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Protein S and protein C deficiencies are commonly identified biochemical abnormalities associated with a hypercoagulable state; they result in an increased incidence of venous thromboembolism. We report the case of a pregnant woman with dual deficiencies of protein S and protein C, who encountered a venous thromboembolism 7 days postpartum despite of the use of danaparoid.

Recently, several investigations concerning disadvantageous genetic factors in human reproduction have progressed. Inherited thrombophilia, such as factor V Leiden, prothrombin, and methylenetetrahydrofolate reductase mutations; gene polymorphisms of detoxification enzyme (CYP1A1); growth factors (insulin-like growth factor-I); and hormones such as angiotensinogen and CYP17 are involved in the pathogenesis of fetal growth restriction. The inherited thrombophilia, gene polymorphisms of coagulation and anticoagulation factor such as thrombomodulin, endothelial protein C receptor, plasminogen activator inhibitor 1, and factor XIII; human lymphocyte antigen (HLA-G); detoxification enzymes (glutathione- S-transferase M1); cytokines such as interleukin (IL) -1 and IL-6; hormones (CYP17); vasodilators (nitric oxide synthase 3); and vitamins (transcobalamin) are involved in the pathogenesis of sporadic and recurrent miscarriage. It is likely that a gene polymorphism or mutation susceptible to reproductive failure has a beneficial effect on the process of human reproduction with or without the environmental interaction. The factor V Leiden mutation has genetic advantages that are believed to be an improved implantation rate in in vitro fertilization and a reduction of maternal intrapartum blood loss. It has also been demonstrated that the CYP17 A2 allele has bidirectional effects on human reproduction, including increases in susceptibility to recurrent miscarriage and fetal growth enhancement.

To determine whether the C677T polymorphism of the methylenetetrahydrofolate reductase ( MTHFR) gene and the Leiden mutation of coagulation factor V (FV) are associated with recurrent spontaneous abortion (RSA) of unexplained etiology in Japanese participants, the genotypes of the two polymorphisms were determined and compared between cases of unexplained RSA and normal pregnant controls. Eighty-three Japanese participants, consisting of 45 women with explained RSA and 38 women with unexplained RSA, and 174 controls were recruited in the study. The frequencies of the T677 allele/TT genotype were not significantly different among women with explained RSA (35.6%/13.3%), women with unexplained RSA (34.2%/7.9%), primigravid controls (35.1%/11.7%), and multigravid controls (39.7%/16.5%). In the cases of unexplained RSA, the frequencies of the T677 allele and TT genotype tended to increase according to the number of previous spontaneous abortions, but the increase was without statistical significance: the frequencies of the T677 allele and TT genotype in women with two abortions were 18.2% and 0%, whereas in women with three abortions the frequencies were 38.0% and 9.5%, and in women with four or more abortions the frequencies were 50.0% and 16.7%, respectively. In addition, no Leiden mutation of FV was detected in the women with RSA or the controls. Neither T677 of the MTHFR nor the Leiden mutation of FV was associated with unexplained RSA in the Japanese population.

It is possible that women with triplet pregnancies are more likely to exhibit pregnancy-induced antithrombin deficiency, gestational thrombocytopenia, and perinatal elevation in serum aspartate aminotransferase (AST) than women with twin pregnancies. We retrospectively reviewed changes in antithrombin activity, platelet count, and blood chemistry in 23 twin and seven triplet pregnancies in which the mothers received antenatal care and gave birth in our hospital during 1999 and 2001. Both antithrombin activity and platelet counts gradually decreased until delivery, then promptly increased after delivery in both twin and triplet pregnancies. A significantly larger number of women developed gestational thrombocytopenia of < 100 x 10 (9)/L (43% [three of seven] versus 4.3% [one of 23]; p < 0.01) and pregnancy-induced antithrombin deficiency of < 60% of normal activity (57% [four of seven] versus 17% [four of 23]; p < 0.05) in triplet than in twin pregnancies. Eight women with pregnancy-induced antithrombin deficiency, including three women with gestational thrombocytopenia, were significantly more likely to develop perinatal elevations of AST, lactate dehydrogenase, serum creatinine, fibrin/fibrinogen degradation products, and D-dimer than were those without pregnancy-induced antithrombin deficiency. These findings suggest that women with triplet pregnancies are at an increased risk of the HELLP syndrome and acute fatty liver of pregnancy compared with women with twin pregnancies.

To assess the association between the egogram and hypertension in pregnancy (HP), a case-control study was carried out. Seventy-one HP cases, primiparous aged 20 to 34 years, and 109 controls, were enrolled among pregnant women who visited our hospitals for obstetrical care. Data from a self-administered questionnaire containing a Self Grow-Up Egogram (SGE) were subjected to univariate and multivariate analyses with prepregnancy body mass index (BMI) and angiotensinogen (AGT) genotype. The mean +/- standard error of total scores for the critical parent (CP) scale were 9.7 +/- 0.5 for cases and 8.3 +/- 0.3 for controls, those for the nurturing parent (NP) scale were 13.6 +/- 0.4 for cases and 13.4 +/- 0.3 for controls, those for the adult (A) scale were 11.3 +/- 0.5 for cases and 10.9 +/- 0.3 for controls, those for the free child (FC) scale were 12.3 +/- 0.3 for cases and 13.8 +/- 0.3 for controls, and those for the adapted child (AC) scale were 10.2 +/- 0.4 for cases and 8.5 +/- 0.4 for controls. A low FC scale score (FCor = 10) and a high AC scale score (AC10) were significantly associated with HP ( p0.05; p0.01, respectively). In the multivariate analysis, FCor = 10, AC10, prepregnancy BMIor = 24, and homozygosity of the T235 allele genotype of the AGT gene were detected as the potent independent risk factors for HP. The odds ratios were 2.2, 2.8, 4.0, and 2.5, respectively. The present results suggest that a low FC score and a high AC score may be potent, independent risk factors for HP.

Hypertension in pregnancy (HP), including preeclampsia (PE), is known to be a multifactorial disease. Recently, an Ile105Val variant of the glutathione S-transferase P1 gene ( GSTP1) was shown to be associated with PE in The Netherlands. We therefore performed an association study of the Ile105Val variant comparing 131 patients with HP and 327 normal pregnant controls in Japan. We analyzed the data in the context of other risk factors before pregnancy. The frequency of the Ile/Val+Val/Val genotype of the GSTP1 was not significantly different between the HP (26%) patients and the controls (28%). However, in primiparous patients, the frequency was significantly different in elderly pregnancy (63% in severe HP vs. 18% in controls; P < 0.05), in the subgroup with the MM+MT genotypes of the angiotensinogen gene (50% in severe HP vs. 26% in controls; P < 0.05), and in the subgroup with the GA+AA genotypes of the endothelial nitric oxide synthase gene (42% in severe HP vs. 13% in controls; P < 0.05). These results suggest that this variant of the GSTP1 may play a role in the manifestation of HP together with other independently and/or synergistically acting factors, particularly in primiparous pregnancy.

To clarify whether the homozygous deletion (DD) genotype of angiotensin-converting enzyme gene ( ACE) is a genetic risk factor for preeclampsia in Japanese women, we performed ACE genotyping in patients with preeclampsia and healthy pregnant women, and analyzed the relationship between preeclampsia and ACE genotype, taking into account some well-known contributing factors for preeclampsia, such as primiparity, positive family history of hypertension, prepregnancy body mass index < 24, and heterozygosity and homozygosity of T235 (MT+TT) genotypes of the angiotensinogen ( AGT) gene. Among all of the subjects, the frequency of the DD genotype was not different between patients with preeclampsia and controls (16% and 12%, respectively). Regarding primiparity, prepregnancy body mass index < 24, and MT+TT genotypes of AGT, no significant differences in the frequency of the DD genotype of ACE were found between patients with preeclampsia and controls, although in a subgroup positive for family history of hypertension, the frequency of the DD genotype tended to be higher in patients with preeclampsia (25%) than in controls (8%; p = 0.061). Carrying the DD genotype may have some influence on the pathogenesis of preeclampsia, perhaps through effects on placental hypoxia or the interaction of hypertensive disease and atherosclerosis, although this influence may not be strong. Additional studies using a larger number of patients and analyses that include other genetic and environmental factors will be necessary to confirm these results.

We present the clinical characteristics of pregnancy histories and subsequent pregnancy outcomes of 13 women who tested positive for anticardiolipin beta2-glycoprotein I antibody (aCLbeta2GPI). Six of the 13 women had a history of recurrent spontaneous abortion (RSA). The prevalence of aCLbeta2GPI syndrome among women with RSA was very low (2.1%). Other women with aCLbeta2GPI were identified by the presence of a biological false-positive serological test for syphilis, intrauterine growth restriction (IUGR), and a history of thrombosis. However, serum aCLbeta2GPI titers in the 13 women varied, with a wide range from 3.6 to 1468 U/mL. Their pregnancy histories, subsequent pregnancy outcomes, and complications were compared according to the classification of serum aCLbeta2GPI titers as low, moderate, or high. The history of second trimester fetal death was found only in women with high serum aCLbeta2GPI titers. All women with high serum aCLbeta2GPI titers experienced severe maternal-fetal complications such as IUGR, fetal distress, systemic thromboembolism, and neonatal sequelae in subsequent pregnancies.

The relationships among perioperative changes in plasma antithrombin (AT) activity, platelet counts, and clinical risk factors for postoperative thromboembolism has not been studied extensively in gynecologic patients. AT activity and platelet counts were determined preoperatively and on postoperative days 1 and 7 in 74 patients who underwent gynecologic surgery. The relationships between each clinical risk factor for postoperative thromboembolism and the decrease in AT activity and platelet count were analyzed using a univariate logistic regression model. No clinically significant thromboembolism occurred in any patient. AT activity and platelet counts decreased significantly on postoperative day 1 and exceeded preoperative levels on day 7. Postoperative patients with malignancy were more likely to exhibit decreased AT activity. AT activity decreased significantly with increases in operating time and blood loss. Known risk factors for postoperative thromboembolism did not appear to be associated with postoperative decreases in platelet counts. Transient hyperconsumption of AT and platelets occurs immediately after gynecologic surgery. Surgery-induced AT deficiency may contribute to postoperative thromboembolism in patients with long operating times and significant blood loss.

The syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome) and of acute fatty liver of pregnancy (AFLP) do not have an abrupt onset. Thrombocytopenia or reduced antithrombin activity, or both, seen at presentation do not result from these complications. There are a small number of pregnant women who exhibit a gradual antenatal decline in platelet counts or antithrombin activity, or both, irrespective of the presence or absence of preeclampsia. Those who develop a profound decrease in either platelet counts or antithrombin activity are at an increased risk for developing perinatal aspartate aminotransferase (AST) elevation. Thrombocytopenia or reduced antithrombin activity, or both, precede the onset of these diseases. Therefore, monitoring of platelet counts and antithrombin activity during pregnancy is clinically useful for identifying women at an increased risk of the HELLP syndrome and AFLP. Because women with twin pregnancies are likely to exhibit a decrease in platelet counts or antithrombin activity, or both, compared with women with singleton pregnancies, HELLP syndrome and AFLP are more likely to occur in women with twin pregnancies.