groups before and after close surveillance. Perinatal outcomes included the reappearance of one or more of the thrombophilic complications considered (fetal death, SGA, severe pre-eclampsia and placental abruption), neonatal birth weight and Apgar score. Other parameters collected were maternal age and ethnicity. The local Institutional Review Board approved the study.
Statistical analysis
Data analysis was performed using the SPSS 14 statistical package (SPSS, Chicago, IL). Comparison of binary variables between thrombophilic and non-thrombophilic groups, were analyzed by Chi-square test or Fisher's exact test as appropriate. T test or Mann Withney test were used to compare continuous variables between the two independent groups. To assess the influence of treatment on the variables in each group, McNemar, Paired T test or Wilcoxon signed ranks test were applied as appropriate. Proportion of live born neonates per woman was calculated as number of live born neonates divided by number of births per woman. The same calculation was made regarding the proportion of preterm deliveries and complicated pregnancies per woman. A p value < 0.05 was considered significant.