Antiphospholipid antibodies increase the risk of pregnancy-induced hypertension and adverse pregnancy outcomes.

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.

Failure of thromboprophylaxis in pregnancy caused by dual deficiencies of protein S and protein C.

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.

MTHFR C677T Polymorphism and factor V Leiden mutation are not associated with recurrent spontaneous abortion of unexplained etiology in Japanese women.

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.

Caffeine intake, CYP1A2 polymorphism and the risk of recurrent pregnancy loss.

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.

Magnetic resonance image findings of placental lake: report of two cases.

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.

Embryo loss pattern is predominant in miscarriages with normal chromosome karyotype among women with repeated miscarriage.

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.

Circulating cytokines during early pregnancy in women with recurrent spontaneous abortion: decreased TNF-alpha levels in abortion with normal chromosome karyotype.

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.

Decrease in a specific killer cell immunoglobulin-like receptor on peripheral natural killer cells in women with recurrent spontaneous abortion of unexplained etiology.

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.

A polymorphism in the CYP17 gene and intrauterine fetal growth restriction.

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.

No difference in natural-killer-T cell population, but Th2/Tc2 predominance in peripheral blood of recurrent aborters.

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.

Pre-conceptional natural killer cell activity and percentage as predictors of biochemical pregnancy and spontaneous abortion with normal chromosome karyotype.

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.

Live birth rate varies with gestational history and etiology in women experiencing recurrent spontaneous abortion.

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.

Intravenous immunoglobulin treatment in women with recurrent abortions: increased cytokine levels and reduced Th1/Th2 lymphocyte ratio in peripheral blood.

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.

Decreased serum levels of macrophage migration inhibition factor in miscarriages with normal chromosome karyotype.

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.

Anticardiolipin beta2-glycoprotein I antibody: is a high titer related to unfavorable pregnancy outcome?

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.

Thromboprophylaxis with low molecular weight heparin in thrombophilia-complicated pregnancy.

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.

Maternal serum and amniotic fluid bisphenol A concentrations in the early second trimester.

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.