József Gábor Joó

Gene expression patterns of the 11β-hydroxysteroid dehydrogenase 2 enzyme in human placenta from intrauterine growth restriction: the role of impaired feto-maternal glucocorticoid metabolism

OBJECTIVE To assess 11-β-hydroxysteroid dehydrogenase 2 (11β-HSD2) gene expression patterns in human placental samples from intrauterine growth restriction (IUGR) pregnancies using normal pregnancy as control. STUDY DESIGN We compared 11-β-HSD2 gene expression in placental samples from all IUGR pregnancies treated in our clinic between January 1, 2010 and January 1, 2011 vs. 140 normal pregnancy samples from the same study period. Clinical characteristics were also assessed and compared between the IUGR and normal pregnancy groups. RESULTS Mean gestational weight gain in the IUGR group was significantly lower than in the control group. Similarly, change in body mass index (BMI) was lower. Impending intrauterine fetal asphyxia was significantly more common in the IUGR group. The 11β-HSD2 gene was underexpressed compared to controls, but this underexpression was only observed after the 33rd gestational week. Within the IUGR group, in cases of impending intrauterine fetal asphyxia the 11β-HSD2 gene was underexpressed compared to both impending asphyxia in non-IUGR cases, or IUGR without impending asphyxia. CONCLUSION Low gestational weight gain appears to predict IUGR. The 11β-HSD2 gene in IUGR is underexpressed and may result in an impaired placental barrier, decreasing protection against maternal glucocorticoids, which are thought to be prominent in fetal programming. Maternal glucocorticoid exposure resulting from an impaired placental barrier may increase the risk for cardiovascular and metobolic disorders later in adult life. In IUGR, before the 33rd gestational week, the expression of the 11β-HSD2 gene remains physiological. The underexpression of this gene after the 33rd week in impending intrauterine fetal asphyxia in IUGR points to an increased sensitivity to hypoxia when impending asphyxia is present in the late phase of IUGR pregnancies.

Gene expression patterns of insulin-like growth factor 1, 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in human placenta from preterm deliveries: influence of additional factors

OBJECTIVE To compare patterns of human placental gene expression of IGF from pregnancies that ended with preterm delivery vs. full term pregnancies as controls. STUDY DESIGN Real-time PCR was used to assess gene expression of IGF in human placental samples from 104 preterm and 140 full term pregnancies. RESULTS In the preterm delivery group, the proportion of smokers was significantly higher than in the control group. A history of preterm delivery was more common in the preterm delivery group compared to the control group. In the preterm delivery group, placental samples showed an underexpression of the IGF-1 gene compared to controls. In cases of male fetal gender an overexpression of both the IGF-2 and the IGFBP-3 genes was observed. CONCLUSION Among environmental factors influencing preterm delivery, smoking was the most significant in our study. In the majority of cases, preterm delivery was induced by intrauterine infection leading to a decreased activity of the IGF system. This mechanism may also play a role in the development of neurological sequelae and in decreased tolerance to fetal distress. The overexpression of the IGF-2 gene observed in the placenta with male fetal gender can be explained by its physiological role in the development of the male phenotype.

Ultrasonographic Findings of Fetal Aneuploidies in the Second Trimester – Our Experiences

Objectives: The aim of this study was to determine the incidence of ultrasound findings in common fetal chromosomal defects on a relatively large series coming out from one institution. We also tried to evaluate possible clusters of ultrasound signs of major chromosomal defects. Methods: Of the 22,150 fetal karyotypings, 514 abnormal karyotypes (2.3%) were diagnosed prenatally between 1990 and 2004. Of them, 374 were further evaluated for abnormal ultrasound signs in this study. These represented the major chromosomal defects of Down syndrome (n = 207), trisomy 18 (n = 70), trisomy 13 (n = 28) and Turner syndrome (n = 69). Results: The incidences of major structural defects and minor anomalies were evaluated then sonographic signs with the highest incidences were established in each of the major chromosomal defects. In fetuses with trisomy 13, besides cardiac defects, the most frequently seen structural abnormalities were central nervous system anomalies and facial anomalies. In fetuses with trisomy 18 and trisomy 21, cardiac anomalies were the most common structural sonographic features, whereas the most common findings were hygroma colli and fetal hydrops in fetuses with Turner syndrome. As far as minor anomalies are concerned, increased nuchal fold was the most predictive marker of each major aneuploidy. Choroid plexus cysts were more common in trisomy 18, whereas echogenic intracardiac foci were more frequently detected in fetuses with trisomy 13 and trisomy 21. Conclusion: This study may help to select the most predictive components of the genetic sonogram which may assist the counseling of women for the actual risk of the major chromosomal abnormalities.

Etiology, prenatal diagnostics and outcome of ventriculomegaly in 230 cases.

Objective: The aim of this study was to review and summarize the information regarding the etiology, diagnostics and outcome of ventriculomegaly. Methods: The study included 230 cases of ventriculomegaly examined between 1979 and 2000. The main diagnostic criterion for ventriculomegaly was the transverse diameter of the ventricular atrium at the level of the glomus of the chorioid plexus measuring >10 mm, irrespective of gestational age. Results: Gender distribution (male:female ratio: 0.98) coincided with that of the general population. In 32% of the cases (72/230), the history was positive; 6% (12/230) had a positive genetic history, while 26% (60/230) were associated with pathological obstetric events. The incidence rate of ventriculomegaly in the patients’ history was found to be 2.61% (6/230). In nearly 60% of the cases included in this study, ventriculomegaly was diagnosed before the 24th week of pregnancy. Fresh fetal infection confirmed by Toxoplasma PCR real-time examination was diagnosed only in cases of severe ventriculomegaly. Based on the measurement of the diameter of the atrium of the lateral ventricle, severe and mild ventriculomegaly was diagnosed in 142/230 (61.7%) and 88/230 cases (38.3%), respectively. Termination of pregnancy was significantly more frequent in cases of severe than of mild ventriculomegaly (92 vs. 66%). Conclusions: The importance of positive obstetric and/or genetic history should be emphasized as it is in direct relationship with the increased incidence of this malformation. Regarding the practice of ultrasonography, mild ventriculomegaly (transverse diameter of the lateral ventricle <15 mm) has a much better prognosis than the severe form (transverse diameter of the lateral ventricle >15 mm) of the malformation. Based on the ultrasonographic diagnosis of ventriculomegaly, TORCH serological examination is also recommended since treating toxoplasmosis by medication may have a promising prognosis for the pregnancy. In cases of isolated ventriculomegaly alone, intrauterine karyotyping is not necessarily indicated, but in cases where ventriculomegaly is associated with other genetic disorders karyotyping should definitely be performed. Since ventriculomegaly is not incompatible with postnatal life by itself, the decision about the fate of the pregnancy is largely dependent on the presence of other organic disorders.

Gene expression patterns of vascular endothelial growth factor (VEGF-A) in human placenta from pregnancies with intrauterine growth restriction

Abstract Objective: In this study, we describe changes in gene expression pattern of vascular endothelial growth factor (VEGF)-A in human placenta obtained from pregnancies with intrauterine growth restriction using placenta from normal pregnancies as control. Methods: We compared gene expression of VEGF-A in placental samples from Intrauterine growth restriction (IUGR) pregnancies versus placenta obtained from normal pregnancies. Among potential confounders, important clinical informations were also analyzed. Results: In the IUGR group, the VEGF-A gene was overexpressed compared to the normal pregnancy group (: 1.32; : 1.56). There was no correlation between the degree of growth restriction and VEGF-A gene expression (: 0.58; : 0.64). Within the IUGR group, there was a trend toward a positive correlation between placental VEGF-A gene activity and gestational age at delivery (: 1.09; : 1.27; : 1.35). Conclusions: Our findings suggest that the increase in placental expression of the VEGF-A gene and the resultant stimulation of angiogenesis are a response to hypoxic environment developing in the placental tissue in IUGR. Thus, it appears to be a secondary event rather than a primary factor in the development of IUGR There is a trend toward a positive correlation between gestational age and placental VEGF-A gene activity.

Incidence of chromosomal abnormalities in the presence of fetal subcutaneous oedema, such as nuchal oedema, cystic hygroma and non-immune hydrops

Introduction: The authors investigated the incidence of chromosomal abnormalities in subcutaneous oedema detected in the fetus by intrauterine ultrasonography. Material and Method: In the 10-year period, intrauterine karyotyping was performed in pregnancies with positive ultrasound findings for subcutaneous oedema, such as nuchal oedema, cystic hygroma and non-immune hydrops. Results: Intrauterine karyotyping in fetal subcutaneous oedema was carried out in 434 cases. The chromosomal investigation was made in nuchal oedema in 374 cases, in 120 patients the chromosomal examination was made in the first trimester because of nuchal translucency, and in 254 cases in the second trimester because of nuchal thickening. Cystic hygroma cases (27 patients), non-immune hydrops cases (20 patients), and combined cases of non-immune hydrops and cystic hygroma (13 patients) were investigated separately. In nuchal oedema, pathological karyotypes were detected in 8.33% in the first trimester and in 5.51% in the second trimester. Chromosomal abnormality was found in 48.15, 20, and 53.8% in cystic hygroma, non-immune hydrops, and combined occurrence of non-immune hydrops and cystic hygroma, respectively. Considering all of the changes accompanied by subcutaneous oedema, 50, 25 and 18.75% of the pathological karyotypes was X-monosomy, trisomy 18 and trisomy 21, respectively. Discussion: It was important to distinguish nuchal oedema and cystic hygroma, and in the case of non-immune hydrops, it was also important to discuss cases with or without cystic hygroma separately. During the investigations, cases of non-immune hydrops with or without cystic hygroma were evaluated as separate categories. Conclusions: The authors emphasize the differentiation of the various types of subcutaneous oedema and the importance of precise information about the risks, provided during genetic counselling.

Risk of chromosome abnormalities in the presence of bilateral or unilateral choroid plexus cysts

Objectives: To evaluate the rate of chromosome abnormalities in cases of uni- and bilateral choroid plexus cysts (CPCs). Methods: A total of 10,875 ultrasound (US) examinations were performed in the second trimester, and 435 cases with CPC (4%) were found. After genetic counseling, 45 patients decided not to undergo karyotyping. The authors performed a chromosome analysis in 390 cases of CPCs. Results: The total risk of chromosome abnormalities was 3.59% (n = 14) and risk of trisomies was 2.05% (n = 8). Trisomy 18 was found in 6 cases (1.54%), trisomy 21 in 1 case (0.26%), and trisomy 9 in 1 case (0.26%). The risk of 45,X karyotype was 0.77% (n = 3). One case of 47,XXY karyotype and 2 cases with other chromosome abnormalities were found. In 212 unilateral cases there were 7 with chromosome abnormalities (3.3%). In 178 bilateral cases there were 7 with abnormal karyotypes (3.93%). The CPC was associated with additional fetal US anomalies (with or without polyhydramnios/oligohydramnios) in 112 cases; chromosome abnormalities were detected in 4 cases (3.57%). 66 cases were associated with polyhydramnios/oligohydramnios but not with other fetal US anomalies; 3 cases of abnormal karyotypes were found (4.55%). The CPC was isolated in 212 cases and 7 cases were associated with chromosome disorders (3.3%). Conclusions: US plays an important role in prenatal diagnostics. Further genetic counseling is recommended in cases with CPCs.

The regulation of apoptosis in intrauterine growth restriction: a study of Bcl-2 and Bax gene expression in human placenta.

Objective: In this study, we assessed Bcl-2 and Bax gene expression patterns in human placental samples from intrauterine growth restriction (IUGR) pregnancies using normal pregnancy as control. Methods: We compared Bcl-2 and Bax gene expression in placental samples from all IUGR pregnancies treated in our clinic between 1 January 2010–1 January 2011 vs. 140 normal pregnancy samples from the same study period. We also assessed clinical parameters such as maternal age, gestational weight gain, gestational body mass index (BMI) change, and maternal birth weight. Results: In IUGR, the Bcl-2 gene was underexpressed compared to normal pregnancy. There was no difference in the Bax gene activity in the two groups. The degree of growth restriction within the IUGR group did not correlate with Bcl-2 or Bax gene activity. Conclusions: Our study revealed that it is the reduced inhibitory activity of the Bcl-2 gene rather than an enhanced stimulatory activity of the Bax gene in the background of the increased apoptosis observed in IUGR. IUGR appears to be more common with maternal age around 20 years and above 35 years. Gestational weight gain and gestational BMI change also predict the risk for IUGR.

Major Diagnostic and Pathological Features of Iniencephaly Based on Twenty-Four Cases

Iniencephaly is quite a rare malformation the etiology of which is still not fully understood. In the majority of cases it is a grave and lethal condition. It is often complicated by other abnormalities affecting the central nervous system (spina bifida, anencephaly), but malformations involving other organs and systems may also be observed. Based on 24 cases the authors have surveyed the diagnostics of iniencephaly with special regard to the disorders affecting the central and non-central nervous systems. In addition, they have compared the results of prenatal diagnostics and pathological investigations. In the sample, maternal age ranged between 17 and 42 (median 24) years. Positive obstetrical-gynecological and genetic findings in the patients’ history have been reported in 4 and 2 cases, respectively. In these cases, the maternal serum α-fetoprotein (AFP) values ranged between 0.7 and 3.9 (median 2.0) MoM, while the amniotic fluid AFP values were between 0.9 and 2.7 (median 1.4) MoM. Spina bifida (50%) and anencephaly (42%) were the most commonly occurring complications affecting the central nervous system. Among the non-central nervous system disorders, malformations of the abdominal (omphalocele) and thoracic walls (diaphragmatic hernia) were found most frequently and the tendency to develop associated polyhydramnios was also very high (75%). Pathological investigations revealed developmental disorders such as cleft lip and palate, ventricular septal defect and facial dysmorphism, which are difficult to detect using ultrasonography.

Abnormal fetomaternal glucocorticoid metabolism in the background of premature delivery: placental expression patterns of the 11β-hydroxysteroid dehydrogenase 2 gene.

OBJECTIVE During pregnancy, 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) is involved in the development of the placental barrier, and its main function is to protect the fetus from the effects of the physiological increase of maternal glucocorticoids. We compared human placental gene expression patterns of 11β-HSD2 from pregnancies that ended with preterm delivery versus full term pregnancies as controls. STUDY DESIGN We used real-time PCR to assess the placental gene expression patterns of 11β-HSD2 in 104 preterm and 140 full term pregnancies (control group) at the time of delivery. RESULTS In the preterm delivery group, the proportion of smokers was 26.9%, significantly higher than in the control group. Preterm delivery began with premature rupture of membranes in 70.2% and spontaneous uterine activity in 29.8%. The 11β-HSD2 gene was underexpressed in the preterm delivery group compared to normal pregnancy between 28 and 36 gestational weeks, but unchanged between 24 and 28 weeks. There was no fetal gender effect on 11β-HSD2 gene expression. CONCLUSION The reduced activity of the 11β-HSD2 gene seen in the preterm delivery group may impair fetal defences against maternal glucocorticoid exposure. In cases of impending premature delivery, glucocorticoid effects, potentially including postnatal neurological abnormalities and growth restriction, may be worsened by prophylactic steroids given to accelerate fetal lung maturity. The impairment in fetal defences against maternal glucocorticoids due to reduced 11β-HSD2 enzyme activity appears to begin after gestational week 28.