Morphology of early intrauterine deaths with full trisomy 15.

OBJECTIVE: The morphologic features of embryos with full trisomy 15 are described. METHOD: A total of 1195 pregnancy losses were examined embryoscopically and cytogenetically. RESULTS: Of 1173 successfully karyotyped specimens, full trisomy 15 was diagnosed cytogenetically in 59 cases (5%). All 59 trisomy 15 embryos were diagnosed cytogenetically in the group of 962 embryonic miscarriages (6%). Trisomy 15 was not registered in 171 anembryonic or yolk sac miscarriages, and no case of full trisomy 15 was observed in 62 fetal miscarriages. Fifty-eight embryos with full trisomy 15 showed structural defects on embryoscopic examination. The most common defects were craniofacial anomalies (n = 73), retarded development of the limbs (n = 39), and abnormally short umbilical cords closely attaching the embryo to the chorionic plate (n = 27). Seven embryos were classified as growth disorganized. Limb reduction defects with a prevalence of 5.6/10 000 births, all affecting upper limb development (10 terminal transverse limb reduction defects and 3 embryos with split hand), were registered in 13 (22%) trisomy 15 embryos. CONCLUSION: Limb reduction defects and craniofacial abnormalities are a typical feature of trisomy 15. Gene dosage imbalances related to trisomy 15 might be the main molecular mechanism underlying the developmental defects observed in the present study and require further investigation.

Live birth after in vitro fertilization and single embryo transfer in a kidney transplant patient: a case report and review of the literature.

BACKGROUND: To present a successful case of in vitro fertilization (IVF) and single embryo transfer (SET) in a kidney transplant (NTX) patient and review of the literature. METHODS: Case report and review of the literature. SETTING: IVF-Unit in a university medical center. PATIENT(S): A 31 year-old nulliparous woman with primary infertility and a history of two kidney transplants. INTERVENTION(S): IVF-SET MAIN OUTCOME MEASURE(S): Live birth, renal transplant function. RESULTS(S): IVF-SET resulted in a pregnancy with labor induction and cesarean delivery in the 37th week of gestation due to rising serum creatinine. There was no significant maternal or fetal morbidity. CONCLUSION(S): Successful IVF-SET is possible in NTX patients. To date, including this case, five cases of IVF in NTX patients have been reported in the literature without an apparently increased renal morbidity.

Polymorphisms of the Nos3 gene and unexplained late intrauterine fetal death.

OBJECTIVE: Genetic polymorphisms associated with vascular diseases have been proposed to be involved in the pathogenesis of late unexplained intrauterine fetal death (IUFD). The Nos3 gene is known to regulate vascular tone via the endothelial nitric oxide synthase/nitric oxide pathway. STUDY DESIGN: In a multicenter case-control study, we evaluated two Nos3 polymorphisms (exon 7 Glu298Asp and a 27bp-repeat in intron 4) in 92 women with IUFD and 92 healthy control women. RESULTS: The investigated Nos3 polymorphisms were not associated with the occurrence of IUFD. In the subgroup of pregnancies affected by IUFD, women with at least one mutant allele of the Nos3 intron 4 polymorphism were diagnosed with IUFD at a significantly earlier gestational age (31.8 [standard deviation (S.D.) = 4.9] weeks versus 34.6 [S.D. = 4.8] weeks, p = 0.02) and showed a significantly reduced birth weight (2113 g [S.D. = 1028] versus 1571 g [S.D. = 568], p = 0.03). CONCLUSION: We are the first to report on Nos3 polymorphisms and IUFD. While not being associated with the incidence of IUFD overall, the intron 4 Nos3 polymorphism might modulate the timing of IUFD in affected pregnancies.

Polymorphisms within the interleukin-1 gene family and unexplained late intrauterine fetal death: a multi-center study.

PROBLEM: Interleukin-1 (IL-1) mediated inflammatory processes have been proposed to be involved in the pathogenesis of late unexplained intrauterine fetal death (IUFD). We determined whether common polymorphisms within the IL-1 gene locus can serve as candidate genes for this condition. METHOD OF STUDY: In a multi-center case-control study, we evaluated the -889 C/T polymorphism of the IL-1alpha gene (IL1A), the -511 C/T polymorphism of the IL-1beta promoter (IL1B promoter), the +3953 C/T polymorphism of IL-1beta exon 5 (IL1B exon 5), and a 86 base pair repeat in intron 2 of the IL-1 receptor antagonist gene (IL1RN) in 94 women with IUFD and 94 healthy controls using pyrosequencing. RESULTS: No significant associations were found between the presence of polymorphic alleles of IL1A (P = 0.9), IL1B promoter (P = 0.3), IL1B exon 5 (P = 0.9), and IL1RN intron 2 (P = 0.7) and the incidence of IUFD. In women with IUFD, polymorphisms were not associated with the timing of fetal death and birth weight. CONCLUSIONS: Polymorphisms within the IL1 gene family are not associated with the occurrence of IUFD overall and do not modulate the clinical characteristics of affected pregnancies in a large series of Caucasian women.

An interleukin-6 gene promoter polymorphism and unexplained late intrauterine fetal death: a multicenter study.

OBJECTIVE: Interleukin-6 (IL-6)-mediated inflammatory processes have been proposed to be involved in the pathogenesis of pregnancy-associated complications such as late unexplained intrauterine fetal death (IUFD). Therefore we determined whether a common guanine/cytosine polymorphism at position -174 of the promoter of the IL-6 gene (IL6) known to affect in vivo protein activity can serve as candidate gene for this condition. METHODS: In a multicenter case-control study, we evaluated the IL6 promoter polymorphism by pyrosequencing in 92 women with IUFD. Ninety-four healthy women with at least one uncomplicated full-term pregnancy and no history of IUFD served as the control group. RESULTS: No significant association was found between the presence of at least one mutant allele of the IL6 promoter polymorphism (P = .2; odds ratio = 1.5 [95% confidence interval, 0.8-2.7]) and the incidence of IUFD. In women with IUFD, the presence of at least one mutant allele of the IL6 promoter polymorphism did not influence timing of fetal death (33.9 [5.1] gestational weeks vs 34.1 [4.9] gestational weeks, P = .8) or birth weight (2055 [1119] g vs 1963 [992] g, P = .7). CONCLUSION: To our knowledge, we are the first to report on a common polymorphism of the IL6 promoter gene in women with late IUFD. The investigated IL6 promoter polymorphism can not be seen as candidate gene for IUFD in Caucasian women.

Polymorphisms of thrombophilic and vasoactive genes and severe preeclampsia: a pilot study.

OBJECTIVE: Carriage of thrombophilic and vasoactive polymorphic alleles has been associated with various pregnancy complications. The effect of carrying multiple polymorphisms is not known. We conducted a case-control study to determine the association between eight polymorphisms of thrombophilic and vasoactive genes and the risk of severe preeclampsia. METHODS: The following polymorphisms were analyzed by sequencing-on-chip-technology using solid-phase polymerase chain reaction on oligonucleotide microarrays: factor 5 (F5) Leiden, factor 2 (F2)-prothrombin G20210A, plasminogen activator inhibitor (PAI)-1 4G/5G, nitric oxide synthase (NOS) 3 T768C, NOS 3 Glu298Asp, angiotensinogen (AGT) Met235Thr, estrogen receptor (ER) alpha Pvu II, and mineralcorticoid receptor (MLR) Ser810Leu. The study comprised 24 patients with severe preeclampsia and 24 controls from a cohort of consecutive white women treated at the Obstetrics Department of the University of Vienna Medical School. Genotypes were correlated with clinical data. RESULTS: The investigated polymorphisms did not influence the risk of severe preeclampsia independently. When separately considering the simultaneous carriage of multiple thrombophilic or vasoactive polymorphisms, neither the combined carriage of thrombophilic polymorphisms (F5 Leiden, F2 G20210A, PAI-1 4G/5G), nor the combined carriage of vasoactive polymorphisms (NOS 3 T768C, NOS 3 Glu298Asp, AGT Met235Thr) conferred an increased risk of severe preeclampsia. Cumulative genotype frequencies for at least two homozygous mutant genotypes, however, were nine of 24 (38%) and two of 24 (8%) for the study and control groups, respectively (P <.05). All of these nine women with severe preeclampsia had at least two homozygous mutant genotypes of four polymorphisms, ie, F5 Leiden, NOS 3 T768C, NOS 3 Glu298Asp, or ER alpha Pvu II. CONCLUSION: Our data fail to document an independent significant influence of the investigated polymorphisms on the risk of severe preeclampsia. In an attempt to build a multigenetic model of severe preeclampsia, the combination of F5 Leiden, NOS 3 T768C, NOS 3 Glu298Asp, and ER alpha Pvu II was the most effective combination to predict the presence of severe preeclampsia in this small series of white women.

Raloxifene prevents the growth of uterine leiomyomas in premenopausal women.

OBJECTIVE: To evaluate the effects of raloxifene administration on uterine leiomyoma size in premenopausal women. DESIGN: Prospective, randomized, open-label, controlled clinical trial. SETTING: Tertiary care unit, University of Vienna, Austria. PATIENT(S): Twenty-five premenopausal women with uterine leiomyomas. INTERVENTION(S): Three months of treatment with raloxifene (180 mg/d) or no treatment. MAIN OUTCOME MEASURE(S): Baseline to end point percent change difference in leiomyoma volume between the therapy and control groups. RESULT(S): Raloxifene treatment prevented the progression of uterine leiomyomas. Compared with no medical intervention, raloxifene resulted in a decrease of myoma volume. Raloxifene was clinically well tolerated. No significant differences were detected in symptoms related to leiomyomas and hormonal status. CONCLUSION(S): In premenopausal women, high-dose raloxifene is well tolerated and inhibits the growth of leiomyomas.

Genetic polymorphisms associated with thrombophilia and vascular disease in women with unexplained late intrauterine fetal death: a multicenter study.

OBJECTIVE: We determined whether gene polymorphisms associated with thrombophilia and vascular disease as etiologic factors were involved in the pathogenesis of pregnancy-associated complications. METHODS: We conducted a multicenter case-control study in which we studied 94 women with late unexplained intrauterine fetal death (IUFD) and 94 healthy women with at least one uncomplicated full-term pregnancy and no history of IUFD. We obtained blood samples from all subjects and analyzed their DNA for 12 common polymorphisms of thrombophilic and vascular genes (factor V Leiden, factor V H1299R, prothrombin G20210A, factor XIII V34L, MTHFR C677T, MTHFR A1298C, beta-fibrinogen-455 G to A, PAI-1 4G/5G, GPIIIa L33P, HFE C282Y, apolipoprotein B R3500Q, and apolipoprotein E2/E3/E4). RESULTS: We found no significant association between any of the polymorphisms investigated and IUFD. Subgroup analyses involving various combinations of polymorphisms and in which gestational age and fetal weight were corrected for also showed no significant results. CONCLUSIONS: Our data represent the largest study to date with respect to thrombophilic and vascular gene polymorphisms in IUFD. In accordance with others, we challenge the importance of thrombophilic and vascular gene polymorphisms in the pathogenesis of this condition.

Detection of corticotropin-releasing hormone receptors R1 and R2 (CRH-R1, CRH-R2) using fluorescence immunohistochemistry in the myometrium of women delivering preterm or at term.

OBJECTIVE: To determine differences in expression of corticotropin-releasing hormone receptors R1 and R2 in the myometrium of women delivering preterm or at term, with or without labor. MATERIAL AND METHODS: Small pieces of myometrial smooth muscle were taken from forty patients undergoing caesarian section. One sample each was taken from all preterm and term patients, with and without labor. Antibodies against CRH-R1/2 and CRH-R2 were used for localization by conventional fluorescence immunohistochemistry. The evaluation of staining was based on examination of the entire histologic section by three independent observers. RESULTS: In women at term, CRH-R2 levels were elevated before labor and decreased with the onset of labor. In eight of 10 term samples from women in labor, no staining was detected. In preterm patients we found no difference in CRH-R2 staining between women with and without labor. The intensity of staining for CRH-R1/2 was generally uniform in all four groups. CONCLUSION: The high level of CRH-R2 expression in term patients without labor, together with the subsequent decrease of CRH-R2 in the myometrium during progression of labor, is consistent with the possibility that CRH may have autocrine/paracrine effects on myometrial contractility in the lower segment of the uterus.

Elevated serum concentrations of androgens in women with pregnancy-induced hypertension.

Alterations of steroid hormone profiles have been suggested to be involved in the pathophysiology of pregnancy-induced hypertension (PIH). The aim of our study was first to investigate serum concentrations of testosterone, dihydrotestosterone, androstenedione and dehydroepiandrostenedione sulfate in women with PIH and normotensive pregnant women and secondly to evaluate an association between elevated serum concentrations of androgens and the development of severe disease. Serum concentrations of androgens were measured in 40 patients with PIH and 40 normotensive pregnant women, matched for gestational age, determined by enzyme linked immunosorbent assay. Multivariate logistic regression models were used to analyze the influence of elevated serum concentrations of androgens on the occurrence of PIH and the development of severe disease. The median serum concentrations of androstenedione and testosterone were significantly elevated in women with PIH compared to controls (6.3 and 5.0 ng/ml, 1.8 and 1.1 ng/ml, p = 0.005 and p = 0.04, respectively). The difference between the median serum concentrations of dihydrotestosterone and dehydroepiandrostenedione sulfate in women with PIH and controls was not significant. Elevated serum concentrations of androstenedione revealed a significant influence on the odds of presenting with PIH (p = 0.043) and were significantly associated with the development of severe disease (p = 0.014). Women with PIH have elevated serum concentrations of androstenedione and testosterone. Moreover, elevated serum concentrations of androstenedione are associated with development of severe disease.

Concentrations of estrogens in patients with preeclampsia.

The role of estrogens in the pathophysiology of preeclampsia remains to be determined. The aim of our study was to compare serum concentrations of 17 beta-estradiol and estriol in women with preeclampsia to normotensive pregnant controls. Serum concentrations of estrogens were measured in women with mild (n = 24) and severe (n = 24) preeclampsia as well as is normotensive pregnant controls (n = 24). Patients were matched for gestational age. Pregnancies complicated by early onset severe preeclampsia are associated with increased rates of maternal and fetal morbidity. Subsequently, we created further subgroups before and after 34 weeks of gestation (34 + 0). Serum estrogen concentrations were determined by standard ELISA technique. Compared to normotensive controls, the differences between the overall median serum concentrations of 17 beta-estradiol in women with mild (3811 v. 3730 pg/ml, P = 0.9) and severe (3811 v. 3630 pg/ml, P = 0.1) preeclampsia were statistically not significant. The differences between the overall median serum concentrations of estroil in controls and in patients with mild (121 v. 76 ng/ml, P = 0.6) and severe (121 v. 79 ng/ml, P = 0.4) preeclampsia were similar. The differences between the median concentrations of 17 beta-estradiol in patient with early onset severe preeclampsia compared to patients with mild preeclampsia (3061 v. 3715 pg/ml, P = 0.004) and controls (3061 v. 3807 pg/ml, P = 0.006) were statistically significant. In addition, the differences between the median concentrations of estriol in women with early onset severe preeclampsia compared to controls were statistically significant (20 v. 92 ng/ml, P = 0.02). The differences between the median concentrations of estrogens in those with late onset severe preeclampsia compared to women with mild preeclampsia were not significant. We found significantly lower concentrations of estrogens in women with early onset severe preeclampsia.

Redistribution of corticotropin-releasing hormone receptor R2 using fluorescence immunohistochemistry in fetal membranes of women delivering preterm or at term.

OBJECTIVE: The aim of our study was to determine whether a difference exists in expression of corticotropin-releasing hormone receptor-R1 (CRH-R1) and corticotropin-releasing hormone receptor-R2 (CRH-R2) in fetal membranes of preterm and term women with or without labor. MATERIAL AND METHODS: Small pleces of fetal membranes were obtained from the placenta of each of forty patients undergoing cesarean section. Ten samples each were taken from preterm and term patients, with and without labor. Antibodies against CRH-R1/2 and CRH-R2 were used for localization by conventional fluorescence immunohistochemistry. The evaluation of staining was based on examination of the entire histologic section by three independent observers. RESULTS: In women at term without labor, CRH-R2 receptor was predominantly expressed in the amniotic epithelium and the amniotic mesenchyme. In laboring women at term, the expression of CRH-R2 receptor was shown in the chorionic mesenchyme and the cytotrophoblast cells, but no specific staining could be detected in the amniotic membranes. Changes in CRH-R2 receptor expression could not be demonstrated during preterm labor of early pregnancies. In preterm women, the antibody against CRH-R1/2 receptor detected additional signals in the amniotic mesenchyme and epithelium, suggesting expression of CRH-R1 in these tissues. In women at term, the overlapping pattern of CRH-R1/2 was recognized in both the chorionic and amniotic mesenchyme, in contrast to the specific CRH-R2 staining, suggesting expression of CRH-R1 in the mesodermal cell compartments. CONCLUSION: At term, changes in CRH-R2 expression are directly related to the progression of normal labor; such changes were not observed during preterm labor of early pregnancies. The increased CRH-R2 expression in the chorionic mesenchyme may possibly provoke rupture of the membranes or at least play a role in some key regulatory events in the initiation of normal labor. The fact that this mechanism does not occur in preterm labor strengthens the hypothesis that onset of labor could be controlled by distinct mechanisms in preterm and term pregnancies.

Serum levels of heat shock protein 70 in patients with preeclampsia: a pilot-study.

OBJECTIVE: To evaluate the serum levels of heat shock protein (Hsp) 70 in patients with severe preeclampsia (PE) in comparison to controls. The pathophysiology of PE can be explained, in part, by alterations of endothelial function caused by endothelial cell activation and injury. HSP 70 is essential for cellular recovery, survival and maintenance of homeostasis. STUDY DESIGN: In a matched pair study, serum levels of Hsp 70 were measured in 55 patients with late (group A, n = 24) and early (group B, n = 31) onset of severe PE, and in 55 normotensive controls (group C, n = 24 and group D, n = 31) matched for gestational age. Early onset of severe PE was defined as onset of disease at less than 34 weeks of gestation (34 + 0). Serum levels were determined using a sandwich enzyme-linked immunosorbent assay. RESULTS: The overall median serum levels of Hsp 70 were 2.82 ng/mL (SD +/- 8.33) in preeclamptic women, and 1.01 (SD +/- 1.38) ng/mL in controls (P = 0.08). The median serum levels of Hsp 70 were 0.52 ng/mL (SD +/- 1.14) in group A and 0.86 (SD +/- 1.29) ng/mL in group C (P = 0.15). The median serum levels of Hsp 70 were 4.94 ng/mL (SD +/- 10.46) in group B and 1.33 (SD +/- 2.28) ng/mL (P = 0.04) in group D. The difference between group A and B was also statistically significant (P = 0.01). CONCLUSION: Our study revealed higher serum levels of Hsp 70 in patients with early onset of severe PE. Further studies are recommended in order to elucidate the possible role of Hsp 70 in the pathophysiology of PE.