The exploration of Hashimoto's Thyroiditis related miscarriage for better treatment modalities.

Hashimoto's thyroiditis (HT) is the most prevalent autoimmune thyroid disease (ATD) worldwide and is strongly associated with miscarriage and even recurrent miscarriage (RM). Moreover, with a deepening understanding, emerging evidence has shown that immune dysfunctions caused by HT conditions, including imbalanced subsets of CD4+ T-helper cells, B regulatory (Breg) cells, high expression levels of CD56dim natural killer (NK) cells, and cytokines, possibly play an important role in impairing maternal tolerance to the fetus. In recent years, unprecedented progress has been made in recognizing the specific changes in immune cells and molecules in patients with HT, which will be helpful in exploring the mechanism of HT-related miscarriage. Based on these findings, research investigating some potentially more effective treatments, such as selenium (Se), vitamin D3, and intravenous immunoglobulin (IVIG), has been well developed over the past few years. In this review, we highlight some of the latest advances in the possible immunological pathogenesis of HT-related miscarriage and focus on the efficacies of treatments that have been widely introduced to clinical trials or practice described in the most recent literature.

Moderately elevated first trimester fasting plasma total homocysteine is associated with increased probability of miscarriage. The Reus-Tarragona Birth Cohort Study.

The association between elevated early pregnancy fasting plasma total homocysteine (tHcy) and miscarriage risk was investigated prospectively in participants (n = 544) from the Reus-Tarragona Birth Cohort study. Pregnancy was confirmed before 12 gestational weeks (GW) by ultrasound scan and a fasting blood sample collected. Pregnancies with complications other than miscarriages were excluded. Miscarriages were diagnosed by ultrasound scan and gestational age at the time of miscarriage estimated by embryo size, where possible. Cases in which blood samples were collected more than a week after the miscarriage, or the miscarriage was of known cause, were excluded. Fasting plasma folate, vitamin B12, tHcy, cotinine (biomarker of smoking), red blood cell (RBC) folate, MTHFR 677C > T (rs1801133) and SLC19A1 80G>A (rs1051266) genotypes were determined. The exposed group consisted of participants with first trimester tHcy ≥ P90 (7.1 µmol/L) (n = 57) and unexposed of those with tHcy < P90 (n = 487). Adherence to folic acid supplement recommendations, plasma folate, plasma vitamin B12, RBC folate and prevalence of optimal RBC folate status (≥ 906 µmol/L) were lower in the exposed compared to unexposed group. The prevalences of the MTHFR 677 TT genotype and miscarriage were higher in the exposed group. The relative risks (95% CI) of pregnancy ending in miscarriage were 2.5 (1.1, 5.7) and 2.1 (1.0, 4.5) for participants in the high tHcy and suboptimal RBC folate groups (compared to the reference groups) respectively. Adherence to folic acid supplement recommendations was positively associated, while the MTHFR 677 TT versus CC genotype and smoking versus non-smoking were negatively associated, with RBC folate status.

Prophylactic Effects of Bee Venom Phospholipase A2 in Lipopolysaccharide-Induced Pregnancy Loss.

Spontaneous abortion represents a common form of embryonic loss caused by early pregnancy failure. In the present study, we investigated the prophylactic effects of bee venom phospholipase A2 (bvPLA2), a regulatory T cell (Treg) inducer, on a lipopolysaccharide (LPS)-induced abortion mouse model. Fetal loss, including viable implants, the fetal resorption rate, and the fetal weight, were measured after LPS and bvPLA2 treatment. The levels of serum and tissue inflammatory cytokines were determined. To investigate the involvement of the Treg population in bvPLA2-mediated protection against fetal loss, the effect of Treg depletion was evaluated following bvPLA2 and LPS treatment. The results clearly revealed that bvPLA2 can prevent fetal loss accompanied by growth restriction in the remaining viable fetus. When the LPS-induced abortion mice were treated with bvPLA2, Treg cells were significantly increased compared with those in the non-pregnant, PBS, and LPS groups. After LPS injection, the levels of proinflammatory cytokines were markedly increased compared with those in the PBS mouse group, while bvPLA2 treatment showed significantly decreased TNF-α and IFN-γ expression compared with that in the LPS group. The protective effects of bvPLA2 treatment were not detected in Treg-depleted abortion-prone mice. These findings suggest that bvPLA2 has protective effects in the LPS-induced abortion mouse model by regulating Treg populations.

Content of fatty acids in a diet and the homocysteine levels in women with fertility disorders.

OBJECTIVES: Assessment of the effects of consumption of fatty acids on the homocysteine levels in women with fertility disorders. METHODS AND RESULTS: The study included 286 women at the age between 23 and 46 years (the mean 33.13±4.21 years) with a fertility disorders. We measured: levels of homocysteine [µmol/L] (n=171), body weight and height (n=286). Body mass index (BMI) was calculated. A diet was assessed by 3-day dietary food records method including one day of the weekend. The mean homocysteine (Hcy) levels were 10.02±2.98 µmol/L. Body weight excess was observed in 29.3% of subjects. The percentage of fatty acids in the total energy [%E] it was demonstrated that the mean rate of MUFAs and PUFAs was statistically significantly lower in diets of women with the homocysteine levels >15 µmol/L compared to the group with the Hcy <10 µmol/L. Based on the results of a correlation between the homocysteine levels and consumption of n-6 fatty acids and n-3 fatty acids it is possible to conclude that there are negative correlations observed indicating that higher consumption of these acids is associated with lower levels of homocysteine. CONCLUSION: Increased consumption of PUFAs, including α-linoleic acid, in a diet seems to be an important factor preventing from hyperhomocysteinemia.

Antioxidant status in women who have had a miscarriage.

PURPOSE: During normal pregnancy there is an oxido-reductive balance between action of pro-oxidative factors. The aim of this study was to evaluate the total antioxidant status (TAS) and glutathione peroxidase (GSH-Px) activity, and the content of selenium (Se), zinc (Zn), copper (Cu) and manganese (Mn) in women who have had a miscarriage. PATIENTS AND METHODS: The study group consisted of 83 women who had had miscarriages. The control group included 35 women in the first trimester of pregnancy, and 35 pregnant women after childbirth. RESULTS: TAS activity and Cu concentration in serum in women who experienced a miscarriage were significantly lower, but Mn level - higher, than in women in the first trimester of pregnancy. The content of Se, Cu and Mn in placental tissue in patients who have had a miscarriage was significantly higher, while Zn content was lower than in pregnant women at full-term delivery. CONCLUSIONS: Our findings, provided in the research, enable us to claim that the total antioxidative status is significantly lower in women who have had a miscarriage. Low level of Zn but high of Mn in the examined biological material may be indicative to the incidence of miscarriage.

Vitamin D insufficiency is associated with increased risk of first-trimester miscarriage in the Odense Child Cohort.

BACKGROUND: Miscarriage is the most common negative outcome of pregnancy, and identification of modifiable risk factors is potentially of great importance for public health. Low vitamin D concentrations in pregnancy are widespread worldwide, and vitamin D deficiency is implicated in immune cell regulation at the feto-maternal interface and several diseases of pregnancy. OBJECTIVE: We investigated whether 25-hydroxyvitamin D serum concentration was a modifiable risk factor for early miscarriage. DESIGN: In a prospective cohort study of 1683 pregnant women donating serum before gestational week 22, we investigated the association between maternal serum concentrations of serum 25-hydroxyvitamin D [25(OH)D] and the risk of subsequent miscarriage (n = 58). RESULTS: The adjusted hazard of first-trimester miscarriage was lower with higher 25(OH)D concentrations (HR: 0.98; 95% CI: 0.96, 0.99). Concentrations of 25(OH)D <50 nmol/L were associated with a >2-fold increased adjusted HR for miscarriage (HR: 2.50; 95% CI: 1.10, 5.69). Concentrations of 25(OH)D were not associated with an increased risk of second-trimester miscarriage. CONCLUSIONS: We found an association between 25(OH)D and first-trimester miscarriages, suggesting vitamin D as a modifiable risk factor for miscarriage. To test this hypothesis, randomized controlled trials should investigate the possible effect of vitamin D supplementation to increase 25(OH)D concentrations in early pregnancy, or before conception, to decrease risk of miscarriage. This trial was registered at clinicaltrials.gov as NCT02434900.

First-trimester plasma tocopherols are associated with risk of miscarriage in rural Bangladesh.

BACKGROUND: Tocopherols were discovered for their role in animal reproduction, but little is known about the contribution of deficiencies of vitamin E to human pregnancy loss. OBJECTIVE: We sought to determine whether higher first-trimester concentrations of α-tocopherol and γ-tocopherol were associated with reduced odds of miscarriage (pregnancy losses <24 wk of gestation) in women in rural Bangladesh. DESIGN: A case-cohort study in 1605 pregnant Bangladeshi women [median (IQR) gestational age: 10 wk (8-13 wk)] who participated in a placebo-controlled vitamin A- or ß-carotene-supplementation trial was done to assess ORs of miscarriage in women with low α-tocopherol (<12.0 µmol/L) and γ-tocopherol (<0.81 µmol/L; upper tertile cutoff of the γ-tocopherol distribution in women who did not miscarry). RESULTS: In all women, plasma α- and γ-tocopherol concentrations were low [median (IQR): 10.04 µmol/L (8.07-12.35 µmol/L) and 0.66 µmol/L (0.50-0.95 µmol/L), respectively]. In a logistic regression analysis that was adjusted for cholesterol and the other tocopherol, low α-tocopherol was associated with an OR of 1.83 (95% CI: 1.04, 3.20), whereas a low γ-tocopherol concentration was associated with an OR of 0.62 (95% CI: 0.41, 0.93) for miscarriage. Subgroup analyses revealed that opposing ORs were evident only in women with BMI (in kg/m(2)) ≥18.5 and serum ferritin concentration ≤150 µg/L, although low BMI and elevated ferritin conferred stronger risk of miscarriage. CONCLUSIONS: In pregnant women in rural Bangladesh, low plasma α-tocopherol was associated with increased risk of miscarriage, and low γ-tocopherol was associated with decreased risk of miscarriage. Maternal vitamin E status in the first trimester may influence risk of early pregnancy loss. The JiVitA-1 study, from which data for this report were derived, was registered at clinicaltrials.gov as NCT00198822.

Reduced serum selenium concentration in miscarriage incidence of Indonesian subjects.

Selenium is an essential nutrient for human health, and maternal selenium concentration has been reported to be associated with pregnancy outcome. To further investigate the possible role of selenium (Se) in miscarriage, we conducted a case-control study to evaluate the correlations among selenium status, glutathione peroxidase activity, and spontaneous abortion. A total of 46 subjects with normal pregnancies and 25 subjects with spontaneous abortion were recruited, and their serum selenium concentrations and serum glutathione peroxidase activities were analyzed. The total serum selenium concentrations in subjects with normal pregnancies were significantly higher than those of subjects with spontaneous abortion; however, the glutathione peroxidase activities were similar in both groups. We further separated the subjects into smoking and nonsmoking groups, and the logistic regression analysis suggested that total serum selenium concentration, but not serum glutathione peroxidase activity or smoking, was significantly correlated with the incidence of miscarriage. The present study thus reaffirms that low serum selenium levels are associated with miscarriage and that selenium plays an important role in pregnancy maintenance.

[Kidney-tonifying and abortion preventing effects of Shou Tai Wan by different extration methods on rats].

OBJECTIVE: To explore the Kidney-tonifying and abortion preventing effect of Shou Tai Wan (STW) by different extration methods on the SD Rats' abortion model. METHODS: Applied hydroxycarbamide and mifepristone (RU-486) to establish the abortion model of corpus luteum inhibition due to Kidney deficiency (disease-syndorme combination model) on SD, rats. Treated the model rats with STW formula. Observed the uterus condition and recorded the embryo number and the miscarriage rate of each rat. 4 kinds of extractions including water extract of STW (A liquid), alcohol extract of STW (B liquid), after the ethanol water extract residue of STW (C liquid) and B + C liquid. Visual observed the uterine lesions embryos and calculated obortion rate. Used chemluninescence methed to cheek the serum estradiol (E2) and progesterone (P) level. Used quantitative RT-PCR (qRT-PCR) to analyze the different of the PR mRNR between the model group and the treated group. RESULTS: Compared with the model group, the abortion rate of B + C liquid was greatly deduced and the embryo number of B + C liquid group, the E2 and P levels were obviously increased in the treated groups. CONCLUSION: STW (B + C) has the best effect of tonifying the kidney and preventing abortion.

[Study on the correlation of serum folate and red blood cell folate level with birth defects and unexplained recurrent pregnancy loss].

OBJECTIVE: To understand the correlation of lower serum folate, and red blood cell (RBC) folate level with birth defects including unexplained recurrent pregnancy loss, and to evaluate the role of RBC folate level as a suitable marker for folate supplement. METHODS: Two hundred and ninety-nine non-pregnant women at child-bearing age with a birth defect history were selected as birth defect group. The levels of serum and RBC folate, and serum vitamin B(12) were determined. By comparing with the group of non-pregnant women at child-bearing age without any birth defect history (control group), we evaluated the correlation between lower serum folate, RBC folate level and main kinds of birth defects including unexplained recurrent pregnancy loss. And the levels of serum and RBC folate of birth defect group were also determined and compared before and after oral folate intake (5 mg/d) for one month. RESULTS: The serum folate level of birth defect group was not different from the control group (17 - 26 vs 14 nmol/L, P > 0.05). The RBC folate level of birth defect group except the urinary defect was significantly lower compared with the control group (233 - 547 vs 689 nmol/L, P < 0.05). After the oral folate intake (5 mg/d), the serum folate level of unexplained recurrent pregnancy loss group and neural tube defects group were significantly increased than before [(22 +/- 9) vs (27 +/- 12) nmol/L, (19 +/- 10) vs (25 +/- 18) nmol/L; P < 0.05]. The RBC folate level of unexplained recurrent pregnancy loss group and congenital heart defect group were significantly increased than before [(374 +/- 275) vs (567 +/- 397) nmol/L, (322 +/- 205) vs (527 +/- 351) nmol/L, P < 0.05]. CONCLUSION: RBC folate level is more closely correlated than serum folate level with the incidence of main birth defect.

[Glucooxidative stress and spontaneous abortion in pregnant women with diabetes mellitus type 1].

UNLABELLED: The pregnancies in women with Diabetes mellitus are in condition of increased glucooxidative stress, which could be toxic for the developing embryo. END-POINTS: To evaluate the levels of selenium and glutation peroxidase in pregnant women with Diabetes mellitus type 1 in the first trimester of pregnancy and to establish whether there is a correlation between the diabetic glycemic control and occurrence of spontaneous abortions. STUDY DESIGN: Prospective study of 75 women for 1 year period. he pregnant women were divided in 3 groups as follows: 1st group--30 pregnant women with Diabetes mellitus type 1 with normal outcome; 2nd group--16 pregnant women with Diabetes mellitus type 1 with spontaneous abortion; 3rd group--29 healthy pregnant controls. The activity of GI-Px in red blood cells was measured in hemolysat of EDTA plasma in Germany. The levels of glucosylated haemoglobin were also evaluated. RESULTS: 1. In all pregnant women the levels of selenium were lower without significant difference between them 1st group--0.12 +/- 0.6 mmol/l, 2ndd group 0.13 +/- 0.1 mmol/l, 3rd group 0.13 +/- 0.7 mmol/l (P > 0.05). 2. There is an increase in the activity of GI-Px, which is statistically significant in the healthy pregnant women 47.8 +/- 13.3 U/g Hb and diabetic pregnant women with normal outcome 48. 6 +/- 8.4 U/g Hb. There is no statistically significant difference in the activity of GI-Px in diabetic pregnant women with spontaneous abortions and the healthy controls (P > 0. 05). 3. Negative correlation between the levels of selenium and the activity of GI-Px was proved in healthy pregnant women (r = - 0.4; P < 0.05). No correlation was found between the level of the selenium and the activity of GI-Px into the two groups of diabetic pregnant women. 4. There is a correlation in the levels of diabetic pregnant women with spontaneous abortions (r = -0.38; P < 0.001). CONCLUSIONS: The increased activity of GI-Px in diabetic pregnant women with spontaneous abortions is a result of increased antioxidative defense of the cell. Probably the ineffective antioxidant defense, leading to a spontaneous abortion is due to the low levels of selenium and high level of pre-prandial glycaemia.

Plasma folate levels and risk of spontaneous abortion.

CONTEXT: Both folate deficiency and folic acid supplements have been reported to increase the risk of spontaneous abortion. The results are inconclusive, however, and measurements of folate have not been available in all studies. OBJECTIVE: To study the association between plasma folate levels and the risk of spontaneous abortion. DESIGN, SETTING, AND POPULATION: Population-based, matched, case-control study of case women with spontaneous abortion and control women from January 1996 through December 1998 in Uppsala County, Sweden. Plasma folate measurements were available for 468 cases and 921 controls at 6 to 12 gestational weeks. MAIN OUTCOME MEASURE: Risk of spontaneous abortion vs maternal plasma folate level. RESULTS: Compared with women with plasma folate levels between 2.20 and 3.95 ng/mL (5.0 and 8.9 nmol/L), women with low (< or =2.19 ng/mL [< or =4.9 nmol/L]) folate levels were at increased risk of spontaneous abortion (adjusted odds ratio [OR], 1.47; 95% confidence interval [CI], 1.01-2.14), whereas women with higher folate levels (3.96-6.16 ng/mL [9.0-13.9 nmol/L] and > or =6.17 ng/mL [> or =14.0 nmol/L]) showed no increased risk of spontaneous abortion (OR, 0.84; 95% CI, 0.59-1.20; and OR, 0.74; 95% CI, 0.47-1.16, respectively). Low folate levels were associated with a significantly increased risk when the fetal karyotype was abnormal (OR, 1.95; 95% CI, 1.09-3.48) but not when the fetal karyotype was normal (OR, 1.11; 95% CI, 0.55-2.24) or unknown (OR, 1.45; 95% CI, 0.90-2.33). CONCLUSION: Low plasma folate levels were associated with an increased risk of early spontaneous abortion.

Blood selenium and glutathione peroxidases in miscarriage.

OBJECTIVE: To investigate the selenium glutathione and glutathione peroxidase (glutathione-Px) levels in blood in women who experience miscarriage. DESIGN: An observational study. PARTICIPANTS: Forty women with miscarriage occurring in the first and second trimesters. METHODS: Concentrations were measured in whole blood and plasma. Glutathione was measured in red cells and glutathione-Px activity was measured in the red cells and plasma. The results were compared with 36 women in the same period of viable pregnancy and 28 age-matched, healthy, non-pregnant controls. RESULTS: The selenium concentrations in whole blood and plasma of women following abortion were the same as in viable pregnancy, but were significantly lower compared with controls. The glutathione levels were significantly higher in women with miscarriage compared with viable pregnancies and with non-pregnant women. Red cell and plasma glutathione-Px activities of women who had had a miscarriage were significantly lower than in both normal pregnancies and the control group. CONCLUSION: The decreased activities of the antioxidant enzymes, red cell and plasma glutathione-Px, may play an important role in the aetrology of spontaneous abortion.

Serum zinc and copper concentrations in relation to spontaneous abortion in cows: implications for human fetal loss.

The purpose of this study was to investigate the effect of the status of dietary zinc and serum zinc and copper concentrations on the risk of fetal loss in 570 cows. three herds received no supplements (herds 1, 3, 4), while cows in herd 2 received supplements of either 7 g zinc week-1 (n = 118), as zinc methionine, or a control diet containing methionine (n = 128). Serum zinc, copper and metallothionein concentrations were determined once a month throughout gestation. Logistic regression and survival analysis were used to examine for associations between risk of fetal loss and serum zinc, copper, copper:zinc, or metallothionein concentrations, supplement level, and maternal age at conception. The risk of fetal loss increased when both serum zinc decreased and copper concentrations increased (P < 0.0001; relative risk = 10.28, 95% confidence intervals = 4.69, 22.5). The attributable risk, for a decline in the zinc concentration by 10 mumol l-1 and an increase in the copper concentration by 5 mumol l-1 was 90.27%. Methionine-supplemented cows had a higher risk of fetal loss compared with zinc-methionine-supplemented cows (one-tailed P = 0.0375; relative risk = 2.98). Cows in herds 1, 3 and 4 had a higher risk for abortion than did zinc-methionine-supplemented cows in herd 2 (relative risk = 26.27, 95% confidence intervals = 2.31, 299.38; relative risk = 40.87, 95% confidence intervals = 3.50, 458.43; relative risk = 41.53, 95% confidence intervals = 3.77, 457.02, respectively). Our results suggest that inflammation and zinc nutriture may play an important role in fetal loss in dairy cows.

Rat embryo development on human sera is related to numbers of previous spontaneous abortions and nutritional factors.

OBJECTIVES: The objectives were to determine (1) if sera from women with histories of spontaneous abortions were teratogenic to cultured embryos more often than were sera of nonaborters, (2) if the teratogenicity could be corrected by adding nutrients to the sera, and (3) if these findings were relevant to reproductive outcomes. STUDY DESIGN: Rat embryos were cultured for 48 hours on sera from 102 subjects who had experienced spontaneous abortions. Samples from 48 were retested with nutrients added and 10 took dietary supplements, were again tested with embryo cultures, and reported on their pregnancy outcomes. RESULTS: The frequencies of teratogenic sera increased with numbers of spontaneous abortions (0 to > or = 5) in a manner that did not deviate from linearity (27% to 89%) (chi 2 p > 0.957). Nutrient supplements were added to 48 samples, and 40 were corrected and 10 subjects were given dietary supplement. Sera from six showed improved embryo cultures, and these women completed their pregnancies. CONCLUSIONS: Rat embryo cultures may provide unique insights into the causes and treatment of spontaneous abortions.

[Treatment of ABO blood type incompatibility caused early abortion with traditional Chinese medicine].

This results of 30 cases with the history of abortion due to ABO blood type incompatibility treated with traditional Chinese medicine (TCM) were reported. The titer of serum IgG anti A/B antibody were determined in these patients. Antibody titer < or = 1:128 before pregnancy or < or = 1:64 after pregnancy were treated with TCM till delivery. 25 cases gave birth at full term, 5 cases were before term. Abortion, stillbirth or hemolytic newborn death were not found. The lower the maternal serum IgG anti A/B titer, the lower the incidence of hemolytic jaundice; while the earlier the treatment after pregnancy, the lower the occurrence of hemolytic jaundice also.

A correlation of the outcome of clinical in vitro fertilization with the inositol content and embryotrophic properties of human serum.

PURPOSE: This study was designed to investigate whether the level of myo-inositol (MI) in human serum is critical for embryotrophic activity. METHODS: The embryotrophic properties of human serum were evaluated by the development of postimplantation mouse embryos [in vitro assay of Tam et al. (Fertil Steril 48:834-839, 1987)]. An enzymatic spectrophotometric method using myo-inositol dehydrogenase was used for determination of serum MI. The level of MI detected in serum was compared with the embryotrophic properties and the pregnancy outcome. The effect of MI on the embryotrophic activity of human serum was studied by supplementing the suboptimal serum samples that were unsupportive of embryo growth with extra MI. RESULTS: Serum obtained from patients having successful IVF pregnancies generally supported better development of postimplantation mouse embryos and contained higher levels of inositol, particularly if the serum sample was collected during the IVF treatment cycle. Serum samples obtained from patients with aborted pregnancies, though supporting mouse embryo development, contained significantly lower concentrations of inositol. An improvement of the embryotrophic properties with exogenous inositol supplement was achieved in some but not all of the suboptimal serum samples studied. CONCLUSIONS: It is possible that other factors in addition to inositol are crucial in promoting better embryonic development.

[Study on the hypothalamic dopaminergic activity in different stages of pregnancy and non-pregnancy].

The purpose of this study was to investigate hypothalamic dopaminergic activity in pregnant women after the administration of metoclopramide (MCP), a dopamine receptor blocker, and to investigate the effects of MCP on the placental steroid and peptide hormones, and to clarify the prolactin (PRL) releasing mechanism in the hypothalamo-pituitary axis during pregnancy using dopaminergic agents and TRH. The following results were obtained. The plasma PRL levels following intravenous MCP remained significantly elevated for 180 minutes (p less than 0.001-0.05) in all groups as compared to the control group, but there were no significant differences between early and late pregnant groups, and between pregnant and nonpregnant groups. Therefore, the dopaminergic activity of the hypothalamus remained unchanged during pregnancy as well as in the nonpregnant state. The administration of MCP or a sudden increase in plasma PRL had no effect on the maternal plasma estradiol-17 beta, progesterone, HCG or HPL during pregnancy. PRL release from the pituitary by MCP was suppressed significantly (p less than 0.01) by pretreatment with bromocriptine. PRL releasing activity of MCP 10mg was significantly higher (p less than 0.01-0.05) than that of TRH 500 micrograms in the pregnant women.