Thrombosis-related characteristics of pregnant women with antithrombin deficiency, protein C deficiency and protein S deficiency in Japan.

BACKGROUND:  We previously conducted a primary survey of pregnant women with hereditary thrombophilia based on national surveillance in Japan, but did not examine their thrombosis-related characteristics. Antithrombin (AT) deficiency, protein C (PC) deficiency and protein S (PS) deficiency are the major types of hereditary thrombophilia in Japan. METHODS: We examined their detailed information related to thrombosis, and evaluated peripartum outcomes in comparison with control data obtained from the Japan Society of Obstetrics and Gynecology. RESULTS: Definite or probable AT deficiency, PC deficiency and PS deficiency were observed in 80, 50, and 317 pregnancies, respectively, from 2014 to 2018 in Japan, with prevalence rates among total deliveries of 0.011%, 0.007%, 0.044%. The number of pregnancies with AT, PC and PS deficiency might have been as many as 27, 17 and 108 every year if complete answers had been provided. In the peripartum period of current pregnancies, 27.5% of women with AT deficiency, 28.0% with PC deficiency and 13.2% with PS deficiency developed thrombosis (p < 0.001 vs. control). Pregnant women with AT and PC deficiency were more susceptible to thrombosis than those with PS deficiency (P < 0.01). Of the thromboses, 92.3% occurred during pregnancy, 62.8% at less than 15 gestational weeks. The earliest onset of thrombosis was 5 gestational weeks. Prophylactic anticoagulation significantly prevented the onset of both antepartum and postpartum thrombosis (p < 0.0001). The rate of recurrent pregnancy loss in women with low PC or PS activities was significantly higher than in controls (p < 0.0001); however, it is unknown whether recurrent pregnancy loss is related to hereditary PS deficiency. There seem to have been few serious maternal or fetal/neonatal complications due to placental insufficiency related to a hypercoagulable state other than growth restriction. CONCLUSIONS: This survey revealed the thrombosis-related characteristics of pregnant women with hereditary thrombophilia in Japan. We suggest prophylactic anticoagulation to prevent maternal or fetal/neonatal complications.

Peripartum management of hereditary thrombophilia: results of primary surveillance in Japan.

This study investigated patients with thrombophilia and current peripartum management practices based on national surveillance in Japan. Between 2014 and 2018, antithrombin (AT), protein C (PC) and protein S (PS) deficiency were observed in 84, 67, and 443 pregnancies, respectively, with incidence rates among total deliveries at 0.012%, 0.009%, and 0.061%. The percentage of institutions that measured both antigens and AT, PC, and PS activity for the diagnosis of thrombophilia was 50.2%, and 46.9% of institutions did not perform gene analysis. Prophylactic anticoagulation therapy was used in the ante- and postpartum management of patients with AT deficiency at 67.1% and 66.3% of institutions, most commonly with 10,000 units of unfractionated heparin. Ante- and postpartum management of PC and PS deficiency was performed at 75.3% and 67.1% of institutions. Approximately half of the institutions performed peripartum prophylactic AT supplementation for AT deficiency. Low trough AT activity before supplementation was most commonly 50 ≤ < 70%, and the highest AT supplementation was 1500 ≤ < 3000 units. The number of pregnancies with AT, PC and PS deficiency might be as many as 29, 23 and 151 every year in Japan if complete answers were provided.

A case of spontaneous rupture of a uterine superficial varicose vein in midgestation.

A 25-year-old gravida two, nulliparous pregnant woman complained of a sudden onset of severe pain in the right lateral abdominal area and went to hospital at 28 weeks and 5 days' gestation. Since cyclic uterine contractions were observed, a diagnosis of preterm labor was made and tocolysis was carried out by the continuous venous infusion of ritodorine. She was transferred to Hamamatsu University Hospital and an emergency cesarean section was carried out due to non-reassuring fetal status. A hemoperitoneum of 850 mL was observed in the peritoneal cavity and an immature male baby weighing 1140 g was born. There was bleeding from a ruptured superficial varicose vein in the right lateral portion of the uterus, which was stopped by compression and the attachment of oxidized cellulose cotton. The clinical management and differential diagnosis were discussed.

A rapid activated protein C sensitivity test as a diagnostic marker for a suspected venous thromboembolism in pregnancy and puerperium.

OBJECTIVE: The purpose of the study was to examine whether changes in response to activated protein C (APC) can be a diagnostic marker of venous thromboembolism (VTE) during pregnancy and puerperium. METHODS: The normalized APC sensitivity ratio (sr) was examined in arbitrarily selected healthy Japanese pregnant females and compared with those in non-pregnant females and patients with VTE at the onset before anticoagulation in pregnancy and puerperium using an endogenous thrombin potential-based assay with a computer-assisted calibrated automated thrombography. RESULTS: Sensitivity to APC in patients with VTE at onset was reduced in comparison to that in late pregnancy period and puerperium (p < 0.01, Student's t test). The odds ratio for VTE was 31.9 with statistical significance in pregnant females with suspected clinical symptoms and APC-sr (≥5), although the odds ratio for VTE was not significant with D-dimer (≥5). CONCLUSION: These data suggest that an APC sensitivity test can be a possible surrogate diagnostic marker of suspected VTE during pregnancy and puerperium.

Case of polyhydramnios complicated by Opitz G/BBB syndrome.

Opitz G/BBB syndrome is a congenital disorder characterized by midline defects, such as hypertelorism, cleft lip and/or palate, hypospadias, and by dysphagia often caused by laryngo-tracheo-esophageal abnormalities. We experienced a case of polyhydramnios in a male dichorionic diamniotic (DD) twin, who was diagnosed with Opitz G/BBB syndrome after birth. It is suggested that severe dysphagia was causatively associated with the development of polyhydramnios. In cases of Opitz G/BBB syndrome, boys are usually more heavily affected than girls, who generally manifest only hypertelorism. In the differential diagnosis of polyhydramnios of unidentified cause in male fetuses, it may be helpful to consider maternal facial characteristics, especially hypertelorism.

Zinc and magnesium ions synergistically inhibit superoxide generation by cultured human neutrophils--a promising candidate formulation for amnioinfusion fluid.

Oligohydramnios is often caused by the premature rupturing of membranes and subsequent intrauterine infections, such as chorioamnionitis, in which event oxidative stress is hypothesized to be closely associated with the damage to the fetal organs. The clinical efficiency of amnioinfusion using warmed saline in cases of premature rupture of membranes is still controversial, especially concerning the prognosis for the fetus. In the present study, we found that human amniotic fluid per se suppresses the release of superoxide from cultured human neutrophils, suggesting an acute or chronic shortage of amniotic fluid in cases of premature rupture of membranes can affect the shielding of intrauterine organs from oxidative stress. The aim of this study was to propose a formula of zinc and magnesium ions in saline for amnioinfusion, by assessing antioxidative activities. A combination of 5 microM zinc and 5mM magnesium in saline synergistically inhibited superoxide production by cultured human neutrophils, equivalent to human amniotic fluid. The intraperitoneal administration of this formula significantly improved the survival rate in a rat model of peritonitis compared to the saline control (46.7% vs. 10%). The combination of these metals with saline may thus be a promising formula for an amnioinfusion fluid with the capacity to protect fetal organs from oxidative stress.

A case of a huge placental lake; prenatal differential diagnosis and clinical management.

Placental lakes are sonolucent or hypoechoic areas in images of the placenta, usually considered a physiological dilation of intervillous space with a rather good obstetrical outcome. However, diagnostic criteria for and the clinical significance of placental lakes are yet to be completely established, because of a wide variety of ultrasound findings, especially on color Doppler examination. We experienced a case of a huge placental lake, larger than the total placental area, located in an entire retroplacental space, concomitant with several penetrations of artery type blood flow. The antenatal differential diagnosis and course of clinical management are reported.

Chorangiosis and placental oxygenation.

Chorangiosis is a vascular hyperplasia in the terminal chorionic villi, usually diagnosed histologically using the criteria of Altshuler. Its true etiology has not been fully identified, but chorangiosis has been proposed to result from a longstanding, rather low-grade hypoxia in the placental tissue. To clarify a possible association of placental oxygenation status with the development of chorangiosis, we measured placental tissue oxygen index (TOI) values using near-infrared spectroscopy (NIRS) before delivery and retrospectively compared them to the detection of placental chorangiosis, in a total of 47 (46 singleton and one set of dichorionic diamniotic twins) pregnant women. Small for gestational age (SGA) and/or maternal complications were observed in all cases of placental chorangiosis. Placental TOI values were significantly elevated in cases of chorangiosis. This indicates high oxygen saturation in the intervillous spaces because placental TOI values are expected to represent the oxygenation of maternal blood in the placental tissue. A possible preceding low efficiency of oxygen transfer to the fetal circulation in the villi might not only augment the oxygen saturation of maternal blood in intervillous spaces, but also cause rather low oxygenation in the capillaries of the villi and result in chorangiosis.