Nobuaki Mitsuda

Effects of Autoantibodies on the Course of Pregnancy and Fetal Growth

Objective To assess the effects of autoantibodies on the course of pregnancy and fetal growth. Methods One thousand one hundred seventy-nine healthy women with singleton gestations were screened in early pregnancy for seven kinds of autoantibodies: antithyroid microsomal antibody, antithyroglobulin antibody, two kinds of rheumatoid factor, antinuclear antibody, anti-DNA antibody, and antimitochondrial antibody. Results In 228 cases (19.3%), at least one autoantibody was found; however, overlap of autoantibodies in the same individual was unexpectedly rare, and only two cases were positive for as many as four autoantibodies. A significantly higher rate of spontaneous abortion was observed in antibody-positive subjects, especially those with antithyroid microsomal (10.4%) or antinuclear antibodies (16.0%), compared with all antibody-negative subjects (5.5%). There were no significant differences in any outcome assessed among subjects positive for antithyroglobulin antibody, anti-DNA antibody, or antimitochondrial antibody compared with all antibody-negative subjects. None of the seven autoantibodies affected the rates of preterm delivery, stillbirth, pregnancy-induced hypertension, malformation, or gender ratio. Conclusion Antithyroid microsomal antibody and antinuclear antibody are the only autoantibodies that increase the abortion rate.

Gestational thyrotoxicosis and hyperemesis gravidarum: possible role of hCG with higher stimulating activity

OBJECTIVE The thyroid gland is physiologically stimulated in normal early pregnancy. However, clinical thyrotoxicosis in normal pregnancy has not been well described. In order to clarify this we examined thyroid function and thyrotoxic symptoms in relation to emesis in normal pregnancy. We also investigated the possible mechanism of gestational thyrotoxicosis.

Prediction of post-partum Graves' thyrotoxicosis by measurement of thyroid stimulating antibody in early pregnancy.

OBJECTIVE Autoimmune thyroid diseases often occur after delivery. However, it has been difficult to predict who will develop Graves thyrotoxicosis after delivery. We tried to establish a systematic method for predicting postpartum onset of Graves thyrotoxicosis. DESIGN We followed up the pregnant women with antithyroid microsomal antibody (MCAb) from early pregnancy to the post‐partum period and analysed the relation between the activities of thyroid stimulating antibodies (TSAb) in early pregnancy and post‐partum occurrence of Graves disease.

Prediction of later development of thyrotoxicosis or central hypothyroidism from the cord serum thyroid-stimulating hormone level in neonates born to mothers with Graves disease**

Letude systematique de la TSH dans le sang du cordon par un dosage radio-immunologique tres sensible est precieuse pour predire une hyperthyroidie ou une hypothyroidie centrale chez les nouveau-nes de meres atteintes de maladie de Basedow

INCREASE IN PERIPHERAL NATURAL KILLER CELL ACTIVITY IN PATIENTS WITH AUTOIMMUNE THYROID DISEASE

Changes in the activity and number of natural killer (NK) cells in peripheral blood in patients with autoimmune thyroid disease were examined. NK activity was measured in a 4-hr 51Cr-release assay and the number of NK cells was analyzed with FITC-conjugated monoclonal antibodies by use of an automated flow cytometer. NK activity in patients with untreated Graves disease (n = 25, 39.7 +/- 13.5%, P less than 0.05) and Hashimotos thyroiditis (n = 18, 41.0 +/- 14.2%, P less than 0.05) was high compared to the activity in non-pregnant controls (n = 61, 32.6 +/- 15.0%). NK activity in patients with postpartum Graves thyrotoxicosis (n = 11, 48.6 +/- 18.9%) was markedly increased compared to the activity in non-pregnant controls (P less than 0.01) and in postpartum controls (n = 29, 33.8 +/- 15.2%, P less than 0.05), although the mean ages of each group did not differ significantly. Moreover, NK activities in the thyrotoxic state were significantly higher than those in the euthyroid state in the same patients with postpartum Graves thyrotoxicosis or with postpartum destructive thyrotoxicosis. The number of CD16 positive cells increased in patients with postpartum Graves thyrotoxicosis. However the number of CD16 and CD57 positive cells were normal in all other groups of patients. These results indicate that an increase of NK activity is associated with exacerbation of autoimmune thyroid disease both in Hashimotos thyroiditis and in Graves disease and suggest that NK cells might have an important role for the control of disease activity in autoimmune thyroid disease.

Changes in natural killer cell activity in normal pregnant and postpartum women: increases in the first trimester and postpartum period and decrease in late pregnancy

Changes in the activity and number of natural killer (NK) cells in peripheral blood in normal pregnant and postpartum women were examined. NK activity was measured in a 4-h 51Cr-release assay and evaluated by conventional relative lytic units and absolute lytic units which represent the total NK activity within a fixed volume of circulating blood. The number of NK cells was analyzed with FITC-conjugated monoclonal antibodies and by use of an automated flow cytometer. Unexpectedly, the relative NK activity increased in the first trimester and also for 1 month postpartum compared to the activity in normal non-pregnant controls. On the other hand, absolute NK activity decreased in the third trimester compared to the activity in normal non-pregnant controls. The percentage of CD57+ cells decreased in the second trimester, but the percentage of CD16+ cells did not change during pregnancy or the postpartum period. The absolute counts of CD57+ cells and CD16+ cells decreased in the second and third trimesters and increased transiently in the postpartum period. These findings indicate that the increased NK activity in the first trimester and at 1 month postpartum is induced by increased cytotoxic activity of individual NK cells, and that the decreased NK activity in late pregnancy is induced by a decrease in the numbers of NK cells. These physiological changes may play an important role in implantation in early pregnancy, protection of the fetal allograft in late pregnancy and in the natural defense against infection during the puerperal period.

Evaluation of TSH receptor antibody by 'natural in vivo human assay' in neonates born to mothers with Graves' disease.

Neonatal thyrotoxicosis induced by transferred TSH receptor antibody (TRAb) is the ideal human in‐vivo experimental system for the evaluation of TRAb. The clinical significance of circulating TRAb in Graves’ disease was evaluated by this ‘natural in‐vivo human assay’. TRAb activity in vitro was measured by radioreceptor assay (thyrotrophin‐binding inhibitor immunoglobulin, TBII) and sensitive cAMP accumulation assay using FRTL‐5 cells (thyroid‐stimulating antibody, TSAb). Further, the binding‐stimulation index (B‐S index) was newly introduced, which was the most useful indicator for prediction of neonatal thyrotoxicosis, calculated as the product of TBII and TSAb (Tamaki et al., 1988a). Maternal serum TRAb indices showed highly significant correlations with the serum free T4 index (FT4I) and free T3 index (FT3I) in neonates (5–10 days after birth) born to 20 mothers with Graves’ disease who had positive TBII and/or TSAb (FT4I: r= 0.825 for TBII, r= 0.908 for TSAb, r= 0.944 for the B‐S index, P > 0.001; FT3I: r = 0.622 for TBII, P > 0.01, r= 0.812 for TSAb, r= 0.791 for the B‐S index, P > 0.001; n= 20). In contrast, in 57 untreated adult patients with hyperthyroid Graves’ disease, the FT4I and FT3I levels were not correlated with any of the TRAb indices. The linear regression relationship between the B‐S index and FT4I found in neonates was applied to values in adult patients with Graves’ disease, and the patients were divided into three groups on the basis of the 95% confidence limit: high, normal, and low responders of thyroid hormone (FT4I) secretion to the B‐S index. FT4I and the ratio of FT4I to the B‐S index were highest and the TRAb indices were lowest in the high responders, while FT4I and the FT4I/B‐S index ratio were lowest and the TRAb indices were highest in the low responders. The FT4I/B‐S index ratio was inversely correlated with the titres of antithyroid microsomal antibody in all the adult patients with untreated Graves’ disease (r=−0.288, P >0.05). The results suggest that in‐vitro assays using animal thyroid cells and cAMP as an index of response are suitable for detecting circulating thyroid stimulating activity in vivo. Secretion of thyroid hormones in Graves’ disease may be regulated not only by circulating thyroid‐stimulating antibodies but also by intrathyroidal stimulatory factors or by inhibitory or destructive factors.

High Incidence of Respiratory Distress Syndrome (RDS) in Infants Born to Mothers with Placenta Previa

OBJECTIVEnTo evaluate the incidence of respiratory distress syndrome (RDS) in infants born to mothers with placenta previa and to assess the risk factors for RDS.nnnMETHODSnNinety-nine pregnant women with placenta previa who delivered by cesarean section at 30-35 weeks of gestation were compared retrospectively with 102 pregnant women matched for week of gestation and birth year, who underwent elective cesarean section. Maternal characteristics, neonatal outcome, and incidence of RDS were analyzed. Umbilical cord blood samples were collected at delivery and were used to determine cortisol, epinephrine, and norepinephrine levels. Students t-test, the chi-square test, and Fishers exact test were used for statistical comparisons. P < 0.05 was considered significant. The Mann-Whitney U test was used for comparison of continuous variables.nnnRESULTSnPreeclampsia, histological chorioamnionitis, and premature rupture of membranes were significantly lower in the placenta previa group (placenta previa: 2.0% vs. control: 14.7%, P < 0.01; 14.1% vs. 30.1%, P < 0.01; 7.1% vs. 17.6%, P < 0.05, respectively). The incidence of RDS was significantly higher in the placenta previa group than in the control group (29.3% vs. 6.9%, P < 0.0001). The cortisol level in umbilical cord blood in the placenta previa group was lower than in the control group (median 7.3, range 4.4-14.9 microg/dl vs. median 10.6, range 4.9-30.3 microg/dl, P < 0.05). There were no significant differences in epinephrine or norepinephrine levels between the two groups.nnnCONCLUSIONSnThe incidence of RDS in infants delivered at 30-35 weeks gestation by cesarean section was significantly higher in mothers with placenta previa than in women without placenta previa. This may reflect decreased fetal stress since the cord blood cortisol levels were found to be lower in women with placenta previa.