Iodine deficiency in pregnant women in Austria.

BACKGROUND/OBJECTIVES: In Austria, iodine deficiency has been considered to be eliminated owing to table salt fortification with iodine, but whether this also applies to pregnant women is unclear. Even mild iodine deficiency during gestation may lead to neurocognitive sequelae in the offspring. SUBJECTS/METHODS: This is a cross-sectional investigation of urinary iodine excretion in 246 pregnant women (first trimester n=2, second trimester n=53, third trimester n=191, gestational diabetes mellitus n=115, no gestational diabetes mellitus n=131). The iodine content of morning spot urine samples was determined using inductively coupled plasma mass spectrometry. RESULTS: Pregnant women in the Vienna area had a median urinary iodine concentration (UIC) of 87 µg/l. Only 13.8% of the cohort were in the recommended range of 150-249 µg/l, whereas 21.5% had a UIC of 0-49 µg/l, 40.2% had a UIC of 50-99 µg/l and 19.5% had a UIC of 100-149 µg/l. In all, 4.9% had a UIC over 250 µg/l. A total of 137 women of foreign origin had a significantly higher iodine excretion compared with Austrian-born women. Maternal or gestational age had no influence on UIC. Although 79 women on iodine supplementation had a significantly higher iodine concentration compared with women without iodine supplementation (97.3 vs 80.1 µg/l, P=0,006), their UIC was below the recommended range, indicating that doses of 100-150 µg per day are not sufficient to normalize iodine excretion. Sodium and iodine concentrations in the urine were tightly correlated (R=0.539, n=61), suggesting that low intake of iodized salt might contribute to insufficient iodine supply. CONCLUSIONS: This study shows that pregnant women in the Vienna area have a potentially clinically significant iodine deficiency and that currently recommended doses of iodine supplementation may not be sufficient.

A two-step screening algorithm including fasting plasma glucose measurement and a risk estimation model is an accurate strategy for detecting gestational diabetes mellitus.

AIMS/HYPOTHESIS: It is currently not clear how to construct a time- and cost-effective screening strategy for gestational diabetes mellitus (GDM). Thus, we elaborated a simple screening algorithm combining (1) fasting plasma glucose (FPG) measurement; and (2) a multivariable risk estimation model focused on individuals with normal FPG levels to decide if a further OGTT is indicated. METHODS: A total of 1,336 women were prospectively screened for several risk factors for GDM within a multicentre study conducted in Austria. Of 714 women (53.4%) who developed GDM using recent diagnostic guidelines, 461 were sufficiently screened with FPG. A risk prediction score was finally developed using data from the remaining 253 women with GDM and 622 healthy women. The screening algorithm was validated with a further 258 pregnant women. RESULTS: A risk estimation model including history of GDM, glycosuria, family history of diabetes, age, preconception dyslipidaemia and ethnic origin, in addition to FPG, was accurate for detecting GDM in participants with normal FPG. Including an FPG pretest, the receiver operating characteristic AUC of the screening algorithm was 0.90 (95% CI 0.88, 0.91). A cut-off value of 0.20 was able to differentiate between low and intermediate risk for GDM with a high sensitivity. Comparable results were seen with the validation cohort. Moreover, we demonstrated an independent association between values derived from the risk estimation and macrosomia in offspring (OR 3.03, 95% CI 1.79, 5.19, p < 0.001). CONCLUSIONS/INTERPRETATION: This study demonstrates a new concept for accurate but cheap GDM screening. This approach should be further evaluated in different populations to ensure an optimised diagnostic algorithm.

The impact of risk factors and more stringent diagnostic criteria of gestational diabetes on outcomes in central European women.

OBJECTIVES: In the face of the ongoing discussion on the criteria for the diagnosis of gestational diabetes (GDM), we aimed to examine whether the criteria of the Fourth International Workshop Conference of GDM (WC) select women and children at risk better than the World Health Organization (WHO) criteria. DESIGN AND SETTING: This was a prospective longitudinal open study in five tertiary care centers in Austria. PATIENTS AND OUTCOME MEASURES: The impact of risk factors, different thresholds (WC vs. WHO), and numbers of abnormal glucose values (WC) during the 2-h, 75-g oral glucose tolerance test on fetal/neonatal complications and maternal postpartum glucose tolerance was studied in 1466 pregnant women. Women were treated if at least one value according to the WC (GDM-WC1) was met or exceeded. RESULTS: Forty-six percent of all women had GDM-WC1, whereas 29% had GDM-WHO, and 21% of all women had two or three abnormal values according to WC criteria (GDM-WC2). Eighty-five percent of the GDM-WHO were also identified by GDM-WC1. Previous GDM [odds ratio (OR) 2.9], glucosuria (OR 2.4), preconceptual overweight/obesity (OR 2.3), age 30 yr or older (OR 1.9), and large-for-gestational age (LGA) fetus (OR 1.8) were the best independent predictors of the occurrence of GDM. Previous GDM (OR 4.4) and overweight/obesity (OR 4.0) also independently predicted diabetes postpartum. GDM-WC1 had a higher rate of obstetrical complications (LGA neonates, neonatal hypoglycemia, cesarean sections; P < 0.001) and impaired postpartum glucose tolerance (P < 0.0001) than GDM-WHO. CONCLUSION: These results suggest the use of more stringent WC criteria for the diagnosis of GDM with the initiation of therapy in case of one fasting or stimulated abnormal glucose value because these criteria detected more LGA neonates with hypoglycemia and mothers with impaired postpartum glucose metabolism than the WHO criteria.

Placental expression and serum levels of cytokeratin-18 are increased in women with preeclampsia.

OBJECTIVE: To evaluate placental expression and serum cytokeratin-18 in women with preeclampsia. METHODS: Serum cytokeratin-18 was evaluated in 44 women with preeclampsia and 44 healthy pregnant women using an immunoradiometric assay. Placental expression of cytokeratin-18 was investigated in specimens from 23 women with preeclampsia and 20 healthy pregnant women by immunohistochemistry. RESULTS: Median serum cytokeratin-18 in women with preeclampsia and healthy pregnant women was 106.7 and 76.0 U/L, respectively (P =.02). Among women with preeclampsia, serum cytokeratin-18 was significantly associated with severity of disease (P =.001) and showed a sensitivity (standard error) and specificity (standard error) of 85% (7%) and 65% (12%), respectively. In placental specimens, the cytoplasm of the syncytiotrophoblast stained positive for cytokeratin-18 with strong and widespread staining in 83% and 45% of placental specimens of women with preeclampsia and healthy pregnant women, respectively (P =.01). CONCLUSION: Elevated serum cytokeratin-18 values are associated with disease severity in women with preeclampsia. Our data provide additional evidence that the placenta might be the source of the elevated serum cytokeratin-18 values in women with preeclampsia.

Placental expression of cytokeratin 18 and serum levels of tissue polypeptide antigen in women with pregnancy-induced hypertension.

OBJECTIVE: We hypothesized that placental cytokeratin (CK) 18 expression and serum levels of tissue polypeptide antigen (TPA), a surrogate marker for CK 18, are increased among women with pregnancy-induced hypertension (PIH). METHODS: Serum levels of TPA were measured in 46 women with PIH and 46 controls, matched for gestational age and parity, using an immunoradiometric assay. Immunohistochemical detection of CK 18 was assessed in placental specimens of 24 women with PIH and 20 controls. Results were correlated to clinical data. RESULTS: Cytokeratin 18 expression was found in the syncytiotrophoblast of 7 of 20 (35%) and 18 of 24 (75%) placental specimens of controls and women with PIH, respectively (p = 0.008). Median serum levels of TPA in controls and women with PIH were 93.0 U/L (range: 12.5-281.6) and 154.2 U/L (range: 37.3-496.6), respectively (p = 0.001). Serum levels of TPA significantly influenced the odds of presenting with PIH, as well as the odds of developing severe disease (p = 0.003, and p = 0.001, respectively). TPA values were significantly higher among women with severe PIH compared with women with mild PIH and controls, independent of gestational age (p = 0.004). Among women with severe PIH, serum TPA was inversely correlated with fetal birth weight (r = -0.3; p = 0.001) CONCLUSION: Cytokeratin 18 is overexpressed in the syncytiotrophoblast of women with PIH. Serum levels of TPA are elevated among women with PIH and correlate with disease severity and low fetal birth weight.

Placental expression and serum concentrations of cytokeratin 19 in preeclampsia.

OBJECTIVE: To evaluate cytokeratin 19 as a serum marker of preeclampsia. METHODS: Serum cytokeratin 19 levels were measured in 46 women with preeclampsia and 46 controls matched for gestational age and parity, using an immunoradiometric assay. Cytokeratin 19 was evaluated immunohistochemically in placental specimens from 28 healthy pregnant women and 24 women with preeclampsia. RESULTS: Cytokeratin 19 was identified in the syncytiotrophoblast in 13 (46. 4%) of 28 and 23 (95.8%) of 24 placental specimens from controls and women with preeclampsia, respectively (P =.03). Median serum levels of cytokeratin 19 in controls and women with preeclampsia were 1.7 (range 0.3-4.7) microg/mL and 2.7 (range 0.8-8.2) microg/mL, respectively (P <.001). Cytokeratin 19 significantly influenced the odds of presenting with preeclampsia (P <.001) and the odds of developing severe disease (P <.001). Serum cytokeratin 19 correlated inversely with fetal birth weight (Kendall tau-b correlation coefficient = -0.2, P =.007). Compared with healthy pregnant women, women with severe preeclampsia had significantly higher and more rapidly increasing cytokeratin 19 serum levels throughout the third trimester (P <.001). CONCLUSION: Placental stimulation of cytokeratin 19, and release of it into maternal circulation, seem to be a feature of preeclampsia. Correlations with clinical characteristics suggest that cytokeratin 19 is a marker of disease severity.

Prognostic significance of tumor angiogenesis in primary fallopian tube cancer.

Tumor angiogenesis has been found to be prognostically significant in many types of malignant tumors. We assessed tumor vascularity in 43 cases of histologically proven primary fallopian tube cancer, FIGO stage I-IV, using the highly specific endothelial cell marker CD34. Microvessel count was determined by counting CD34-positive cells at 200 x magnification. The 5-year disease-free survival probability was 43.8% (+/- 11.5%) in 24 patients whose tumors had a microvessel count < or = 19 microvessels/field and 19.7% (+/- 9.5%) in the > 19 microvessels/field group (P = 0.046). Stage and microvessel count were statistically significant for disease-free survival in univariate analysis. Therefore, a larger sample size would be required to detect an independent and statistically significant prognostic effect of microvessel density in primary fallopian tube cancer in multivariate analysis.

Diagnostic value of tissue polypeptide-specific antigen (TPS) in neuroblastoma and Wilms' tumour.

Although tissue polypeptide-specific antigen (TPS) has been described as a potentially useful serum marker of tumour activity in adult epithelial tumours, few data are available for childhood malignancies. Neuroblastomas and Wilms' tumours are the commonest types of solid malignancies found in the retroperitoneum of children. At this time, a widely used marker for Wilms' tumour is not available. Using an enzyme-linked immunosorbent assay (ELISA) kit, serum TPS levels in 23 children with neuroblastomas, nine with Wilms' tumours and 22 with benign tumours were evaluated to test the usefulness of the marker in identifying malignancies. Compared with healthy children (n = 110), the preoperative least-square means (LSM) of serum TPS were considerably elevated in both neuroblastoma (LSM = 209 U l(-1)) and Wilms' tumour (LSM = 235 U l(-1)), whereas values in benign tumours were only slightly elevated. Although the Wilms' tumours were associated with higher preoperative serum TPS levels, there was no statistically significant difference compared with neuroblastomas. Receiver operating characteristic analysis (ROC curves) showed a high sensitivity and specificity for both malignancies. Successful treatment resulted in decrease in TPS serum values. Serum TPS measurements in children presenting with abdominal masses can help in diagnosing the two commonest extracranial solid malignancies of childhood. Furthermore, TPS could acquire a pivotal role in monitoring therapy.

p53 protein overexpression: a strong prognostic factor in uterine papillary serous carcinoma.

Uterine papillary serous carcinoma (UPSC) is an uncommon but aggressive type of endometrial cancer associated with rapid progression of disease and poor prognosis. We investigated 23 cases of UPSC. p53 expression was studied in archival paraffin-embedded tissue by immunohistochemistry. Eleven tumors (47.8%) showed p53 overexpression whereas 12 tumors (52.2%) were p53 negative. One of 8 stage I/II (12.5%) and 10/15 stage III/IV (66.6%) tumors revealed p53 staining (P = 0.027). The median overall survival was 43.3 months. Patients with advanced-stage (III, IV) disease had a 5-year overall survival probability (5-year OS%) of 24% compared to 100% in those in stages I and II (log-rank, P = 0.018). Myometrial invasion, lymphatic space invasion, or lymph node involvement did not correlate with the 5-year OS of these patients. Patients whose tumors overexpressed p53 had a significantly shorter survival than those whose tumors did not (P = 0.033). This study confirms the influence of p53 overexpression on survival in UPSC patients.

Embryonal rhabdomyosarcoma of the uterine cervix: case report and review of the literature.

Embryonal rhabdomyosarcoma (RMS) of the female genital tract usually occurs during childhood in the vagina. In rare cases, RMS can originate in the uterine cervix, with a peak incidence in the second decade. A combined modality approach to treating RMS using multidrug chemotherapy, radiotherapy, and surgery has markedly improved survival. Early stage embryonal RMS of the cervix has been found to have an excellent prognosis. The present case and literature review indicate that extensive surgery does not improve survival in patients with stage I disease.

Influence of postoperative treatment on survival in patients with uterine papillary serous carcinoma.

BACKGROUND: Uterine papillary serous carcinoma (UPSC) is an uncommon, aggressive type of endometrial cancer associated with an advanced stage at initial presentation, rapid progression of disease, and poor prognosis. METHODS: Twenty-three patients with UPSC were included in this study. History, treatment, follow-up, and 5-year overall survival probability (5-yr OS%) were evaluated. RESULTS: All women underwent total hysterectomy and bilateral salpingo-oophorectomy. Positive lymph nodes were found in 10 of 17 patients who underwent pelvic lymphadenectomy. Eight patients had FIGO Stage I/II, whereas 15 patients showed Stage III or IV tumors. After surgery 5 women underwent radiotherapy, 5 chemotherapy, and 8 both radiotherapy and chemotherapy. Chemotherapy consisted of cisplatin/carboplatin plus cyclophosphamide. Adjuvant irradiation consisted of vault and external beam irradiation. The median duration of follow-up was 39.4 months (25th and 75th percentiles; 26. 1, 68.1). The median overall survival was 43.3 months (12.9, 75th percentile not reached). Three of 10 patients who received only chemotherapy or radiotherapy are alive, whereas 7/8 patients who received a combination of both are alive with no evidence of disease at the time of reporting. The 5-yr OS% was 80% in those who received radio- and chemotherapy and only 30% in those who were treated with radiotherapy alone (log rank = 0.05). CONCLUSION: These results stress the need to study and evaluate the usefulness of combined chemo- and radiation therapy in patients with uterine serous papillary cancer.

Tissue polypeptide-specific antigen in pediatric patients: assessment of normal values.

Measurement of serum concentrations of tissue polypeptide-specific Antigen (TPS) has been demonstrated to the useful in diagnosis and monitoring of adult epithelial tumors. So far, no data have been available on normal or pathologic TPS values in children. Therefore, the present study was designed to evaluate the normal values of TPS in childhood. Using a commercial enzyme linked immunosorbent assay (ELISA) kit, serum TPS was determined in 361 healthy children. Median (M) TPS was found to be 107 U/l at birth (n = 124). By the end of the first week, the value rose to M = 150 U/l (n = 68) and then continuously decreased with age (1 week-1 year, n = 45, M = 88 U/l; 1-7 years, n = 75, M = 51 U/l) until reaching the adult level (8-18 years, n = 49, M = 34 U/l). Additionally, the serum TPS values of 45 mothers right after delivery (M = 161 U/l) were assessed, and there was no correlation to the marker levels determined in the cord blood of their children. The age-dependent distribution of serum TPS in healthy children must be taken into account in the clinical application of this tumor marker.

Correlation of vascular endothelial growth factor expression and microvessel density in cervical intraepithelial neoplasia.

BACKGROUND: Angiogenesis (the formation of new blood vessels) appears to be required for the growth of invasive tumors, but little information exists about its role in the development of preinvasive lesions. We examined microvessel density and expression of vascular endothelial growth factor in specimens of cervical intraepithelial neoplasia (CIN), a preinvasive lesion of the uterine cervix, to determine whether a connection could be established between these parameters of angiogenesis and the grade of dysplasia (i.e., tissue abnormality). METHODS: Sections of biopsy specimens from 83 patients with grades I-III CIN were examined retrospectively. Microvessels were localized by use of a polyclonal antibody directed against factor VIII-related antigen; vascular endothelial growth factor was detected by means of a monoclonal antibody. Reported P values are two-sided. RESULTS: Highest microvessel densities and highest expression of vascular endothelial growth factor were found in a narrow border region between CIN lesions and the underlying stroma. A significant correlation was observed between high vascular endothelial growth factor expression and high microvessel density (Kendall's tau = 0.27; 95% confidence interval [CI] = 0.03-0.50; P = .018). Mean microvessel density values +/- standard deviations for CIN I, CIN II, and CIN III lesions were 19.4 +/- 5.8, 21.9 +/- 7.0, and 34.1 +/- 14.8, respectively (Kendall's tau = 0.46; 95% CI = 0.30-0.61; P<.0001). Corresponding values for vascular endothelial growth factor expression were 8.3 +/- 3.5, 8.4 +/- 2.0, and 12.2 +/- 3.6, respectively (Kendall's tau = 0.41; 95% CI = 0.20-0.60; P<.0001). CONCLUSIONS: Our results are consistent with the idea that progression of cervical dysplasia is dependent on angiogenesis.

Prophylactic cerclage in pregnancy. Effect in women with a history of conization.

OBJECTIVE: To evaluate the effect of prophylactic cerclage on the course of pregnancy in women with prior conization. STUDY DESIGN: In a retrospective, observational study, the outcome of pregnancies in 69 women with (n = 30) and without (n = 39) cerclage who previously underwent conization was evaluated regarding hospitalization due to threatened preterm labor and delivery before 37 weeks of gestation. RESULTS: The occurrence of preterm delivery was 23.3% in the cerclage group and 20.5% in the control group (P = .78). Women with prophylactic cerclage were hospitalized significantly more often due to threatened premature labor: with cerclage, 66.7%; without cerclage, 33.3% (P = .006). CONCLUSION: Prophylactic cerclage should be used more sparingly in women with a history of conization because it does not prevent premature delivery and tends to induce preterm uterine contractions.

CD44 is an independent prognostic factor in early-stage cervical cancer.

The expression of specific cell-adhesion molecule CD44 isoforms (splice variants) is associated with metastatic spread and poor prognosis in human malignancies. The aim of this study was to evaluate whether CD44 isoform expression is a prognostic factor in early-stage cervical cancer. We used 4 different variant exon sequence-specific murine monoclonal antibodies to the CD44 isoforms CD44v3, CD44v5, CD44v6 and CD44v7-8 to study the prognostic value of CD44 splice variants in 200 cases of International Federation of Gynecology and Obstetrics (FIGO) stage-IB cervical cancer by immunohistochemistry. In the univariate analysis, the expression of CD44v3 (log-rank test, p = 0.03) and CD44v6 (log-rank test, p = 0.03) was correlated with poor overall survival. In the subgroup of patients without metastatic disease in the pelvic lymph nodes, expression of CD44v6 was correlated with poor disease-free and overall survival (log-rank test, p = 0.04 and p = 0.01, respectively). Multivariate analysis, correcting for the confounding variables pelvic lymph-node involvement, depth of invasion and histologic grading, revealed CD44v6 to be an independent prognostic factor for overall survival of patients with early-stage cervical cancer. The results of this study indicate that CD44v6 is an additional prognostic marker in surgically treated cervical cancer. The assessment of CD44 isoform expression could be of clinical value in deciding upon adjuvant therapy, resulting in a more individualized management of therapy.

Angiogenesis in vulvar intraepithelial neoplasia.

Vulvar intraepithelial neoplasia (VIN) has been reported to be a precursor of invasive vulvar cancer. Switching to the angiogenic phenotype is considered a key step in tumor growth. Microvessel density (MVD) and vascular endothelial growth factor (VEGF), a highly angiogenic peptide, are important parameters of tumor angiogenesis. Forty-three histologic slides with 38 VIN I-III lesions were immunohistochemically stained for factor VIII-related antigen (F8-RA) and 44 slides with 37 VIN I-III for VEGF, since F8-RA reliably highlights tumor microvessels. Determination of MVD and VEGF expression was done by counting microvessels and VEGF-positive cells at a magnification of 200x and 400x. The highest concentration of F8-RA-stained MVD and VEGF expression was found at a small subepithelial area at the border of the VIN lesion to the stroma underneath but concentrations were low in all specimens of normal epithelium. High VEGF expression was significantly correlated to high MVD. For both MVD and VEGF expression the differences between VIN I and VIN III and between VIN II and VIN III were statistically significant (P < 0.0001). VIN III lesions are the clinical relevant precursors of invasive cancer of the vulva, as outlined by intense expression of VEGF protein and a highly dense network of microvessels underlying the dysplastic epithelium.

Short-term effects of topical testosterone in vulvar lichen sclerosus.

OBJECTIVE: To evaluate the systemic and therapeutic effect of topical testosterone treatment in vulvar lichen sclerosus. METHODS: This prospective clinical, single-arm study included ten postmenopausal women with vulvar lichen sclerosus. Testosterone propionate (0.04 g daily) was administered topically for 4 weeks. Serum androgens (testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate) were determined before and after 4 weeks of treatment, and vulvodynia was evaluated by a horizontal visual analogue scale. RESULTS: Serum levels of total testosterone increased in all patients (P < .01) and exceeded normal range in eight of ten women. Vulvodynia improved in nine of ten patients (paired t test: P < .01). Four of ten patients showed clinical signs of hyperandrogenism (enlargement of the clitoris, alterations of the voice, increase in libido) after 4 weeks of treatment. The only patient without subjective improvement had elevated basal serum androgen levels and showed clinical signs of hyperandrogenism before therapy. CONCLUSION: Topical testosterone is effective in normoandrogenic women with lichen sclerosus. Androgen status should be evaluated before treatment, and dosage should be individualized to avoid virilization and metabolic side effects. Because there is a marked systemic effect, clinical controls and a follow-up with evaluation of serum testosterone levels are recommended. Other steroids should be included in therapeutic decisions.

[Diagnosis and therapy of cervical intraepithelial dysplasia in Austria: a survey]. / Diagnostik und Therapie zervikaler intraepithelialer Dysplasien in Osterreich: eine Bestandsaufnahme.

PURPOSE: To assess the present state of diagnosis, therapy and follow-up of cervical intraepithelial neoplasia (CIN) in Austria. MATERIAL AND METHODS: 100 questionnaires were sent to all departments of Gynecology and Obstetrics in Austria. The anonymous questionnaire consisted of 22 multiple choice questions. It was possible to choose one or more answers by ticking applicable boxes, with the option in individual cases of giving additional information in the form of free text. RESULTS: 55 (55%) departments returned their answered questionnaires, indicating growing consciousness of quality control in medicine. It was found that in the collection of cytologic specimens 67% of the departments used a wooden spatula and cotton swabs. Management of patients with Pap smears indicating low grade squamous intraepithelial lesion (LSIL) and abnormal colposcopy, in 36 (65%) departments consisted of punch biopsy for histological diagnosis. After 3 recurrent Pap smears indicating LSIL, 76% of the hospitals treated such patients by conization, regardless of the histological grade of the lesion. Following inadequate resection of CIN III by conization, operative management of patients was the most commonly used regimen. CONCLUSION: We regard the results of this survey as a basis for the development of further quality management strategies in the prevention, diagnosis and therapy of cervical intraepithelial neoplasia in Austria.