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The aim of this trial was to investigate the efficacy of massive !.v. immunoglobulin (M1V1g) treatment for women with a history of recurrent spontaneous abortion (RSA) due to unexplained aetiology. The study included nine women (11 pregnancies) with a history of four or more consecutive RSA with unexplained aetiology and no live births. The mean number of fetal losses was 4.5 (range 4-6 abortions). Over the course of 5 days, immunoglobulin (20 g/day) was infused i.v. at gestational weeks 4-7. No additional infusions were carried out. Two pregnancies out of the 11 conceptions resulted in missed abortions at gestational weeks 6 and 7 respectively. Mosaicism (46XX/48XX, + 16, + 20), and tetraploidy (92XXXX) were found by chromosome analyses of the two aborti. Eight out of the other nine pregnancies resulted in full term deliveries of healthy neonates. One pregnancy developed intrauterine growth retardation and fetal distress, resulting in a premature delivery (30 gestational weeks) by Caesarean section. Thus, excluding the two abortions with chromosome aberrations, the MIVIg treatment was effective in all nine pregnancies of RSA women with unexplained aetiology. This MIVIg treatment (100 g administered in early gestation) may be a beneficial alternative to previous IVIg infusion methods, and should be further evaluated in a multicentric, placebo-controlled study, employing a larger number of homogeneous patients who fall into a high risk category of first trimester abortions. [ABSTRACT FROM PUBLISHER]

Antiphospholipid antibody (aPL) is associated with thromboembolism. There is scant evidence of a relationship between the aPL profile and serious adverse pregnancy outcome. The aim of this study was to assess whether aPL measurements during early pregnancy were useful in predicting a serious adverse pregnancy outcome. In this prospective study, we measured aPLs, including lupus anticoagulant (LA), IgG, IgM, IgA anticardiolipin antibody (aCL), IgG, IgM phosphatidylserine-dependent antiprothrombin antibody, and IgG kininogen-dependent antiphosphatidylethanolamine antibody (aPE) during the first trimester in a consecutive series of 1155 women. The 99 th percentile cut-off values in each aPL were determined using samples from 105 women who did not exhibit any pregnancy morbidity. We assessed the predictive risk of a serious adverse pregnancy outcome adjusted for confounding factors. We found that IgG aCL was associated with developing pregnancy-induced hypertension (PIH) (odds ratio 11.4, 95% CI 2.7-48); IgG aPE with PIH (8.3, 2.4-29), severe PIH (20.4, 4.5-91), and premature delivery (PD) (12.7, 3.1-50); and LA with PD (11.0, 2.8-44) and low birth weight (8.0, 2.1-31). The combinations of IgG aPE plus IgG aCL (17.5, 4.7-66.7) or IgG aPE plus LA (22.2, 5.4-909) measurements predicted severe PIH with 30.8% sensitivity and 99.2% specificity. We conclude that aPL measurements during early pregnancy may be useful in predicting adverse pregnancy outcome.

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.

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.

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.

Some case-control studies have demonstrated that caffeine intake and high CYP1A2 activity increase risks of recurrent pregnancy loss (RPL) but the multifactorial effect is obscure. To investigate whether susceptible women who have more caffeine intake are at high risk of RPL, a case-control study of 58 cases with two or more RPL and fertile 147 controls was performed. The association between daily caffeine intake together with CYP1A21F (AA versus CA and CC) genotype and RPL was assessed. Without consideration of the genotype, there were no significant differences of the RPL risk in proportion to daily caffeine intake [less than 100 mg (reference); 100-299 mg: odds ratio (OR), 1.29; 95% confidence interval (CI), 0.66-2.50; 300 mg or more: OR, 1.82; 95% CI, 0.72-4.58; P for trend, 0.20]. However, the RPL risk significantly increased only among women who had homozygous CYP1A21F alleles with a dosage effect of daily caffeine intake [less than 100 mg (reference); 100-299 mg: OR, 1.94; 95% CI, 0.57-6.66; 300 mg or more: OR, 5.23; 95% CI, 1.05-25.9; P for trend, 0.03]. It was demonstrated for the first time that an increase in caffeine intake deteriorates the fecundity among susceptible women.

Two cases with a large cystic mass within the placenta are reported. By ultrasonography, it was found that both women had a subchorionic hypoechoic lesion (11.0 x 4.8 x 4.0 cm and 6.6 x 3.7 x 2.2 cm, respectively) at 24 and 35 weeks of gestation, respectively. In both cases, turbulent blood flow generated by a pulsatile jet flow (pulse rate; 40 to 60 beats per minute) into the cystic lesion seen on real-time imaging and lesions being low intensity on T1-weighted and isointensity on T2-weighted magnetic resonance image suggested that they contained fresh maternal blood. In both cases, the sonolucency of the lesions did not change until cesarean deliveries of females, both of whom were small-for-gestational-age infants (1940 g at 37 weeks and 2195 g at 37 weeks, respectively). Biochemical analysis of the fluid in the cystic lesion sampled during the cesarean section in the latter case confirmed that the fluid had originated from the maternal blood. These lesions histologically corresponded to large avillous areas surrounded by normal villi. Thus, a huge placental lake was diagnosed in both cases., (Copyright 2005 John Wiley & Sons, Ltd.)

Objective: The aim of this study was to assess pregnancy loss patterns in women with repeated miscarriage (RM), according to fetal chromosome karyotypes and aetiologies of RM., Methods: In this cohort study, 168 fetal chromosome karyotypes of miscarriages were investigated. The pregnancy loss patterns were compared between 75 miscarriages from RM women who had a history of two or more consecutive miscarriages and 93 miscarriages from control women whose previous pregnancies ended in live births without a history of RM. By serial ultrasonography, embryo loss (EL) was defined as miscarriage before fetal heat movement was identified and fetal loss (FL) as miscarriage after fetal heat movement was identified. The EL rate was calculated as EL/(EL+FL)., Results: The EL rate (66.7%) in miscarriages with normal karyotypes among RM women (n=42) was higher (P<0.05) than that (45.7%) in controls (n=46), while the EL rate (30.3%) in miscarriages with abnormal karyotypes among RM women (n=33) did not differ from that (25.5%) in the controls (n=47). The EL rate (71.4%) in miscarriages with normal karyotypes among unexplained RM women (n=21) was much higher (P<0.05) than that in the controls., Conclusions: By evaluating fetal karyotypes, we demonstrated for the first time that EL was predominant in miscarriages with normal karyotype among RM women.

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.

Problem: Enhanced secretion of type-2 T-helper (Th2) cytokine is a characteristic feature in normal physiological pregnancy. A study has demonstrated defective production of interleukine-4 (IL-4) and other Th2 cytokine in women with recurrent pregnancy loss (RPL). Several studies have suggested that IL-4 variable number of tandem repeat (VNTR) gene polymorphism is probably associated with different IL-4 production., Methods of Study: The IL-4 VNTR genotypes were assessed in 109 Japanese women with RPL and 210 ethnically matched women experiencing at least one live birth and no spontaneous abortion., Results: No significant differences in IL-4 VNTR genotype frequencies were found between the RPL and the control [B1B1 genotype (reference); B1/B2 and B2/B2 genotypes, odds ratio, 0.91; 95% confidence interval, 0.58-1.45]., Conclusion: The present study suggests that the IL-4 VNTR allele is not a major genetic regulator in RPL.

Objective: The aim of the present study was to assess whether or not serum cytokine concentrations during early pregnancy are related to the subsequent outcomes in women with recurrent spontaneous abortion (RSA)., Patients and Methods: Serum concentrations of five cytokines--tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-4, IL-6, and IL-10--were measured by ELISA methods. Sera were collected from 73 RSA women at 6-7 weeks of gestation. Of the 73 pregnancies, 10 subsequently ended in abortion with normal fetal chromosome karyotype (AbNK), 12 ended in abortion with abnormal karyotype (AbAK), and the other 51 pregnancies ended in live birth (Lb)., Results: The serum TNF-alpha concentration in women with AbNK (mean 0 pg/ml) was lower than that in women with subsequent AbAK (0.06 pg/ml) (p < 0.05). The TNF-alpha positive percentage among women with AbNK (0%) was also lower than that among women with AbAK (50.0%) (p < 0.05)., Conclusions: Decreased serum TNF-alpha concentration during early pregnancy might be associated with subsequent abortion in RSA women.

Background: The aim of this study was to assess the natural killer (NK) cell and natural killer T (NKT) cell populations and cytokine expression of T-helper (Th) cells in the endometrium of women who suffered from unexplained repeated miscarriage (RM)., Methods: The percentages of NK cells, NKT cells and CD4(+) cells expressing intracellular interferon (IFN)-gamma, interleukin (IL)-4 and tumour necrosis factor (TNF)-alpha were measured by flow cytometry in the endometrium of 20 RM women and 17 fertile control women in the mid-luteal phase of the menstrual cycle., Results: No significant differences in CD56(+) NK cell or CD3(+)CD4(-)CD8(-)Valpha24(+)Vbeta11(+) NKT cell percentages were found between RM and control women. However, in RM women compared with control women, the percentages of CD3(+) cells (mean 40.3 versus 56.5%), CD4(+)IFN-gamma(+) cells (28.4 versus 39.5%) and CD4(+)TNF-alpha(+) cells (32.9 versus 45.8%) were significantly lower. The Th1/Th2 cell balance in RM women did not differ from that of controls., Conclusions: Immunodystrophism detected as diminution of the Th cell population rather than Th1 predominance, NK cell or NKT cell accentuation in the endometrium might underlie the pathophysiology of unexplained RM. This finding provokes an additional controversy on the Th1/Th2 balance concerning RM aetiology.

Problem: The aim of this study was to investigate immunophenotypic characteristics of natural killer (NK) cells by assessing specific molecules expressed in women with recurrent spontaneous abortion (RSA) of unexplained etiology., Method of Study: Peripheral blood cells were obtained from 20 RSA women and 15 fertile controls. The expression of perforin, CD94, CD161, CD158a, CD158b, and CD244 on CD3- CD56+ NK cells was analyzed by flow cytometry., Results: A significant decrease in CD158a expression was demonstrated in RSA women (mean +/- SD, 22.9 +/- 8.7%) as compared with that in controls (33.6 +/- 15.7%) (P < 0.05). The percentage of NK cells showing dual expression of CD94 and CD161 was relatively higher in RSA women (55.1 +/- 10.2%) than in the controls (47.1 +/- 19.0%), but without statistically significant (P = 0.096). The expression of perforin, CD158b, or CD244 in RSA women did not differ from that in the controls., Conclusions: A divergence of the specific NK cell repertoire might be related to the etiology of RSA.

Objective: To investigate the relationships between recurrent pregnancy loss and single nucleotide polymorphisms (-634C-->G and -174G-->C genotypes) in the promoter region of the interleukin (IL)-6 gene in the Japanese population., Design: A case-control study., Setting: Obstetrics and gynecology department of a university hospital., Patient(s): Cases were 76 women with recurrent pregnancy loss; controls were 93 fertile women., Intervention(s): Determination of IL-6 promoter gene polymorphisms performed by polymerase chain reaction and gel electrophoresis., Main Outcome Measure(s): Frequency and distribution of the promoter region of the IL-6 gene allele., Results: There was a significant difference in the -634C-->G genotype frequency (CC vs. CG/GG) between women with recurrent pregnancy loss and controls. The risk of recurrent pregnancy loss was lower in the carriers of the G allele than in women with the wild type (CC) (odds ratio = 0.46; 95% confidence interval = 0.24-0.91). On the other hand, we did not detect any carrier of -174C among the 169 subjects., Conclusion(s): The results suggest that, in the Japanese population, women carrying the -634G allele of the IL-6 gene might have a decreased risk of recurrent pregnancy loss.

Hypertension in pregnancy (HP) is a multifactorial disease manifested due to a complex combination of environmental factors and several predisposing genes including factors in the renin angiotensin system. The aim of this study was to assess the association between the A1166C variant of the angiotensin II type 1 receptor (AT1) gene and severe HP. We carried out association studies and multivariate analyses including other candidate causal factors of HP such as the M235T variant of the angiotensinogen (AGT) gene, prepregnancy body mass index (BMI), and family history of hypertension in Japanese subjects. One hundred and fourteen patients with severe HP and 291 normal pregnancy controls were genotyped. Among primiparous subjects, the frequency of "AC+CC genotype of AT1" was significantly higher in severe HP than in the controls. A multivariate analysis with "AC+CC genotype of AT1" and "TT genotype of AGT" revealed that these were independently associated with primiparous severe HP. However, when "family history of hypertension" and "prepregnancy BMI > or =25" were added as factors examined in the multivariate analysis, only "TT genotype of AGT" and "family history of hypertension" were found to be independent potent factors. The present results suggest that the C1166 allele of the AT1 gene may be concerned with the predisposition to essential hypertension independently of the T235 allele of the AGT gene.

Intrauterine fetal growth restriction is a multifactorial disorder, and its aetiology includes both environmental and genetic components. We aimed to investigate whether maternal genetic polymorphisms of metabolic enzymes affects fetal growth and pregnancy duration. Genomic DNA was obtained from 134 women who experienced singleton deliveries beyond 24 weeks of gestation. Maternal age, birth weight, gestational age at birth and frequencies of fetal growth restriction, prematurity and pregnancy-induced hypertension were compared among genotypic subgroups of cytochrome p450 (CYP) and glutathione S-transferase (GST) genes. The polymorphisms of CYP1A1 (MspI), CYP17 (MspAI) and GSTP1 (BsmAI) genotypes, and the presence or absence of GSTM1 and GSTT1 genes were analysed by PCR-based methods. The frequency of fetal growth restriction (<10th percentile/<-1.5 SD; 22.7%/11.4%) in 44 women who were homozygous for the A1 allele (A1A1) of CYP17 was significantly higher than that (7.8%/2.2%) in 90 women who carried the A2 allele (A1A2/A2A2) of CYP17 (P < 0.05), with an odds ratio =3.41 (95% confidence interval = 1.18-9.84). The gestational age at birth (mean +/- SD, 37.5 +/- 3.1 weeks) in 67 women with GSTM1 null genotype was significantly lower than that (38.5 +/- 2.4 weeks) in 67 women who carried GSTM1 (P < 0.05). The polymorphism of CYP17 that encodes the cytochrome p450c17alpha enzyme might be associated with the pathophysiology underlying fetal growth restriction.

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 CYP17 gene encodes the enzyme cytochrome P450c17alpha, which mediates both 17alpha-hydroxylase and 17,20-lyase activity in the steroid biosynthesis pathway. A T-->C polymorphism in the 5' promoter region of CYP17 has been described. To examine the association between recurrent pregnancy loss (RPL) and a polymorphism in CYP17, a case-control study of 117 cases with RPL and 164 controls was conducted. This polymorphism was investigated by PCR/restriction fragment length polymorphism using DNA from peripheral lymphocytes. The T-->C transition in the variant allele (A2) creates a new recognition site for the restriction enzyme MspA1, which permits designation of the wildtype allele (A1) and A2. Women with the A2 allele of CYP17 had an increased risk of RPL [A1/A1 genotype (reference); A1/A2 genotype: odds ratio (OR), 1.68; 95% confidence interval (CI), 0.94-3.01; A2/A2 genotype: OR, 2.37; 95% CI, 1.16-4.83; P trend, 0.016]. Additionally, there was a similar tendency for the increased risk of primary RPL [A1/A1 genotype (reference); A1/A2 genotype: OR, 2.14; 95% CI, 1.14-4.01; A2/A2 genotype: OR, 2.50; 95% CI, 1.16-5.41; P trend, 0.015]. These results suggest that possession of the A2 variant of CYP17 may predispose to an increased risk of RPL with a gene dosage effect.

Problem: The aim of the present study was to determine whether pre-conceptional natural killer (NK) cell activity and percentage are predictive of subsequent spontaneous abortion in women with recurrent spontaneous abortion (RSA)., Method of Study: Pre-conceptional NK cell activity and percentage in peripheral blood of women who had a history of two or more RSA was prospectively assessed. The 51Cr release assay and flow cytometric analysis were performed. A total of 113 RSA women were recruited, and 85 conceived later., Results: Pre-conceptional NK cell activity/percentage values in women whose next pregnancies ended in biochemical pregnancy and spontaneous abortion with normal fetal karyotype (n = 17, median 47%/17.1%), but spontaneous abortion with abnormal karyotype (n = 9, 27%/15.7%), were higher than those in live births (n = 59, 33%/13.1%). High values of pre-conceptional NK cell activity (> 46%; relative risk 3.6, 95%CI 1.6-8.0) and percentage (> 16.4%; 4.9, 1.7-13.8) were found to predict biochemical pregnancy and spontaneous abortion with normal karyotype in the next pregnancy., Conclusion: Pre-conceptional NK cell abnormalities were predictive of spontaneous abortion with normal fetal karyotype.

Problem: The aim of this study was to assess the natural-killer-T (NKT) cell population and cytokine expression in the peripheral blood of women with a history of recurrent spontaneous abortion (RSA)., Method of Study: The percentages of CD3+ CD4- CD8- TCRValpha24+ Vbeta11+-NKT cells and cells expressing intracellular interferon (IFN)-gamma, interleukin (IL)-4, and tumor necrosis factor (TNF)-alpha either with CD4+ or CD8+ cells were measured by flow cytometry at the midluteal phases in 15 RSA women and 15 fertile control women., Results: No significant differences in the NKT cell percentages were found between RSA and control women. However, in RSA women, the CD4+ IL-4+ cell and CD8+ IL-4+ cell percentages were significantly higher, and the Th1/Th2 and Tc1/Tc2 cell ratios were significantly lower, than those in the control., Conclusions: Th2/Tc2 dominance was found in the general circulation of RSA women; this finding provokes a new controversy on the Th1/Th2 balance concerning RSA etiology.

Objectives: The aims of this study were to assess pregnancy outcome in relation to etiologic factors of recurrent spontaneous abortion (RSA)., Study Design: The pregnancies from consecutive 216 RSA women were assessed for live birth rates (LBR) according to etiology. The LBR in 110 pregnancies from RSA women with unexplained etiology was investigated according to various therapies. An attempt to karyotype the abortuses was made., Results: Excluding pregnancies ending in abortion with abnormal karyotype, the LBR in primary recurrent spontaneous aborters (68.8%) who experienced three or more abortions was significantly lower than that in primary repeated aborters (82.4%) who experienced two abortions. The LBR ranged from 50 to 100% according to the etiology. In RSA women with unexplained etiology, the LBR in those undergoing massive intravenous immunoglobulin (MIVIg) therapy (100%) was significantly higher than those with low dose aspirin (57.1%) and luteal support therapy (67.3%)., Conclusions: Excluding pregnancies ending in abortion with abnormal karyotype, we found that LBR varied with abortion history and etiologic factors of RSA.

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.

Background: The aim of this study was to determine serum concentrations of macrophage migration inhibition factor (MIF) during normal pregnancies, and to assess whether serum MIF concentrations early in pregnancies predict the subsequent outcome in women with recurrent miscarriage (RM)., Methods: Serum MIF concentrations were measured by ELISA. Sera were collected from normal women in the first (Group I, n = 29), second (Group II, n = 25) and third trimester (Group III, n = 26) and from 78 RM women at 4-6 weeks gestation. Eleven of these 78 pregnancies subsequently ended in first trimester miscarriage with normal fetal chromosome karyotype (MsNK), seven ended in first trimester miscarriage with abnormal karyotype (MsAK), and three ended in biochemical pregnancy. The other 57 pregnancies ended in live birth (LB) between 32-41 weeks gestation, and only one woman developed preeclampsia., Results: Median MIF concentrations in Group I, II and III were similar at 17.6, 16.4 and 15.1 ng/ml respectively. MIF concentrations during early gestation in RM women with subsequent MsNK, MsAK and LB were 8.1, 11.4 and 16.4 ng/ml respectively. MIF concentrations in RM women with MsNK were significantly lower than those in RM women with LB (P < 0.01) and than those in Group I (P < 0.01), II (P < 0.05) and III (P < 0.05)., Conclusions: Decreased serum MIF concentrations during early gestation were found in RM women with MsNK, and might be related to the aetiology of miscarriage.

Problem: The aim of this study was to investigate changes in peripheral blood Th1/Th2 cytokine levels and lymphocyte ratios after massive intravenous immunoglobulin (MIVIg) treatment for women with recurrent spontaneous abortion (RSA) of unexplained etiology., Method of Study: Serum Th1 (IFN-gamma, TNF-alpha) and Th2 cytokine (IL-4, IL-10) levels were assessed by ELISA methods (n = 9) and peripheral blood Th1/Th2 lymphocyte ratios (n = 4) by flow cytometry before and after MIVIg treatments in women with four or more consecutive RSA., Results: Pre-treatment serum IFN-gamma (0.06 +/- 0.09 pg/mL, mean +/- SD), TNF-alpha (0.21 +/- 0.45 pg/mL), IL-4 (0.70 +/- 1.16 pg/mL), and IL-10 (1.12 +/- 1.67 pg/mL) increased to 0.17 +/- 0.16 pg/mL, 0.77 +/- 0.28 pg/mL, 1.82 +/- 0.89 pg/mL, and 3.44 +/- 0.48 pg/mL, respectively, after MIVIg treatments (P < 0.05). CD4-positive IFN-gamma/IL-4 lymphocyte ratios (17.3 +/- 9.1) were reduced to 11.5 +/- 7.1 after treatment (P < 0.05)., Conclusions: Massive intravenous immunoglobulin treatments increased peripheral blood cytokine levels and decreased Th1/Th2 lymphocyte ratios; thus, MIVIg treatments modify the peripheral Th1/Th2 balance.

To assess human exposure to bisphenol A (BPA) over a 10-year period, BPA concentrations in maternal serum (MS) and amniotic fluid (AF) obtained at early second trimester were determined. ELISA was used to measure BPA in 200 MS/AF pairs in women carrying fetuses with normal karyotypes (Group I) and in 48 pairs with abnormal karyotypes (Group II). In Group I, BPA concentrations in AF (median: 0.26 ng/ml) were lower (P<0.01) than in MS (2.24 ng/ml). Over a 10-year period, yearly BPA concentrations in MS decreased from 5.62 to 0.99 ng/ml (P<0.001). Eight of the Group I AF samples had relatively high concentrations of BPA (2.80-5.62 ng/ml). In Group II, BPA concentrations in AF (0 ng/ml) were lower (P<0.01) than in MS (2.97 ng/ml). MS BPA concentrations in Group II were higher (P<0.01) than in Group I.

We treated three thrombophilia-complicated pregnant women (two antiphospholipid antibody syndrome, one protein C deficiency) with low molecular weight heparin (dalteparin). All three pregnancies including one twin pregnancy ended in live births without a decrease in bone mineral density. This treatment modality was effective and safe preventing thrombosis during their pregnancies.

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 assess the role of NK cells in nonpregnant women with a history of spontaneous abortion., Study Design: 113 nonpregnant women with a history of spontaneous abortion were assessed for peripheral NK cell activity and percentage of NK cell subsets, in relation to the cause of abortions, the number of spontaneous abortions, and subsequent pregnancy outcome (n = 56)., Results: Neither NK cell activity nor subsets showed a significant difference in relation to the cause or number of spontaneous abortions. NK cell activity in nonpregnant women who later experienced subsequent abortion with normal chromosomes (n = 10) (mean +/- SD: 42.8 +/- 15.8%) was relatively higher than that in women with subsequent live birth (control, n = 39) (32.1 +/- 13.7%) (p = 0.099). NK cell activity in women who later experienced subsequent abortion with abnormal chromosomes (n = 7) (28.7 +/- 21.4%) was the same as the level in the control., Conclusion: Peripheral NK cell activity or subsets during nonpregnant status were not related to the cause or number of previous spontaneous abortions. A relation between preconceptional NK cell activity and later experiencing abortion with normal chromosomes should be further studied., (Copyright 2001 S. Karger AG, Basel)

We report a case of agnathia-holoprosencephaly which was prenatally diagnosed based on helical computed tomography (CT) images obtained at 23 weeks of gestation. Ultrasound examination first showed the presence of alobar holoprosencephaly, but the facial structures were not clearly detailed. However, three-dimensional imaging by helical CT precisely demonstrated the most striking feature of agnathia: absence of the mandible. This technique provided us valuable information that contributed to the in utero diagnosis. In utero helical CT is a useful examination tool for the diagnosis of osteogenic abnormalities., (Copyright 2001 John Wiley & Sons, Ltd.)

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.)

Congenital thrombophilia is known to cause significant maternal complications, and possibly has an adverse effect on normal fetal development. The aim of this study was to assess the prevalence of factor XII (FXII) deficiency in women with a history of recurrent miscarriage. Two hundred and forty-one consecutive Japanese women with a history of two or more recurrent miscarriages were prospectively assessed for their etiology by conventional screening methods. Seven women were found to have reduced FXII activity (19. 2-46.1%) and prolonged activated partial thromboplastin time (33. 3-51.3 s). Of these 7 women, 6 had experienced early pregnancy losses, while 1 woman had experienced repeated mid-trimester fetal losses with coincidental gestational thrombocytopenia. In 241 women with a history of recurrent miscarriage, the prevalence of FXII deficiency was 2.9%., (Copyright 2000 S. Karger AG, Basel)

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.

Rat thyroid cell strain FRTL-5 is widely used to analyze thyroid stimulators, and responds to purified hCG with increased cyclic AMP production. The aim of this study was to determine the in vitro thyrotropic activity of an immunological hCG molecule according to gestational age during normal pregnancy using the FRTL-5 cell culture system. Sera were collected from 7 normal nonpregnant control and a total of 72 normal pregnant women. Seventy-two pregnant women consisted of 40 women in the first trimester (7-14 weeks' gestational age (GW) (group I)), 16 women in the second trimester (15-28 GW, group II), and 16 women in the third trimester (29-40 GW, group III). Concentrations of serum hCG and FT4 of group I were higher than those of groups II and III (p < 0.001). In the in vitro assay, the supernatants were subjected to radioimmunoassay for cAMP. In order to analyze in vitro thyrotropic activity of an immunological hCG molecule, cAMP accumulation rate expressed as cAMP accumulation (nM) divided by maternal serum concentration of hCG (IU/ml) was determined in all three groups. By regression analyses, a statistically significant positive correlation was observed between serum hCG concentration and cAMP accumulation in group I (r = 0.399; p < 0.05), group II (r = 0.915; p < 0.0001) and group III (r = 0.671; p < 0.01). cAMP accumulation rate in group I (0.355 +/- 0.022, mean +/- SE) was significantly low when compared with group II (0.508 +/- 0.051) (p < 0.01) and group III (0.556 +/- 0.063) (p < 0.001). Thus, it was found for the first time that the in vitro thyrotropic activity of an immunological hCG molecule in the first trimester was lower than those of the second and the third trimesters. In terms of the in vitro thyrotropic activity, an immunological hCG molecule in the first trimester differs from that of the later trimesters.

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.

The aim of this study was to evaluate risk factors for the occurrence of fetal/neonatal passive immune thrombocytopenia (PIT) in pregnancy complicated with ITP. We studied 52 pregnancies with ITP and the 54 neonates retrospectively. Neonatal platelet counts were compared with maternal platelet counts, platelet-associated IgG (PAIgG) values and the presence of antiplatelet antibody in maternal circulation, history of previous PIT, maternal treatments for ITP, and other maternal/neonatal factors including gestational age and birth weight. Logistic regression analysis for multivariables was performed. PIT (platelet counts < 100 x 10(3)/microl) without neonatal mortality or any morbidity was observed in eight (15.4%) of 52 pregnancies. The presence of circulating antiplatelet antibodies in maternal blood, splenectomy prior to pregnancy, and a history of previous PIT were observed more frequently with statistical significance in women giving birth to neonates who developed PIT. By logistic regression analysis, splenectomy prior to pregnancy was found to be the single significant variable (p=0.017, odds ratio 9.33) among the risk factors for PIT. Thus, splenectomy prior to pregnancy is related to increased risk for PIT in ITP-complicated pregnancy.

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.

We investigated whether HLA-DR genes are associated with the etiology of unexplained recurrent spontaneous abortion (URSA), by using the polymerase chain reaction-sequence-specific primers (PCR-SSP) method, which is more accurate than serological typing. In women (n = 27) who experienced three or more consecutive spontaneous abortions in the first trimester, the frequency of the DR4 allele was significantly increased (relative risk = 4.25, P = 0.020) when compared with controls (n = 22) who experienced two or more full-term deliveries and no miscarriage. After high-resolutional analysis by a second PCR-SSP in positive cases for the DR4 allele phenotypic frequencies of HLA-DRB1*04 sub-alleles were disclosed. The most frequent sub-allele was DRB1*0405, followed by DRB1*0406 in both women with URSA and controls. However, none of the specific sub-alleles were attributed statistically to the increase in the DR4 allele in women with URSA.