Determination of clinically significant tests for antiphospholipid antibodies and cutoff levels for obstetric antiphospholipid syndrome.

OBJECTIVE: The objective of this paper is to determine which kinds of assays for antiphospholipid antibodies (aPL) should be tested for clinical practice for patients with recurrent pregnancy loss (RPL). MATERIALS AND METHODS: We studied 560 patients with a history of RPL prospectively. We determined the obstetric significance of 11 commercially available tested assays for lupus anticoagulant (LA)-aPTT StaClot, phosphatidylserine-dependent antiprothrombin (aPS/PT) IgG, IgM, classical cardiolipin (CL) IgG, IgM, CL IgG, IgM, IgA, and ß2glycoprotein I (ß2GPI) IgG, IgM, IgA Phadia. Obstetric significance was defined as the potential for anticoagulant therapy to improve the subsequent live birth rate, or a difference in the live birth rate between positive and negative untreated cases. RESULTS: The LA-aPTT StaClot assay and aPS/PT IgG assay, but not CL IgG, were found to have obstetric significance. Our conventional tests covered positive cases with the aPS/PT IgM and classical CL IgG assays. The results of the LA-aPTT StaClot, LA-aPTT and LA-RVVT assays showed different distributions, although strong or moderate correlation was observed. CONCLUSION: LA-aPTT StaClot and aPS/PT IgG might be suitable for use in routine practice for patients with RPL. Each test for aPL should be ascertained for obstetric significance, because similar assays may have different outcomes.

Perinatal management of neonatal alloimmune thrombocytopenia associated with anti-group A antibody.

OBJECTIVE: To prevent neonatal alloimmune thrombocytopenia due to anti-group A antibody perinatal management was performed. BACKGROUND: We previously reported a case of severe intracranial haemorrhage associated with neonatal alloimmune thrombocytopenia due to anti-group A isoantibody. MATERIAL/METHODS: A 40-year-old Japanese woman, gravida 4 para 1, was pregnant with her second baby. The previous sibling developed severe thrombocytopenia and died 10 days after birth due to intracranial haemorrhage. He was diagnosed with neonatal alloimmune thrombocytopenia; the causative antibody was found to be the anti-group A antibody. Prednisone was started at 7 weeks' gestational age. Intravenous immunoglobulin 1 g kg(-1) week(-1) was started at 29 weeks' gestational age and continued to delivery. Serological studies and genotyping were performed. RESULTS: The second boy was delivered at 33 weeks' gestational age by caesarean section. He was discharged without intracranial haemorrhage or thrombocytopenia. The anti-group A antibody titre in the maternal serum was 2048-4096 (normal range: 4-64). The anti-group A antibody titre in the newborn's serum was 4. Cross-matching between the maternal serum and the paternal platelets was positive. CONCLUSION: Owing to the history of neonatal alloimmune thrombocytopenia causing intracranial haemorrhage and death of the previous sibling, strict follow-up of the subsequent pregnancy was conducted.

Efficacy of diffusion-weighted magnetic resonance imaging in detecting infected cysts in a case of polycystic kidney disease.

Hepatic and/or renal cyst infection is a major complication in patients with polycystic kidney disease. In many cases, drainage of infected cysts is necessary, although accurate detection of infected cysts from among the numerous hepatic or renal cysts present is often difficult, because the findings of infected cysts on computed tomography and T1- and T2-weighted magnetic resonance imaging resemble those of normal cysts. We describe here a case of polycystic kidney disease complicated by hepatic cyst infection. On diffusion-weighted magnetic resonance imaging (DWMRI), which is occasionally used in the diagnosis of cerebral abscesses, infected hepatic cysts showed higher signal intensity than other cysts, facilitating differentiation of the cysts requiring drainage from numerous other cysts. Infected cysts showed a marked decrease of the apparent diffusion coefficient (ADC) values compared with those of normal cysts. DWMRI was very effective in detecting infected cysts in our patient and may be of value in other such cases with polycystic kidney disease.

Endocapillary proliferative glomerulonephritis with crescent formation and concurrent tubulointerstitial nephritis complicating retroperitoneal fibrosis with a high serum level of IgG4.

Renal lesions of IgG4-related disease have been reported recently. Most of them are tubulointerstitial nephritis, and a definite glomerulonephritis complicating IgG4-related disease is very rare. We report here a case of definite glomerulonephritis and concurrent tubulointerstitial nephritis complicating retroperitoneal fibrosis with a high serum level of IgG4. A 68-year-old Japanese woman was referred to our hospital for investigation of anasarca. We diagnosed her disease as a nephrotic syndrome and left hydroureteronephrosis due to retroperitoneal fibrosis. Her laboratory data revealed a high serum level of IgG4, renal injury, hypoproteinemia, hypocomplementemia, a positive finding of circulating immunocomplex (CIC), and negative findings ofautologous antibodies suggesting systemic lupus erythematosus (SLE) or Sjögren's syndrome (SS). A diagnosis of SLE or SS could not be made clinically. Right renal biopsy revealed endocapillary proliferative glomerulonephritis with crescent formation and concurrent tubulointerstitial nephritis. Infiltration of plasma cells in interstitium was more conspicuous than seen with ordinary tubulointerstitial nephritis, and in most of them IgG4 was positive. We placed a percutaneous nephrostomy catheter in her left kidney, and prescribed prednisolone and cyclosporine. The responses to prednisolone and cyclosporine therapies were very good. Further studies are needed to clarify the relationship between glomerulonephritis and IgG4-related disease. However, when considering renal lesions of IgG4-related disease, we think that hypocomplementemia, a positive finding of CIC, negative findings of autologous antibodies suggesting SLE or SS, conspicuous interstitial infiltration of IgG4-positive plasma cells, and a good response to steroid or immunosuppressant therapy are key points.

The gene expression level of transforming growth factor-beta (TGF-beta) as a biological prognostic marker of hepatocellular carcinoma.

The question that transforming growth factor-beta (TGF-beta) provides a tumor-suppressive or a tumor promoting role is still unknown in hepatocellular carcinoma (HCC). In the present study, we quantitatively investigated the gene expression levels of TGF-beta in liver tissues from patients with HCC. We also evaluated the prognostic importance of TGF-beta gene in HCC patients. A total of 59 patients with primary HCC who underwent hepatectomy between 1993 and 2001 were enrolled. TGF-beta gene expression levels of tumors and of noncancerous livers were analyzed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). The percentage of apoptotic cells in tumor cells (apoptotic index: AI) was evaluated with immunohistochemistry. Also the expression of survivin protein (apoptosis inhibitor) in tumors was detected by immunohistochemistry. TGF-beta gene expression levels of tumors were compared with clinicopathological findings of patients. The relative expression level of TGF-beta mRNA of 59 tumor tissues did not differ from those of 8 normal liver tissues or 59 noncancerous liver tissues. The mean AI of 29 tumors with normal expression levels of TGF-beta gene (4%) was significantly higher than that of 30 tumors with low expression levels of TGF-beta gene (2.5%, p = 0.03). Thirteen out of 30 tumors (43%) with low expression level of TGF-P gene showed survivin positive, while only 4 out of 29 tumors (14%) with preserved expression of TGF-beta gene showed survivin positive. This difference was significant (p = 0.012). The overall 5-year survival rate of 29 patients with tumors with preserved TGF-beta gene prolonged to 72% compared with that of 30 patients who had tumors with suppressed TGF-beta gene (58%, p = 0.156). In HCC, TGF-beta gene may play a defensive role against tumor progression by regulating survivin protein expression and by controlling occurrence of spontaneous apoptosis in tumors.

[Immunohistochemical study of dihydropyrimidine dehydrogenase (DPD) and p53 in biopsied specimens of esophageal cancer before chemoradiotherapy].

We studied whether the immunohistochemical status of dihydropyrimidine dehydrogenase (DPD) and p53 can be used to predict the sensitivity to chemoradiotherapy (CRT) in patients with esophageal cancer. In 19 patients who did not undergo preoperative CRT, the immunoreactivity of DPD and p53 in biopsied specimens correlated well with those in surgically resected specimens (DPD: 100%, p53: 73%). Fifteen patients were treated with 5-FU (250-300 mg/body/day: day 1-5, 8-12), low-dose cisplatin (10 mg/body/day: day 1, 8) and radiotherapy (30-40 Gy). The response rate (CR + PR) for CRT in these patients was 40%. All tumors that showed CR or PR demonstrated low expression of DPD. However, all tumors with high DPD expression showed MR or NC. However, the expression of p53 did not correlate with the response rate for CRT. Therefore, the effect of CRT for esophageal cancer may be predicted by immunohistochemical examination of DPD in biopsied tumor specimens.

Clinical and laboratory features of anticentromere antibody positive primary Sjögren's syndrome.

OBJECTIVE: To determine whether the clinical and laboratory characteristics of anticentromere antibody (ACA) positive, anti-SSA/Ro antibody (SSA) negative primary Sjogren's syndrome (SS) differ from SSA positive, ACA negative primary SS. METHODS: Twelve patients with ACA positive primary SS (ACA SS) and 19 patients with SSA positive primary SS (SSA SS) were examined. We compared the age, laboratory data, proportion with Raynaud's phenomenon (RP), activity of natural killer cells (NK), titer of antibodies against Epstein-Barr virus, and histological findings of minor labial salivary glands. The presence of anti-chromo antibodies (AChA) was evaluated by immunoblotting of patients' sera. RESULTS: The mean age of the ACA SS group was higher than that of the SSA SS group (p < 0.05). Serum IgG level was lower in ACA SS than in SSA SS (p < 0.0001). Serum IgG level of the ACA SS group with one exception was close to the normal range. Leukocytopenia was less frequently observed in ACA SS than in SSA SS (p < 0.05). RP was seen more frequently in the ACA SS group than the SSA SS group (p < 0.05). NK activity of the ACA SS group was higher than that of the SSA SS group (p < 0.05). Most of the ACA SS patients' NK activity was normal, in contrast to the tendency for NK activity in SS to be low. Virus capsid antigen IgA titer of the ACA SS group was lower than that of the SSA SS group (p < 0.05). Histological findings of minor labial salivary glands of both groups showed a similar severity of lymphocytic infiltrates, destruction of normal structures, and pattern of infiltrating lymphocyte subsets. AChA was positive in 11 of the 12 sera of ACA SS patients. CONCLUSION: The results confirm that ACA positive primary SS differs from SSA positive classic SS in several significant respects.

Correlation between spontaneous apoptosis and the expression of angiogenic factors in advanced gastric adenocarcinoma.

The aim of this study was to investigate whether angiogenic factors influence the occurrence of spontaneous apoptosis in advanced gastric cancer. The apoptotic indices (AIs) of 97 tumors from 97 patients with advanced gastric cancer (pT3, pN0, pM0, Stage II) were analyzed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL) method. Intratumoral microvessel densities (IMVDs) of tumors stained with anti-CD34 monoclonal antibody were quantified under x 200 magnification using computer-assisted image analysis. The expressions of angiogenic factors, such as vascular endothelial growth factor (VEGF), thymidine phosphorylase (dThdPase), transforming growth factor-alpha (TGF-alpha), and p53 were analyzed immunohistochemically and compared with IMVDs and AIs. The mean IMVD of the 97 tumors was 365/mm2 (range 147-990/mm2). The mean AI of tumors was 2.1% (range 0-11.3%). A significant inverse correlation between the AIs and the IMVDs was shown (p = -0.278, P = 0.0064). The mean IMVDs of tumors with high expressions of dThdPase, TGF-alpha, or p53 were significantly higher than those of tumors with low expressions of these factors. The mean AI of tumors with high expressions of dThdPase was significantly lower than that of tumors with low expressions of dThdPase (P = 0.023). However, no significant correlations were detected between AIs and the expression levels of VEGF, TGF-alpha, or p53. In gastric cancer, dThdPase may play an important role in tumor progression by increasing microvessels and by suppressing apoptosis of cancer cells.

Micro-lymph node metastasis and its correlation with cathepsin D expression in early gastric cancer.

BACKGROUND AND OBJECTIVES: Limited operations for early gastric cancer (EGC) have been recommended based on data from lymph node (LN) metastasis detected by hematoxylin and eosin (HE) staining. Recently, the clinical importance of micro-LN metastasis has been reported. In this study, the indication of limited operations for EGC was re-evaluated based on the data from micro-LN metastasis detected by cytokeratin (CK) immunostaining. Also, the correlation between micro-LN metastasis and lysosomal acidic protease cathepsin D (CD) expression in primary tumors was evaluated. METHODS: A total of 5,949 LNs from 160 patients with EGC were stained by anti-CK monoclonal antibody (CAM 5.2). Also, the 160 primary EGCs were stained by CD. RESULTS: The incidence of LN metastasis increased from 7.5% (12/160) by HE-staining to 27.5% (44 of 160) by CK immunostaining. The incidence of micro-LN metastasis increased according to the depth of tumor invasion (mucosal cancer: 19% and submucosal cancer: 36.8%) and the size of tumors (< or = 1.0 cm: 5.9%, 1.1-2.0 cm: 25.6%, and > 2.1 cm: 31.7%). The CK-staining patterns were classified into the three subgroups (CK-negative, n = 116; single cell type, n = 27; and clustered type, n = 17). The occurrence of cancer recurrence was significantly higher in clustered type (17.6%) than in single cell type (3.7%) and in CK-negative (0%, P < 0.0001). The mean percentage of CD-positive cancer cells of primary tumors in clustered type (17.2%) was significantly higher than in single cell type (12.3%) and in CK-negative (7.5%, P = 0.0036). CONCLUSIONS: The acidic protease CD may play an important role of cancer metastasis in EGC. The limited operation without lymphadenectomy should be indicated for EGC with CD-negative.

IgG anti-laminin-1 autoantibody and recurrent miscarriages.

PROBLEM: The present study assesses the clinical significance of anti-laminin-1 auto-antibodies (auto-Abs) in recurrent miscarriages. METHOD OF STUDY: A total of 207 recurrent aborters with a history of two or more consecutive first-trimester miscarriages were tested for the presence of anti-laminin-1 Abs, beta2-glycoprotein I-dependent anticardiolipin Abs, lupus anticoagulants, anti-DNA Abs, and anti-nuclear Abs, before they had conceived again. Recurrent aborters then were followed up during subsequent pregnancies and their outcomes were evaluated relative to their blood test results prior to pregnancy. RESULTS: Fifty-five (31.1%) women out of 177 recurrent aborters were positive for IgG anti-laminin-1 auto-Abs. The levels of IgG anti-laminin-1 auto-Abs in recurrent aborters were significantly higher than those in healthy pregnant women and in healthy non-pregnant women (P = 0.0043 and 0.0073, respectively). The live birth rate of subsequent pregnancies in IgG anti-laminin-1 auto-Abs-positive recurrent aborters was significantly lower than the IgG anti-laminin-1 auto-Abs-negative recurrent aborters (P = 0.0320). There were no specifically significant relationships observed between IgG anti-laminin-1 auto-Abs and other tested auto-Abs. CONCLUSION: IgG anti-laminin-1 auto-Abs are associated with recurrent miscarriages and the subsequent pregnancy outcome of recurrent aborters.

Factor XII but not protein C, protein S, antithrombin III, or factor XIII is a predictor of recurrent miscarriage.

OBJECTIVE: To investigate whether a decrease in the values of protein C (PC), protein S (PS), antithrombin III (ATIII), factor XII (FXII), or factor XIII (FXIII) has predictive value for subsequent miscarriages. DESIGN: Prospective study. SETTING: Nagoya City University Medical School. PATIENT(S): A total of 536 patients with a history of two or more first-trimester miscarriages. INTERVENTION(S): One hundred and twelve patients treated with low-dose aspirin were excluded from the analysis. MAIN OUTCOME MEASURE(S): The subsequent pregnancy outcome of 424 patients was compared for abnormal and normal levels of each parameter. RESULT(S): There were no differences in the subsequent miscarriage rates between abnormal and normal values of PC, PS, ATIII, and FXIII. However, the rate with abnormal FXII is significantly higher than that with normal FXII. CONCLUSION(S): A decrease in FXII (but not in PC, PS, ATIII, or FXIII) predicts subsequent miscarriage in patients with a history of first-trimester recurrent miscarriages.

Pharmacokinetics of intraoperative intrapleural cisplatin chemotherapy of various osmolarities in cases of esophageal cancer.

Intraoperative intrapleural (i.pl.) cisplatin (CDDP) treatment during thoracotomy was performed for esophageal cancers. Three patients underwent isotonic (308 mOsm/l) CDDP treatment. Hypotonic CDDP treatments with a 154 mOsm/l solution and a 62 mOsm/l solution were administered to 4 and 9 patients, respectively. The maximum concentrations (Cmax) of both total and filterable platinum in the plasma after injection of the hypotonic solution were significantly higher than those after injection of the isotonic solution. The area under the curve of concentration versus time (AUC) of the plasma of the 62 mOsm/l solution was significantly higher than that of the 154 mOsm/l and isotonic solution. Although higher levels of the Cmax may increase side-effects, the hypotonic condition of the i.pl. fluid and increased AUC in the plasma may escalate the accumulation of platinum in i.pl. cancer cells. These results suggest that hypotonic i.pl. CDDP is tolerable and may be useful for treatment of the incipient phase of pleural carcinomatosis and for prophylaxis of postoperative recurrence.

Effect of ACE gene polymorphism on age at renal death in polycystic kidney disease in Japan.

Polycystic kidney disease (PKD) is one of the most common genetic disorders and a major cause of renal death or end-stage renal disease (ESRD) requiring regular hemodialysis. The responsible genes recently have been cloned; however, genetic factors influencing the rate of progression to ESRD in patients with PKD have yet to be defined. Several studies have shown increased activity of the renin-angiotensin system (RAS) in patients with PKD. In addition, genetic polymorphisms of the RAS have been associated with the development of cardiovascular diseases. Therefore, these polymorphisms are good candidates for disease-modifying genetic factors or markers in PKD. In two previous reports of white subjects with a cumulative survival analysis, it was suggested that patients with P:KD1 homozygous for the deletion allele of the angiotensin-converting enzyme (ACE) gene are at increased risk for early renal death. To confirm this hypothesis in Japanese subjects, 103 individuals with PKD were genotyped for several components of the RAS, ie, ACE insertion/deletion (I/D) polymorphism, angiotensinogen (AGT) M235T, and angiotensin II type 1 receptor (AT1) A1166C. Seventy-six of the 103 patients (73.8%) reached ESRD at an average age of 52.1 +/- 11.3 years. The frequencies of each genotype of the genes were similar to those expected from Hardy-Weinberg equilibrium. There was a tendency to an excess of patients homozygous for the D allele in patients with ESRD (DD in patients with ESRD, 11.8%; DD in patients without ESRD, 3.7%; chi-square, 1.505; P: = 0.22). Cumulative renal survival was significantly less in those with the DD genotype compared with ID/II genotypes. Estimated mean renal survival was 46.4 years (95% confidence interval, 39.5 to 53.3) in subjects with the DD genotype and 57.2 years (95% confidence interval, 54.2 to 60.2) in ID/II genotypes (chi-square, 7.76; P: = 0.0053). There was no association between age at onset of ESRD and either M235T or A1166C polymorphism. These findings suggest that Japanese patients with PKD homozygous for the D allele of the ACE gene are at increased risk for developing ESRD at an early age.

Clinicopathological findings in patients with gastric adenocarcinoma with familial aggregation.

BACKGROUND/AIMS: The clinicopathological characteristics of gastric cancer (GC) with a positive family history of site-specific GC have not been well discussed. The aim of this study was to estimate the risk of familial aggregation of GC in a hospital-based case-control study and to analyze the clinicopathological characteristics of GC with familial aggregation of GC. METHODS: Our series was comprised of 926 histologically confirmed patients with GC (588 males and 338 females) and 2,052 non-cancer outpatients between 1985 and 1996. The odds ratios (ORs), as estimators of relative risks, together with the corresponding 95% confidence intervals (CIs) for a family history of GC and for a family history of other cancers were calculated. Moreover, the clinicopathological findings of patients with GC who had a GC family history were compared with those of patients with GC who had no GC family history. RESULTS: A positive family history of GC was associated with a statistically significant increase in the risk of GC (OR = 2.15; 95% CI = 1.77-2.63), while no association was observed between the risk of GC and a family history of other cancers (OR = 1.11; 95% CI = 0.91-1.36). The incidence of a multifocal occurrence of GCs was higher in patients with a family history of GC (19.4%) than in patients without a family history of GC (12%, p = 0.005). The risk (OR) of occurrence of multiple cancers in the stomach in patients who had a family history of GC was 1.77 (95% CI = 1.19-2.64). CONCLUSIONS: Our results suggest that a family history of GC seemed to be a risk factor for the development of GC. Further, a family history of GC was found to be associated with a multifocal occurrence of GC.

Adverse influence of numbers of previous miscarriages on results of paternal lymphocyte immunization in patients with recurrent spontaneous abortions.

PROBLEM: To determine whether an increase in the number of previous miscarriages in recurrent spontaneous abortion patients is a risk factor in subsequent pregnancies with paternal lymphocyte immunotherapy. METHOD OF STUDY: Live birth rates with reference to previous abortion numbers in recurrent spontaneous abortion patients were statistically compared between paternal lymphocyte immunotherapy and control groups, the latter retrospectively researched using historical data before 1981 in our clinic. RESULTS: The overall live birth rate was 73% (169/232) in the immunotherapy group, and 48% (47/97) in controls (P <0.05). According to previous abortion numbers, the rates were 77% (114/148) versus 55% (36/65) (P < 0.05) for three previous abortions, 70% (40/57) versus 38% (8/21) (P < 0.05) for four and 56% (15/27) versus 27% (3/11) (not significant) for five, in the study and control groups, respectively. CONCLUSIONS: The results confirm the efficacy of paternal lymphocyte immunotherapy, but demonstrate that the success rate deteriorates with the number of previous miscarriages.

Psychosocial factors regulating natural-killer cell activity in recurrent spontaneous abortions.

PROBLEM: The preconceptional natural-killer cell (NK) activity predicts subsequent miscarriage among women with unexplained recurrent spontaneous abortion (RSA). Psycho-neuro-immuno-endocrine network has recently been proposed as a mechanism for abortions. We therefore examined which psychosocial factors influenced the NK activity among women with RSA. METHOD OF STUDY: We measured the preconceptional NK activity of 61 women with a history two consecutive unexplained first-trimester miscarriages and no live births. We also administered semi-structured interviews and a battery of self-report questionnaires to assess their social support, personality, self-esteem and psychiatric symptoms. RESULTS: The preconceptional NK activity was negatively correlated with the women's neuroticism personality trait (r= -0.32, P = 0.01) and current depressive symptoms (r = -0.26, P= 0.05), and positively correlated with their self-esteem (r = 0.34, P = 0.01). CONCLUSIONS: In addition to several substances such as transforming-growth-factor beta and granulocyte-macrophase colony-stimulating factor, we found that low neuroticism, low depression scale score and high self-esteem contributed to high NK activity among women with RSA.

Pharmacokinetics of hypotonic cisplatin chemotherapy administered into the peritoneal and the pleural cavities in experimental model.

The pharmacokinetics of intraperitoneal (i.p.) and intrapleural (i.pl.) hypotonic cisplatin (CDDP) were compared under the same experimental conditions. The same dose of CDDP was administered in hypotonic (62 mOsm/L) and isotonic (308 mOsm/L) solutions to the peritoneal and pleural cavities of Ehrlich carcinoma cell bearing mice. The intracellular amount of platinum increased for more than 60 minutes after an i.pl. injection of the hypotonic solution of CDDP, whereas it increased for up to 30 minutes after an i.p. injection. Although hypotonic conditions augmented the amount of platinum taken-up by Ehrlich cells, the amount was significantly greater in the pleural cavity than in the peritoneal cavity. In Donryu rats, the levels of platinum in the i.p. and i.pl. fluids decreased rapidly after injection of hypotonic solution as compared with isotonic solution. The extent of this decrease was greater in the peritoneal cavity than in the pleural cavity. In the hypotonic condition, the area under the curve of concentration versus time (AUC) for platinum of i.pl. fluid was greater than that of i.p. fluid. When i.p. and i.pl. hypotonic CDDP were administered, the osmolarity of the fluid returned rapidly to the isotonic level, with equilibration in 30 or 180 minutes respectively. The lower osmolarity continued for a longer duration in the pleural cavity than in the peritoneal cavity. These results indicate that the pleural cavity may require a smaller amount of CDDP to achieve the same effect on intracellular uptake of platinum than the peritoneal cavity.

Elevation of transforming growth factor-beta1 is associated with recurrent miscarriage.

To investigate the significance of transforming growth factor-beta1 (TGF-beta1) in reproduction we have compared plasma levels in normal pregnant women and patients suffering miscarriages. We examined 188 normal pregnant women and 12 pregnant women with miscarriages. Eight women with severe recurrent miscarriages (mean +/- SD of previous number of miscarriages; 10.4 +/- 2.4 times) were also examined before conception; 34 nonpregnant women served as controls. Plasma TGF-beta1 level increased with the gestational week and returned within the normal range 1 month after delivery. The levels among pregnant women with miscarriages (mean +/- SD; 2.44 +/- 0.83 ng/ml) were significantly higher than those of pregnant controls (1.74 +/- 0.95 ng/ml) of matched gestational weeks; levels among nonpregnant women with severe recurrent miscarriages were extremely elevated (4.1 +/- 3.04 ng/ml) compared to the control value (1.34 +/- 0.59 ng/ml). These data suggest that TGF-beta1 may be necessary to maintain pregnancy but also may be a risk factor for recurrent miscarriages.