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The etiology of recurrent pregnancy loss (RPL) remains unclear, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We examined the relation between RPL and polymorphisms in four genes, human aryl hydrocarbon (Ah) receptor, cytochrome P450 (CYP) 1A1, CYP1A2 and CYP1B1, which are involved in the metabolism of a wide range of environmental toxins and carcinogens. All cases and controls were women resident in Sapporo, Japan and the surrounding area. The Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotypes were assessed in 113 Japanese women with recurrent pregnancy loss (RPL) and 203 ethnically matched women experiencing at least one live birth and no spontaneous abortion (control). No significant differences in Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotype frequencies were found between the women with RPL and the controls [Ah receptor: Arg/Arg (reference); Arg/Lys and Lys/Lys, odds ratio (OR)=0.67; 95% confidence interval (CI)=0.40-1.11, CYP1A1: m1m1 (reference); m1m2 and m2m2, OR = 0.86; 95% CI = 0.53-1.40, CYP1A2: C/C and C/A (reference); A/A, OR = 1.16; 95% CI = 0.71-1.88, CYP1B1: Leu/Leu (reference); Leu/Val and Val/Val, OR = 1.18; 95% CI = 0.68-2.02]. The present study suggests that the Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not major genetic regulators in RPL.

The aetiology of recurrent pregnancy loss (RPL) remains unclear, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We examined the relation between RPL and polymorphisms in two genes, glutathione S-transferases (GST) M1 and T1, which are involved in the metabolism of a wide range of environmental toxins and carcinogens. A case-control study of 115 cases with RPL and 160 controls was conducted. All cases and controls were women resident in Sapporo, Japan and the surrounding area. They were genotyped for polymorphisms of GSTM1 and GSTT1 using PCR-based methods. We found that 65.2% of the cases with RPL and 45.6% of the controls had the GSTM1 null genotype [odds ratio (OR) = 2.23, 95% confidence interval (CI) = 1.36-3.66]. On the other hand, 47.0% of the cases and 49.4% of the controls had the GSTT1 null genotype (OR = 0.95; 95% CI = 0.58-1.55). The results suggest that women with GSTM1 null polymorphism may therefore have an increased risk of RPL.

Apoptosis is thought to participate pathophysiologically in the rupture of human fetal membranes (ROM). The aim of this study was to assess apoptosis of the amnion and the chorion in relation to ROM and chorioamnionitis (CAM). The amnion and chorion at the position of the cervical os and fundus of the uterus were obtained from 44 patients. Apoptotic DNA fragmentation was densitometrically determined, and the relative ratio was used for the quantitative evaluation. Among patients without CAM, the relative ratios of apoptosis in the amnion from patients with ROM were higher than those in patients without ROM (P< 0.05). Among patients without ROM, the apoptotic levels in the amnion from patients with CAM were higher than those in patients without CAM (P< 0.05). These were the cases with the amnion at the position of cervical os and fundus, but not with the chorion. The highest ratio of apoptosis was seen in the amnion from patients with CAM and ROM. Among patients with ROM and no CAM, the apoptotic levels at the cervical os in the amnion (P=0.059) and chorion (P< 0.05) was higher than those at the fundus. The increased apoptosis of human fetal membranes was related to ROM and CAM. Apoptosis plays a role in the pathophysiology of ROM., (Copyright 2002 Elsevier Science Ltd.)

Problem: The aims of this study were to investigate the efficacy of massive intravenous immunoglobulin (MIVIg) treatment for women with recurrent spontaneous abortion (RSA) of unexplained etiology, and to investigate changes in peripheral natural killer (NK) cell activity and subsets., Method of Study: MIVIg treatment was performed in 18 pregnancies from 15 women with 4 or more consecutive RSA of unexplained etiology. NK cell activity and subsets were assessed in 8 of the pregnancies., Results: 14 pregnancies resulted in live births and 4 resulted in abortions with chromosome abnormality. The pre-infusion NK cell activity (mean + SD. 40.9 + 17.0%) at 4.4 +/- 0.5 weeks of gestation (GW) decreased to 15.0 +/- 7.90% at post-infusion status (5.4 +/- 0.5 GW). Pre-infusion percentages of CD56+ CD16- cells (3.5 +/- 2.1%) and CD56+ CD16- cells (16.8 +/- 8.8%) decreased to 3.0 +/- 2.2% and 11.1 +/- 6.9%, respectively, after MIVIg treatment., Conclusions: MIVIg treatment was effective in all 14 pregnancies from RSA women of unexplained etiology, excluding 4 abortions with chromosome abnormality. Peripheral NK cell activity and subsets were suppressed by MIVIg treatment.

Women with antithrombin (AT) III deficiency are prone to pregnancy-associated venous thromboembolism. We report 2 cases with genetically confirmed ATIII deficiency, one with a mutation in exon 3A and the other with an exon 4 deletion, in whom the pregnancies were successfully managed with prophylactic therapies for thrombosis. A 35-year-old pregnant woman was treated with intravenous infusions of ATIII concentrate alone, and the other 22-year-old pregnant woman was mainly treated with subcutaneous injections of heparin and oral low-dose aspirin therapy. Both pregnancies resulted in vaginal deliveries of healthy neonates. The literature concerning prophylactic therapies for thrombosis in ATIII deficiency-complicated pregnancy is reviewed, and the clinical problems, including the adverse effects of the therapies, are discussed.

Problem: The aim of this study was to assess the role of natural killer (NK) cells in pregnant women with a history of recurrent spontaneous abortion (RSA)., Method of Study: Consecutive 66 pregnant women with a history of RSA were prospectively assessed for peripheral NK cell activity, percentage of the NK cell subsets, and subsequent pregnancy outcome., Results: NK cell activity in women with subsequent live birth (group I) at 4-5 gestational weeks (GW) (mean +/- SD, 32.5 +/- 12.31%) significantly decreased at 6-7 GW (28.1 +/- 12.1%) and at 8 9 GW (28.0 +/- 11.8%). NK cell activity in women with subsequent abortion with normal chromosomes (group II) at 6 7 GW (41.2 +/- 19.0%) was significantly higher than that in group I women, while NK cell activity at 6-7 GW in women with subsequent abortion with abnormal chromosomes (group III) was the same as the level in group I women., Conclusions: High NK cell activity at 6-7 GW correlates with subsequent abortion with normal chromosomes.

A pregnant woman developed acute demyelinating poly-neuropathy (Guillain-Barré syndrome (GBS)) in the 28th week of gestation (GW) after flu-like infection. Hypertension, liver dysfunction, and a decrease in consciousness level developed at 29GW. Blood chemical analysis revealed increased levels of liver enzymes GOT 247 IU/l and GPT 624 IU/l. Viral serological study showed a positive test for Epstein-Barr virus IgM. Weakness of bilateral facial muscles and limbs, a loss of tendon reflexes, and generalized paresthesia were detected by neurologic examinations. Over the course of 5 days, a massive dose (100g) of intravenous immunoglobulin (MIVIg) was infused in 30GW. An average manual muscle testing score by the Medical Research Council method and peak flow value began to be significantly restored during and after MIVIg infusions. Values of the liver enzymes gradually decreased, and improvement of the muscle weakness and dysbasia was observed. Her pregnancy normally ended in spontaneous vaginal delivery of a healthy infant in 37GW. This is the first report confirming the efficacy of MIVIg, without plasmapheresis, in GBS-complicated pregnancy.

Congenital and acquired thrombophilia are associated with an increased risk of pregnancy-associated venous thrombosis and fetal loss. Two hundred eighty-nine patients with a history of recurrent spontaneous abortion were subjected to screening examinations for the etiology of these abortions. Endocrine abnormality (28.0%), uterine abnormality (10.4%), autoimmune diseases (1.4%), antiphospholipid antibody syndrome (4.5%), and balanced type chromosome translocation (4.2%) were found as underlying causes of recurrent abortions, and the remaining 55.0% of the 289 patients were classified as having an unexplained etiology. Congenital thrombophilia such as protein C (PC) deficiency, protein S (PS) deficiency, antithrombin deficiency, and factor V Leiden mutation was not frequently detected; only one patient had PS deficiency. A reduced factor XII activity was found at a frequency of 4.2%. The frequency of methylene tetrahydrofolate reductase gene C677T mutation in recurrent aborters (0.38) was the same as that found in a fertile control group. Although the prevalence of anti-beta2-glycoprotein I antibody (abeta2-GPI) syndrome was very low (1.7%), patients with a high titer of immunoglobulin G (IgG) class abeta2-GPI, despite anticoagulation therapy, experienced severe fetomaternal complications in subsequent pregnancies. The rate (13.8%) of positive tests for serum IgA class abeta2-GPI in patients with unexplained etiology was higher than that in the controls (0%) (P < .05). We conclude that congenital thrombophilia is rare in Japanese patients who had experienced consecutive spontaneous abortions.

Preeclampsia is known to be a multifactorial disease. Recently, the angiotensinogen gene has been shown to be a candidate gene that could be related to preeclampsia, and acquired factors such as lifestyle during pregnancy have also been considered to be risk factors. The aim of this study was to investigate the interrelations among the angiotensinogen gene and various acquired risk factors in preeclampsia. Fifty-eight primiparous patients with pre-eclampsia were compared with 164 normal primiparous controls. A variant of the angiotensinogen gene (M235T) was analyzed along with the acquired factors obtained from both medical records and a questionnaire consisting of 98 questions. Univariate analysis disclosed 11 factors that were significantly associated with preeclampsia (P < .05). Multivariate analysis revealed four significant independent factors: "prepregnancy high body mass (body mass index > or = 24)," "T235 homozygotes of the angiotensinogen gene," "mentally stressful condition during pregnancy," and "salty dishes preferred during pregnancy." The odds ratios of the four factors were 6.2, 2.5, 3.0 and 2.6, respectively, in a multiple logistic model. Our results support the concept that T235 of the angiotensinogen gene is a potent, independent risk factor for preeclampsia, as well as other lifestyle-related risk factors.

Objective: The aim of this study was to establish the risk of postpartum thyroid dysfunction (PPTD) in women who had normal thyroid function during pregnancy and no history of thyroid disease., Design: Four thousand and twenty-two consecutive pregnant women were screened for thyroid function and antithyroid antibody. Among women with normal thyroid function during pregnancy and no history of thyroid disease, thyroid function were assessed in 131 of 388 antithyroid antibody positive (Group I) and 1030 of 3503 antibody negative (Group II) women at 1 and 3 months postpartum. In Group I women who experienced PPTD, the frequency of later manifestation of Hashimoto's disease was compared according to titres of antithyroid antibodies., Measurements: Blood samples in early pregnancy, and at 1 month and 3 months postpartum were obtained using the dried blood spot method. Levels of fT4 were measured by RIA, TSH by fluoroimmunoassay or ELISA, antimicrosome antibody (AMC) and antithyroglobulin antibody (ATG) by indirect agglutination reactions., Results: The prevalence of PPTD at 1 month and 3 months postpartum were found to be 6.9% and 21.3% in Group I, and 5.3% and 4.7% in Group II, respectively. The prevalence of PPTD was significantly higher at 3 months postpartum in Group I (P<0.05). 27.3% of women with PPTD in Group I were later found to have Hashimoto's disease and 9.1% manifested hypothyroidism without goitre. A high AMC titre (> or = 25600) at 3 months postpartum in women with PPTD was related to the manifestation of Hashimoto's disease. AMC titres of PPTD women and women who developed Hashimoto's disease were significantly higher than those of control women who did not experience PPTD., Conclusion: A high prevalence of PPTD was found in women with antithyroid antibodies who were euthyroid during pregnancy. Prolonged follow-up of the subsequent thyroid function may be needed in women who experience PPTD and/or show a high titre of antithyroid antibody.

A 35-year-old Japanese woman with a low level (42-54%) of blood antithrombin (AT) III, experienced two induced abortions due to deep venous thrombosis at 8 weeks of gestation (GW) and cerebral thrombosis at 10 GW. The present pregnancy was successfully managed with intravenous administration of AT III (6,000-8,000 U/wk). Analysis of polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) for exons 3A and 4 of the AT III gene (AT3) using her DNA revealed extra expansion bands with altered migration. The DNA sequencing demonstrated novel mutations in exon 3A of AT3: a G to T substitution at nucleotide position 5333 in codon GAG for Glu 113, causing a stop codon (E113X), and an A to T substitution at position 5338 in codon AAA for Lys 114, forming Asn (K114N). These novel mutations, especially E113X, in AT3 may be related to recurrent thrombosis in the pregnancy., (Copyright 2000 Wiley-Liss, Inc.)

Problem: Maternal anti-SSA(B) antibody crosses the placenta and causes fetal myocarditis, congenital heart block (CHB), hydrops fetalis, and intrauterine fetal death. The aim of this study was to evaluate corticosteroids' efficacy as a treatment for CHB., Method of Study: One fetus with complete CHB and one fetus with incomplete CHB due to anti-SSA(B) antibody received maternal prednisolone (PSL) and dexamethasone (DEXA) treatments. Heart rate, cardiothoracic ratio (CTR), left ventricular fractional shortening (FS), and preload index (PLI) were longitudinally measured by serial fetal echocardiograms., Results: In the former case, after maternal PSL/DEXA administration, improvement of cardiohemodynamics, i.e., the reduction of PLI from 1.7 to 0.4, CTR from 70 to 52%, and FS from 63 to 54% were observed. In the latter case, second degree 2:1 block was converted to 3:2 block/sinus rhythm, resulting in the increase of the fetal heart rate from 65 to 116 beats per minute (bpm)., Conclusions: We disclosed for the first time the beneficial effects of corticosteroids in the fetal cardiohemodynamics and conduction system of affected fetuses with the presence of maternal anti-SSA(B) antibodies.

The contribution of genetic factors to hypertension in pregnancy, including pre-eclampsia, has been well documented. The association with a common molecular variant of the angiotensinogen (AGT) gene, in which methionine (M235) is substituted for threonine (T235) at residue 235, has been reported in both Caucasians and Japanese. In the present study, we examined 115 cases of pure type of hypertension in pregnancy (PHP) and 381 normal pregnant controls in order to look for subgroups in which the AGT gene is the major factor in the PHP pathogenesis. By classification of PHP cases according to the clinical diagnosis, gravidity, and maternal age, we found significantly higher frequencies of T235 in both all PHP patients and preeclampsia/eclampsia patients than in normal controls. These results are discordant with those reported for Caucasian subjects where only a group of preeclamptic primigravidae was associated with the AGT variant, possibly indicating the existence of a racial difference. We also found that the variant frequency was significantly higher in the PHP subgroup with maternal age of 20-34 years (0.93) than in a subgroup of multigravid PHP patients age 35 years or older (0.77, P < 0.05) or in normal controls of age 20-34 years (0.76, P < 0.001). The result indicates that the AGT variant plays a significant role in hypertension in the age group 20-34 years., (Copyright 1999 Wiley-Liss, Inc.)

Problem: The aim of this study was to elucidate fetomaternal risks in systemic lupus erythematosus (SLE)-complicated pregnancy., Method of Study: Pregnancy course, complications, and fetal outcome in 82 pregnancies of 55 patients with SLE were investigated., Results: These 82 pregnancies resulted in 14 fetal losses and 66 live births. Without clinical manifestation of SLE-flare, 4 of 8 patients who had low serum complement activity during the pregnancies delivered small-for-date neonates. The rate of the intrauterine growth retardation was significantly higher than that observed in pregnancies with normal complement activity. The frequency of premature deliveries (60%) in patients who received more than 15 mg/day of prednisolone was significantly high when compared with pregnancies maintained by 0-15 mg/day (13.1%)., Conclusions: These data demonstrate the preconceptional and perinatal management necessary in SLE and suggest that the pregnancy with hypocomplementemia, the disease activity, and/or a relatively high maintenance dose of corticosteroid should be carefully managed and monitored.

The aim of this study was to evaluate risk factors for occurrence of neonatal passive immune thrombocytopenia (PIT) in pregnancy complicated by idiopathic thrombocytopenic purpura (ITP). We studied 63 pregnant women with ITP and the 66 neonates retrospectively. Neonatal platelet counts were compared with maternal platelet counts, platelet-associated gamma G immunoglobulin (PAIgG) values, and the presence of antiplatelet antibody in the maternal circulation, history of previous PIT, maternal treatments for ITP, and other maternal or neonatal factors. PIT (platelet counts <100 x 10(3)/microL) was observed in 9 (14.3%) of 63 pregnancies. Presence of circulating antiplatelet antibody in maternal blood, splenectomy prior to pregnancy, and history of previous PIT were observed more frequently with statistical significance in patients giving birth to neonates who developed PIT. No effect on occurrence of PIT was found by the administration of corticosteroids or immunoglobulin. Splenectomy prior to pregnancy was found by logistic regression analysis to be a single significant variable (p = 0.021, odds ratio 7.20, confidence intervals: 1.35 to 38.3) among the risk factors for PIT.

Objective: Transient elevation of serum free T4 (gestational transient hyperthyroxinaemia; GTH) occurs occasionally during normal pregnancy, especially in early gestation. However, the frequency of GTH and its clinical features remain unclear to date. The aim of this study was to determine the occurrence rate of GTH and the relation between serum levels of hCG, free T4 (fT4), and TSH in a large number of pregnant women., Design: The four criteria of GTH were as follows: (1) no past history of thyroid disease, (2) negative tests for MCHA and TGHA, (3) no multiple pregnancies or trophoblastic disease and (4) transient hyperthyroxinaemia at less than 16 weeks of gestation. Thyroid function and hCG levels in 23,163 pregnant women were evaluated by mass sreening. If individual fT4 levels were more than the upper limit, blood re-sampling and the clinical and laboratory analysis of thyroid function were performed to exclude women with thyroid disease. The concentrations of hCG, fT4, and TSH in women with GTH and normal pregnant controls (n = 218) were compared. Regression analysis was performed for the comparison between hCG, fT4, and TSH levels in women with GTH., Measurements: Blood samples were obtained using dried blood spots. Blood levels of fT4 was measured by radioimmunoassay, TSH and hCG were measured by fluoroimmunoassay. Anti-microsome antibody (MCHA) and anti-thyroglobulin antibody (TGHA) were measured by indirect agglutination reaction., Results: GTH was observed in 66 of 23,163 women. The overall occurrence rate of GTH was 0.285%. In 22 of the 66 GTH women, serum TSH was undetectable. Using regression analyses, the concentration of fT4 was correlated with hCG levels in women with GTH (P < 0.05, r = 0.269), whereas the concentration of TSH was not correlated with hCG or fT4 level. The concentrations (M +/- SD) of fT4, TSH, and hCG in women with GTH were 42.5 +/- 12.3 pmol/l, 0.20 +/- 0.31 mU/l and 190.2 +/- 98.8 x 10(3) IU/l, whereas those of controls were 14.6 +/- 3.8 pmol/l, 1.43 +/- 1.25 mU/l and 60.1 +/- 45.1 x 10(3) IU/l. The concentrations of fT4 and hCG were significantly (P < 0.0001) higher than those of normal controls, and TSH was significantly (P < 0.0001) lower than those of normal controls., Conclusion: The occurrence rate of gestational transient hyperthyroxinaemia was 0.285%, and could possibly be attributed to increased levels of circulating hCG. Based on the data obtained from a large number of pregnant women, we propose gestational transient hyperthyroxinaemia as a definite clinical entity.

Objective: To evaluate prenatal diagnosis of limb-body wall complex (LBWC) by ultrasonography in eight cases., Study Design: The diagnosis was based on two of the following: exencephaly/encephalocele with facial clefts, thoracoschisis and/or abdominoschisis and limb defect. The ultrasonographic findings were compared with the autopsy findings in each case., Results: The average weeks of gestation at which malformations were diagnosed by ultrasonography was 21.7 +/- 4.7 (mean +/- SD, n = 8). All eight fetuses were diagnosed as having characteristic abnormalities and six of them as having scoliosis by ultrasonography. Four of the eight were examined for maternal serum alpha-fetoprotein (MSAFP); the levels exceeded 2.5 multiples of the mean according to the standard value at our hospital. Chromosomal analysis was performed for six cases and revealed that they were normal in karyotype. All eight cases showed abdominoschisis, scoliosis and abnormalities of the lower extremities. A single umbilical artery was present in seven cases (87.5%), and a short umbilical cord was present in seven (87.5%)., Conclusion: Ultrasonographic detection of abdominoschisis, scoliosis abnormalities of the lower extremities, a single umbilical artery and a short umbilical cord is important for the prenatal diagnosis of LBWC. An extremely elevated level of MSAFP is also indicative of the complex.

Fetal anemia causes hydrops fetalis and fetal ascites/hydrothorax, and in severe cases the prognosis is poor. Little other than alloimmunity and viral infections are known as mechanisms causing fetal anemia. The aim of this study was to elucidate any pathogenesis in fetal anemia due to otherwise idiopathic etiology. The levels of three hematopoietic cytokines, IL-3, erythropoietin (EPO), and granulocyte colony-stimulating factor (G-CSF) were measured in blood samples obtained by cordocentesis from six fetuses with anemia (Hb <10.0 g/dl) and 34 fetuses without anemia. Cordocentesis was performed prior to the onset of labor or uterine contractions in all pregnant women. The concentration of IL-3 in fetuses with anemia [M+/-(SD), 8.3 (10.1) pg/ml] was significantly lower than that in fetuses without anemia [59.9 (71.0) pg/ml]. EPO and G-CSF levels were not different between the two groups. In addition, through in vitro colony formation assay, using blood stem cells from two fetuses with severe anemia and three fetuses without anemia, it was found that colony forming unit-erythroid, burst forming unit-erythroid and granulocyte macrophage-colony forming unit were significantly suppressed in blood stem cells from the two fetuses with severe anemia. Thus, the malfunction of differentiation and proliferation of blood stem cells and the decrease of hematopoietic cytokine levels in the fetal circulation may be responsible for the occurrence of fetal anemia.

In order to better understand the effect of obstetric management on the prognosis of very low birth weight (VLBW) fetuses, we retrospectively studied perinatal factors and the outcome of two hundred twenty-eight VLBW infants without major anomaly excluding cases of multiple pregnancy. The frequency of malpresentation were significantly high in the early neonatal death group (p < 0.05) and in the cerebral palsy/mental retardation (CP/MR) group (p < 0.01). A stepwise regression analysis for the CP/MR detected dependent variables as malpresentation, use of tocolytic agents (beta(2)-stimulant plus MgSO4) and pH < 7.20 in cord artery. Delivery method was not a dependent variable for the early neonatal death or the CP/MR. We analyzed a relation between fetal presentation-delivery method, and the prognosis. Among four groups (cephalic-vaginal, cephalic-cesarean, breech-vaginal, breech-cesarean), the cephalic-vaginal group had the lowest incidence of the poor prognosis (death and major handicap) where the breech-vaginal had the highest incidence. Breech groups (vaginal plus cesarean) had significantly high incidence of the poor prognosis when compared with that of cephalic groups (vaginal plus cesarean) (p < 0.05). Significant difference of the prognosis between the cephalic-vaginal group and the cephalic-cesarean group was not observed. These findings suggest that the delivery method is not a risk factor, but the malpresentation itself may be a risk factor for the poor prognosis of VLBW infants.