DiGeorge syndrome chromosome region deletion and duplication: Prenatal genotype-phenotype variability in fetal ultrasound and MRI.

OBJECTIVE: The aim of the study was to assess genotype-phenotype correlation of prenatally diagnosed fetal DGS and dup22q11 syndrome by fetal molecular genetic analysis, fetal ultrasound, and/or MRI. METHODS: In this retrospective consecutive case series, pregnant women were screened for fetal anomalies during a period of 10 years. Fetal genotype was assessed in 72 cases upon the occurrence of five prenatal fetal phenotypic features: cardiac anomalies, hypo/aplastic thymus, craniofacial malformations, urinary abnormalities, or IUGR; genotype-phenotype correlation was tested to potentially improve prenatal diagnosis of fetal DGS and dup22q11 syndrome. RESULTS: Fetal genotypes of deletions or duplications in proximal clusters of LCR22s (A-B) were associated with fetal cardiac anomalies in combination with hypo/aplastic thymus and craniofacial malformations, suggesting a correlation with deleted HIRA. TOF associated with aplastic thymus in combination with renal defects indicated a relevant correlation with TBX1 deletion. Deletions in central LCR22s (B-D) with the loss of CRKL supposed a trend of genotype-phenotype correlation with fetal urinary abnormalities. CONCLUSION: Genotype-phenotype correlation might improve prenatal diagnosis of fetal DGS and dup22q11 syndrome. Hence, prenatal screening and counseling is highly enhanced by a combination of fetal molecular genetic analysis, fetal ultrasound, and/or MRI. The implications of these findings remain to be explored.

Combination of first trimester serum afamin levels and three-dimensional placental bed vascularization as a possible screening method to detect women at-risk for adverse pregnancy complications like pre-eclampsia and gestational diabetes mellitus in low-risk pregnancies.

OBJECTIVE: Aim of the study was to assess the correlation of first trimester serum afamin levels with three-dimensional placental bed vascularization in pregnant women and its prognostic value for predicting pre-eclampsia and future fetal and maternal complications during pregnancy. METHODS: In this nested case-control study all pregnant women registered for delivery during a period of 3 years were routinely screened in the first trimester. Serum afamin levels were assessed in 764 women and correlated to 5 pregnancy outcome groups: gestational hypertension (n = 76), pre-eclampsia (n = 33), intrauterine growth restriction (n = 91), pre-term birth (n = 39), gestational diabetes mellitus (n = 170); In addition, measurements of first trimester myometrial vascularization index were performed and, in combination with afamin tested as a possible screening method to detect women at-risk for the development of adverse complications in low-risk pregnancies at the time of the first trimester. RESULTS: The results showed significantly higher serum afamin levels in women with pre-eclampsia (P<.05) and gestational diabetes mellitus (P<.05) compared to healthy pregnant women. There was no significant difference in serum afamin levels between all other pregnancy outcome groups and healthy controls. In women developing pre-eclampsia during pregnancy, afamin (OR = 1.0197, P < .05) and myometrial vascular index (OR = 0.9235, P < .001) were verified to have a significant prognostic value. Detection of pre-eclampsia in first trimester screening by a combination of afamin and myometrial vascular index performed best (AUC = 0.818). DISCUSSION: Hence, first trimester screening for pre-eclampsia could be provided by a combination of afamin and placental bed vascularization. Moreover, the combination of first trimester serum afamin levels with BMI could provide a possible screening for gestational diabetes mellitus.

First Trimester Vaginal Ureaplasma Biovar Colonization and Preterm Birth: Results of a Prospective Multicenter Study.

BACKGROUND: While there is a proven association of upper genital tract Ureaplasma infection during pregnancy with adverse pregnancy outcome, the effect of vaginal Ureaplasma colonization on preterm delivery has been controversially debated. OBJECTIVES: We hypothesized that women with isolation of vaginal U. parvum but not U. urealyticum are at increased risk for spontaneous preterm birth (SPB) compared to women with negative results. METHODS: A vaginal swab taken between 12 and 14 weeks of gestation was analyzed for the presence of Ureaplasma biovars by PCR in 4,330 pregnant women. RESULTS: Of the study cohort, 37% were positive for U. parvum, 5.9% for U. urealyticum, and 3.1% for both. The rates of SPB were 10.4% (OR 1.7, 95% CI 1.3, 2.2, p < 0.001) and 8.9% (OR 1.4, 95% CI 0.9, 2.3, p = 0.193) in the groups with isolation of U. parvum and U. urealyticum, respectively, compared to 6.4% in the group with negative PCR results. Multiple logistic regression and interaction analyses showed that vaginal colonization with U. parvum but not U. urealyticum was a statistically significant risk factor for SPB (adjusted OR 1.6, 95% CI 1.2, 2.1, p < 0.001), independent of other risk factors such as bacterial vaginosis and history of SPB. CONCLUSION: Our study demonstrates a statistically significant and independent association between first-trimester vaginal colonization with U. parvum and subsequent SPB.

First trimester serum afamin concentrations are associated with the development of pre-eclampsia and gestational diabetes mellitus in pregnant women.

OBJECTIVE: Aim of this study was to assess the prognostic capability of afamin to predict pregnancy complications. METHOD: First-trimester screening was consecutively performed in 4948 pregnant women, of whom 474 women developed pregnancy complications [gestational hypertension (n=84), pre-eclampsia (n=30), intrauterine growth restriction (n=107), preterm birth (n=44), and gestational diabetes mellitus (n=209)]. To each woman with pregnancy complications an uncomplicated pregnancy was matched for body mass index. Afamin serum concentrations were measured in 948 pregnant women at the first-trimester screening. RESULTS: Median afamin concentrations were significantly higher in women developing pre-eclampsia or gestational diabetes mellitus when compared to women with uncomplicated pregnancies (76mg/L vs. 65mg/L, p=0.001 and 80mg/L vs. 69mg/L, p<0.001). There was no difference in median afamin values between all other pregnancy complications and their matched controls. Increased afamin (i.e. >65mg/L) was a strong and independent predictor for the development of pre-eclampsia (risk ratio, 24.58; 95%CI, 2.82-214.12; p=0.004) as well as gestational diabetes mellitus (risk ratio, 2.07; 95%CI, 1.33-3.22; p=0.001). CONCLUSION: In this large nested case-control study increased afamin concentrations were a strong and independent predictor for pre-eclampsia and gestational diabetes mellitus, suggesting a potential role of afamin as predictive marker for pregnancy-related metabolic disorders.

MATERNAL HEIGHT AND PRE-PREGNANCY WEIGHT STATUS ARE ASSOCIATED WITH FETAL GROWTH PATTERNS AND NEWBORN SIZE.

The impact of maternal height, pre-pregnancy weight status and gestational weight gain on fetal growth patterns and newborn size was analysed using a dataset of 4261 singleton term births taking place at the Viennese Danube Hospital between 2005 and 2013. Fetal growth patterns were reconstructed from three ultrasound examinations carried out at the 11th/12th, 20th/21th and 32th/33th weeks of gestation. Crown-rump length, biparietal diameter, fronto-occipital diameter, head circumference, abdominal transverse diameter, abdominal anterior-posterior diameter, abdominal circumference and femur length were determined. Birth weight, birth length and head circumference were measured immediately after birth. The vast majority of newborns were of normal weight, i.e. between 2500 and 4000 g. Maternal height showed a just-significant but weak positive association (r=0.03: p=0.039) with crown-rump length at the first trimester and with the majority of fetal parameters at the second trimester (r>0.06; p0.09; p0.08; p0.17; p0.13; p0.13; p<0.001), were significantly positively associated with newborn size. Some of these associations were quite weak and the statistical significance was mainly due to the large sample size. The association patterns between maternal height and pre-pregnancy weight status with fetal growth patterns (p<0.001), as well as newborn size (p<0.001), were independent of maternal age, nicotine consumption and fetal sex. In general, taller and heavier women gave birth to larger infants. This association between maternal size and fetal growth patterns was detectable from the first trimester onwards.

Smoking prevalence among pregnant women from 2007 to 2012 at a tertiary-care hospital.

UNLABELLED: The harmful effects of smoking during pregnancy are well known, but we lack prevalence data concerning this subject in Austria. The aim ofz the present study was to determine the prevalence and any changes in the prevalence of smoking during pregnancy in the last few years. The investigation was conducted at a perinatal center in Vienna, Austria. Further aims of the study were to evaluate maternal characteristics associated with smoking and demonstrate the harmful effects of smoking on neonatal outcome in this population. Once inquired, self-reported smoking during pregnancy, maternal age, and neonatal data from 2007 to 2012 were evaluated retrospectively. Of birth records, 11,142 were analyzed. From 2007 to 2012, the prevalence of smoking declined significantly from 19.1 to 15.6 %. The overall prevalence was 18.1 % and was highest (43.7 %) among young women (<20 years). The risk of small for gestational age (SGA) was significantly higher among newborns of smoking mothers. CONCLUSION: The prevalence of smoking among pregnant women has declined in Austria in the last few years but is still quite high. Prevention programs should focus on young women, who are at highest risk in this regard. WHAT IS KNOWN: • Smoking during pregnancy is known to exert harmful effects What is New: • Paucity of epidemiological data regarding this subject in Austria • Significant decline of self-reported smoking during pregnancy from 2007 to 2012 in Vienna.

The vitamin E-binding protein afamin increases in maternal serum during pregnancy.

BACKGROUND: Afamin is a liver-derived plasma glycoprotein with vitamin E-binding properties and a putative function in fertility. This study evaluated serum afamin concentrations during and postpartum to uncomplicated pregnancies and investigated a potential association between afamin concentrations and pregnancy outcome. METHODS: Afamin serum concentrations were measured in women with uncomplicated pregnancies in a retrospective cohort (n=466) at different gestational ages and a prospective observational study (n=76) in the first, second and third trimester. Furthermore, afamin was determined in the first trimester in a cross-sectional pilot study including women with preeclampsia (PE), pregnancy-induced hypertension (PIH) and women without pregnancy complications (n=13 each). Finally, expression of afamin was investigated in human placental tissue by RT-PCR and immunohistochemistry. RESULTS: Afamin concentrations increased linearly almost two-fold during pregnancy in both retrospective and prospective studies in women without pregnancy complications with median afamin serum concentrations of 61.9 mg/l, 79.6 mg/l, and 98.6 mg/l in the first, second, and third trimester, respectively. After delivery, median afamin concentrations decreased to baseline values of 54.6 mg/l. In the pilot study with pregnancy complications, women with PE displayed significantly higher median afamin concentrations than did women with uncomplicated pregnancy (70.0 mg/l vs. 55.4 mg/l, P=0.007). Expression analyses revealed no placental afamin expression at either mRNA or protein level in uncomplicated pregnancy. CONCLUSION: A linear increase in the maternally expressed glycoprotein afamin during pregnancy may serve as basic reference for subsequent investigations of afamin in pregnancy-related disorders.

Carriage of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism does not influence the first and second trimester uterine artery Doppler flow.

OBJECTIVE: MTHFR C677T polymorphism is a genetic factor increasing both risk factors for atherosclerotic vascular diseases and obstetric complications like preeclampsia (PE) and fetal growth restriction (FGR). Increased uterine artery impedance, measured by uterine artery Doppler in the second trimester of pregnancy is also associated with PE and FGR. In this study we aimed to analyze whether MTHFR influences first and second trimester uterine artery impedance. STUDY DESIGN: In a prospective, controlled, open, single center study of 1955 consecutive singleton pregnant women, smears from buccal gingival cells were analyzed for MTHFR by hybridisation on micro arrays. Uterine artery PI values and unilateral or bilateral diastolic notch were measured at 12 and 22 weeks of gestation. Statistical significance was calculated by the x(2)-test. RESULTS: MTHFR C677T polymorphism showed a normal distribution in our population. Mean uterine artery Doppler values and bilateral or unilateral notch occurrences from 1697 statistical evaluated women did not show significant differences in any MTHFR genotype (C/C, C/T, T/T) both at 12 or 22 weeks of gestation. CONCLUSION: In summary, the data presented in this adequately powered, prospective, controlled study establish that the MTHFR C677T polymorphism does not influence Doppler flow measurements.

Interleukin-10 -1082 G/A promoter polymorphism and pregnancy complications: results of a prospective cohort study in 1,616 pregnant women.

OBJECTIVE: To investigate the frequency of the interleukin-10 (IL-10)-1082 G/A single nucleotide polymorphism in women with intrauterine fetal death (IUFD), pre-eclampsia (PE), preterm delivery (PD), and small for gestational age (SGA) infants. METHODS: In a prospective cohort study, DNA from 1,616 consecutive pregnant women was analyzed for IL-10 -1082 G/A by polymerase chain reaction. Women who developed at least one of the predefined pregnancy complications were used as cases and compared to women without pregnancy complications. RESULTS: Of 1,616 women, 254 (15.7%) developed at least one pregnancy complication. IL-10 -1082 G/A allele frequencies (G: 233/508 [45.9%] and A: 275/508 [54.1%] versus G: 1,143/2,724 [42.0%] and A: 1,581/2,724 [58.0%], respectively; p=0.10; OR 0.85; 95% CI 0.69-1.04) and genotype distributions (A/A+G/A: 201/254 [79.1%] and G/G 53/254 [20.9%] versus A/A+G/A: 1,125/1,362 [82.6%] and G/G 237/1,362 [17.4%], respectively, p=0.19; OR 0.79; 95% CI 0.54-1.15) were not significantly different between cases and controls. We observed no statistically significant difference in IL-10 -1082 G/A genotype distribution comparing controls and women with IUFD, PE, PD <37 weeks gestation, and SGA infants (<10th percentile). CONCLUSION: IL-10 -1082 G/A polymorphism is not a genetic marker for identifying women at increased risk of common pregnancy complications.

Interleukin 6-174 G/C promoter polymorphism and pregnancy complications: results of a prospective cohort study in 1626 pregnant women.

PROBLEM: To investigate the frequency of the interleukin-6 (IL-6) -174 G/C single nucleotide polymorphism (SNP) in women with intrauterine fetal death (IUFD), pre-eclampsia (PE), preterm delivery (PD), and small for gestational age (SGA) infants. METHOD OF STUDY: In a prospective cohort study, DNA from 1626 consecutive pregnant women was analyzed for IL-6 -174 G/C. Women who developed at least one of the predefined pregnancy complications were used as cases and compared with women without pregnancy complications. RESULTS: Of 1626 women, 259 (15.9%) developed at least one pregnancy complication. IL-6 -174 G/C allele frequencies and genotype distributions were not significantly different between cases and controls. Similarly, no statistically significant difference in IL-6 -174 G/C genotype distribution in women with IUFD, PE, PD <34 weeks, PD >34 weeks and SGA infants <10th percentile was observed. CONCLUSION: IL-6 -174 G/C is not a genetic marker for identifying women at increased risk of common pregnancy complications.

Absence of an association of tumor necrosis factor (TNF)-alpha G308A, interleukin-6 (IL-6) G174C and interleukin-10 (IL-10) G1082A polymorphism in women with preeclampsia.

OBJECTIVE: TNF-alpha G308A, IL-6 G174C and IL-10 G1082A polymorphisms have recently been associated with preeclampsia (PE). The aim of this study was to clarify whether the occurrence of TNF-alpha, IL-6 and IL-10 polymorphisms is increased in women of our population with PE in a previous pregnancy. METHODS: A retrospective, controlled, open, multicenter study was carried out in 107 women with a history of PE and 107 women with uncomplicated pregnancies. Smears from buccal gingival cells were analyzed for the polymorphisms of TNF-alpha, IL-6 and IL-10 by hybridization on microarrays. Statistical significance was calculated by the chi-quadrant test. RESULTS: Heterozygocity for the gene polymorphisms did not occur more often in preeclamptic women compared with controls (TNF-alpha: 29.0% versus 24.3%, p>0.05; IL-6: 46.7% versus 51.4%, p>0.05; or IL-10: 49.5% in each). Moreover, there was no significant difference between preeclamptics and controls with regard to homozygocity for TNF alpha (1.9% versus 3.7%, p>0.05); IL-6 (17.8% versus 13.1%, p>0.05); and IL-10 (30.8% versus 32.7%, p>0.05). CONCLUSION: In contrast to the findings of some other investigators, gene polymorphisms do not seem to be important in our population for development of PE.

A tumor necrosis factor-alpha promoter polymorphism and pregnancy complications: results of a prospective cohort study in 1652 pregnant women.

The purpose of this article is to investigate the frequency of the tumor necrosis factor-alpha (TNF-alpha) -308 G/A single nucleotide polymorphism in women with intrauterine fetal death, preeclampsia, preterm delivery, and small-for-gestational-age (SGA) infants. In a prospective cohort study, DNA from 1652 consecutive pregnant women was analyzed for TNF-alpha -308 G/A by polymerase chain reaction. Women who developed at least 1 of the predefined pregnancy complications were used as cases and compared to women without pregnancy complications. Of 1652 women, 268 (16.2%) developed at least 1 pregnancy complication. TNF-alpha -308 G/A allele frequencies (G: 463/536 [86%] and A: 73/536 [14%] vs G: 2366/2768 [85%] and A: 402/2768 [15%], respectively; P = .6; odds ratio [OR], 0.93; 95% confidence interval [CI], 0.69-1.25) and genotype distributions (G/G+G/A: 259/268 [97%] and A/A 9/268 [3%] vs G/G+G/A: 1352/1384 [98%] and A/A 32/1384 [2%], respectively; P = .4; OR, 0.20; 95% CI, 0.002-14.81) were not significantly different between cases and controls. The authors observed no statistically significant difference in TNF-a -308 G/A genotype distributions comparing controls and women with intrauterine fetal death, preeclampsia, preterm delivery <34 weeks' gestation, preterm delivery >34 weeks' gestation, SGA infants <3rd percentile, and SGA infants of the 4th to 10th percentile. TNF-alpha -308 G/A is not a genetic marker for identifying women at increased risk of common pregnancy complications.

Methylenetetrahydrofolate reductase C677T polymorphism and pregnancy complications.

OBJECTIVE: To investigate the frequency of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in women with intrauterine fetal death, preeclampsia, preterm delivery, and small for gestational age (SGA) infants. METHODS: In a prospective cohort study, DNA from 2,000 pregnant women were analyzed for MTHFR C677T by DNA microarray (wild-type allele, C; mutant allele, T). RESULTS: One thousand six hundred seventy-five women completed the study. Of these, 16.6% (278 women with 556 genetic alleles) developed at least one pregnancy complication and were designated study cases. There were 1,397 women (with 2,794 genetic alleles) who served as controls. MTHFR C677T allele frequencies were significantly different between cases and controls (C [wild-type]: 346 of 556 [62%]; T [mutant]: 210 of 556 [38%] compared with C: 1,911 of 2,794 [68%]; T: 883 of 2,794 [32%]; P=.005; odds ratio [OR] 1.23, 95% confidence interval [CI] 1.06-1.42). Genotype distributions were also different between cases and controls (C/T+T/T [abnormal]: 174 of 278 [63%]; C/C [normal]: 104 of 278 [37%] compared with C/T+T/T: 728 of 1,397 [52%]; C/C 669 of 1,397 [48%]; P=.002; OR 1.54, 95% CI 1.18-2.02). The clinical effect of the MTHFR C677T polymorphism was restricted to women with SGA infants (P=.05; OR 1.33, 95% CI 1.00-1.77). No significant differences in genotype distributions were observed among women with intrauterine fetal death, preeclampsia, and preterm delivery. CONCLUSION: MTHFR C677T is a genetic marker for identifying women at increased risk of SGA infants. LEVEL OF EVIDENCE: II.

Association of congenital cardiac defects and the C677T methylenetetrahydrofolate reductase polymorphism.

OBJECTIVE: MTHFR C677T polymorphism and hyperhomocysteinemia have been associated with congenital malformations of the heart and neural tube defects. A common missense mutation in the MTHFR gene (C to T substitution at position 677) produces a variant with reduced enzymatic action. The aim of this retrospective case control study was to investigate whether the occurrence of the MTHFR polymorphism is increased in mothers and fathers of children with a congenital heart disease (CHD) in our population. METHODS: We genotyped 31 couples with CHD offspring and 31 control couples for this study by obtaining smears from buccal gingiva cells and analyzed these for the MTHFR polymorphism by hybridization on microarrays. RESULTS: Statistical significance was calculated using the chi-square test and Pearson-exact test, respectively. The prevalence of homozygosity or heterozygosity for the MTHFR polymorphism was not significantly increased in parents of CHD affected children. Nevertheless significance was observed for the association between aortic arch anomalies and the mothers. CONCLUSIONS: The results of this study do not show any significant association between the MTHFR C677T polymorphism and CHD in our population. Although the numbers are small (n = 3), the MTHFR (C677T) polymorphism may be linked to the development of aortic arch anomalies.

Postdelivery levels of anti-D IgG prophylaxis in D- mothers depend on maternal body weight.

BACKGROUND: Current recommendations for anti-D prophylaxis for women who deliver a D+ offspring vary from country to country, and the introduction of new reagents require pharmacokinetic studies that show serum levels after the injection. Serum levels of anti-D may depend on the maternal body mass index (BMI). STUDY DESIGN AND METHODS: Serum concentrations of total anti-D IgG and IgG1-4 subclasses were determined by flow cytometry in 26 D- women, who had received prophylaxis after delivery of a D+ offspring. Blood samples were drawn on Days 1, 2, 3, and 14 after injection, and the BMI was recorded. RESULTS: Anti-D levels increased continuously in all women during the first 3 days. The increase was significantly affected by the BMI if higher than 27 kg per m2 (p<0.001). The higher the BMI, the less was the increase of serum anti-D. Mean peak levels 72 hours after injection was 89 ng per mL in lean women, but estimated levels were 28 to 60 percent lower in women with a BMI of 28 to 40 kg per m2. The effect of a BMI higher than 27 kg per m2 on anti-D was not gradual but progressive. Similarly, the BMI affected serum concentrations of anti-D subclasses IgG1-4 (p<0.001). CONCLUSION: The BMI needs consideration for the adjustment of the dosage of anti-D, provided its bioavailability to suppress alloimmunization is reflected by measurable amounts in the serum.

A sonographic study of perinatal hip development: from 34 weeks of gestation to 6 weeks of age.

A sonographic study of perinatal hip development was performed by consecutive measurement of Graf's alpha and beta angles in fetal and newborn hips. The study group consisted of infants with sonographically normal hip findings at birth. Forty fetuses were examined by fetal hip sonography at 34, 36 and 38 weeks of gestation. Postnatally, hip sonography was performed in the first and sixth week of age. Maturation curves of the bony (alpha-angle) and cartilaginous (beta-angle) acetabular roof from 34 weeks of gestation to 6 weeks of age were established. Prenatally, the mean alpha-angles were above the level that corresponds to a mature hip joint. A significantly higher value of the mean alpha-angles was found after birth. The mean beta-angles of the fetuses did not differ from those of the newborns. Our results revealed that the fetal hip joint is sonographically mature at 34 weeks of gestation. Further progression of hip development occurs around term.

Triploidy in a twin pregnancy: small placenta volume as an early sonographical marker.

INTRODUCTION: We report a case of a twin pregnancy with triploidy of maternal phenotype of one foetus and no chromosomal anomaly of the other twin and the role of sonographical placental volumetry. CASE: At 12 weeks of gestation, a dichorionic twin pregnancy discordant in growth is diagnosed. 3D ultrasound reveals a distinctly small placental volume of foetus II. Amniocentesis at 16 weeks discloses triploidy of this foetus. Sonography reveals asymmetrical foetal growth retardation, a severe heart defect and bilateral cleft lip and palate, typical findings in triploidy. Selective feticide at week 20+3 is followed by pre-term birth of foetus I at 27 weeks. CONCLUSION: Small placental volume in addition to growth restriction of one foetus early in the course of a twin pregnancy could be an important early marker influencing the decision for chorionic villous sampling at 12 weeks instead of amniocentesis at 16 weeks and it could lead to an earlier selective pregnancy termination of a triploid twin. This would lower the risk of pre-term birth and enable a better outcome for the remaining healthy foetus.