Stepwise sequential screening for trisomy 21 in assisted reproduction pregnancies.

We offered a modified stepwise sequential integrated screening for Down syndrome to 72 singleton and 16 twin pregnancies obtained with assisted reproductive techniques, observing no cases of trisomy 21 and obtaining a false positive rate of 10% in singleton and 7% in twin pregnancies. In our population, this approach for regulating access to invasive karyotyping can avoid a substantial number of unnecessary procedures, comparing favourably with current practice even in spontaneous pregnancies.

Association between birth weight and first-trimester free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A.

STUDY OBJECTIVE: To assess the relationship between first-trimester maternal serum PAPP-A and free beta-hCG and birth weight. DESIGN: Observational study. SETTING: Teaching hospital. PATIENT(S): Singleton pregnancies (n = 1,630) at 10-14 weeks of gestation. INTERVENTION(S): Fluorimetric immunoassays for maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta-hCG. MAIN OUTCOME MEASURE(S): Customized birth weight percentiles, calculated taking into account maternal height, weight, ethnic origin, parity, smoking status, and fetal gender. RESULT(S): There was a significant positive correlation between birth weight and PAPP-A, but not free beta-hCG levels. Maternal serum levels of PAPP-A were significantly lower in small-for-gestation (SGA) newborns than in control subjects and were significantly higher in large-for-gestation (LGA) newborns than in control subjects. Maternal serum free beta-hCG levels were lower in pregnancies complicated by pre-eclampsia than in normotensive ones. Multivariable analysis found PAPP-A to be an independent predictor of absolute birth weight, SGA, and LGA. Free beta-hCG was found to be an independent predictor of gestational hypertension and pre-eclampsia. Neither of the two markers was associated with preterm delivery. CONCLUSION(S): Maternal serum PAPP-A levels in the late first trimester of pregnancy are associated with subsequent fetal growth (including both physiologic variation and abnormal growth), and decreased free beta-hCG is more predictive of hypertensive disorders of pregnancy.

Correlation between first-trimester uterine artery Doppler indices and maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A.

OBJECTIVE: To assess the correlation between first-trimester uterine artery Doppler measurements and maternal serum levels of free beta-hCG and pregnancy-associated plasma protein A (PAPP-A). DESIGN: Observational study. SETTING: Teaching hospital. PATIENT(S): Four hundred thirty-three women at 10-14 weeks of gestation. INTERVENTION(S): Doppler ultrasound of the uterine arteries. Fluorimetric immunoassays for free beta-hCG and PAPP-A. MAIN OUTCOME MEASURE(S): Uterine artery mean resistance index (RI), pulsatility index (PI), and number of early diastolic notches. Maternal serum levels of free beta-hCG and PAPP-A. RESULT(S): There were 401 uncomplicated pregnancies. In this group, free beta-hCG and PAPP-A did not significantly correlate with uterine artery RI or PI (r values between -0.089 and 0.029, all nonsignificant). Free beta-hCG and PAPP-A levels did not significantly change with the number of notches. Uterine artery resistance and PAPP-A levels were independently correlated with birth weight. CONCLUSION(S): Preliminary evidence suggests that first-trimester uterine artery Doppler measurements do not correlate with maternal serum levels of free beta-hCG and PAPP-A. This may allow their combined use in multivariate screening for pregnancy complications.

Correlation between first trimester fetal bone length and maternal serum pregnancy-associated plasma protein-A (PAPP-A).

BACKGROUND: Pregnancy-associated plasma protein-A (PAPP-A) is produced by the embryo and placenta during pregnancy, and its maternal serum concentrations are related to subsequent fetal growth. Evidence from animal models and in vitro experiments suggests that PAPP-A is particularly involved in the regulation of bone development. The aim of this study was to assess the correlation between late first trimester fetal bone length and maternal serum levels of PAPP-A. METHODS: In a cross-sectional observational study, ultrasound measurements of fetal long bones and fluorimetric immunoassays for maternal serum PAPP-A were performed in 514 singleton pregnancies at 10-14 weeks of gestation. RESULTS: There were 501 uncomplicated pregnancies. There were significant correlations between PAPP-A values and length of humerus, femur and tibia [r values 0.12 (P = 0.01), 0.11 (P = 0.01) and 0.10 (P = 0.03), respectively]. The association with the length of ulna and foot did not reach statistical significance (r values 0.08 and -0.03, respectively). CONCLUSIONS: Maternal serum PAPP-A levels at 10-14 weeks of gestation are significantly associated with the length of fetal long bones such as humerus, femur and tibia. This provides further evidence that PAPP-A may be involved in the regulation of bone development.

Lack of effect of dietary nucleotide supplementation on erythrocyte 2,3-diphosphoglycerate concentration. A study on preterm neonates.

BACKGROUND: Recently we demonstrated an increased 2,3-diphosphoglycerate (2,3-DPG) erythrocyte concentration in rat pups subjected to nucleotide-enriched artificial feeding. DESIGN: The present study was carried out to test the hypothesis that a possible increase in 2,3-DPG concentration can also be obtained in human neonates who are fed nucleotide-enriched formula. Preterm neonates born or referred to the neonatal intensive care unit of the G. Gaslini Hospital, Genoa University, with a gestational age >30 weeks and <37 weeks were enrolled in our randomized trial. Recruitment took place within 48-72 hours from birth. Only newborns of mothers deciding not to breast-feed were eligible to be randomized for the supplemented group (FN) or non-supplemented group (RF). Breast-fed newborns were considered the control group (C). The study window (for supplementation and blood samples) was restricted to the first two weeks following birth (from the 2nd (t1) to the 16th (t2) day of life). At the end of our study, only 21 neonates were eligible for statistical analysis. RESULTS: The stimulating action of dietary nucleotides on 2,3-DPG concentration failed to be demonstrated; increases in 2,3-DPG concentration that were observed in newborns fed with nucleotide supplemented formula (FN) were comparable to those observed in newborns fed with regular formula (RF) and breast-fed newborns. CONCLUSIONS: The EC recommendation for the amount of nucleotides allowed in formula milk does not seem to be high enough to have positive effects on 2,3-DPG synthesis. Whether this possible 'pharmacological' effect can be achieved by a higher intake of ingested nucleotides and/or a change in the proportions of single nucleotides contained in milk formulas remain interesting end points to be elucidated.

Polymorphisms in the osteopontin promoter affect its transcriptional activity.

Understanding the molecular mechanisms that underlie regulation of transcription of the human osteopontin encoding gene (OPN) may help to clarify several processes, such as fibrotic evolution of organ damage, tumorigenesis and metastasis, and immune response, in which OPN overexpression is observed. With the aim to evaluate variants with functional effect on transcription, we have analyzed the promoter region and focused our investigation on three common variants present in the first 500 bp upstream of the transcription start site. Transfection of constructs carrying the four most frequent haplotypes relative to variants at -66, -156, and -443 fused to the luciferase reporter gene in a panel of different cell lines showed that one haplotype conferred a significantly reduced level of reporter gene expression in all tested cell lines. We describe that the -66 polymorphism modifies the binding affinity for the SP1/SP3 transcription factors, the -156 polymorphism is included in a yet uncharacterized RUNX2 binding site, and the -443 polymorphism causes differential binding of an unknown factor. The finding of differential effects of various combination of variants in haplotypes may contribute to explain data of association studies reported in several already published articles. Future association studies using haplotypes instead of single OPN variants will allow to achieve more accurate results referable to differential expression of OPN in several common diseases, in which OPN is considered a candidate susceptibility gene.

Early vaginal bleeding and first-trimester markers for Down syndrome.

OBJECTIVES: To assess the effect of early vaginal bleeding on first-trimester markers for Down syndrome. METHODS: A retrospective study was conducted on 2330 normal singleton fetuses who underwent first-trimester combined screening for Down syndrome based on ultrasound and maternal serum markers. Fetal nuchal translucency (NT), maternal serum pregnancy-associated plasma protein A (PAPP-A), free beta-hCG and the false-positive rate of the test were compared between pregnancies with (n = 253) and without (n = 2077) a history of early vaginal bleeding. RESULTS: The mean +/- SD log(10) MoM for NT, PAPP-A and free beta-hCG was -0.024 +/- 0.101, 0.007 +/- 0.244, 0.047 +/- 0.273 and -0.011 +/- 0.108, -0.006 +/- 0.223, 0.008 +/- 0.264 in pregnancies with and without a history of early vaginal bleeding, with a p value of 0.07, 0.40 and 0.03 respectively. The false-positive rate was 2.4% and 3.6% (p = 0.33). CONCLUSIONS: An earlier episode of vaginal bleeding is associated with an increase in maternal serum free beta-hCG levels at first-trimester combined screening for Down syndrome. However, this phenomenon is unlikely to significantly affect the false-positive rate of the test.

Homocysteine, folate, vitamin B12 levels, and C677T MTHFR mutation in children with renal failure.

Hyperhomocysteinemia is well documented in chronic renal failure (CRF) and premature and progressive occlusive vascular disease is common in CRF. The combined effects of renal failure, folate and vitamin B(12) levels, and a common mutation (C677T) in the methylenetetrahydrofolate reductase (MTHFR) gene that leads to total plasma homocysteine (tHcy) elevation in CRF children were investigated. Forty-two children (15 females) with CRF, mean age 10.3+/-4.7 years, were included. The mean glomerular filtration rate (GFR) was 37.3+/-16.9 ml/min per 1.73 m(2). The control group comprised 33 children (18 females) with a mean age of 8.6+/-3.4 years. There were 40% of CRF patients with hyperhomocysteinemia. Folate and vitamin B(12) deficiencies were identified in 14% (n=6) and 5% (n=2), respectively, of all patients. On univariate analysis, the tHcy serum concentration was negatively correlated with the plasma folate concentration (P<0.05) in controls, and with GFR (P<0.05) in patients. On multiple regression analysis for the predictors of tHcy serum concentrations, folic and vitamin B(12 )were significant in controls, whereas only GFR was significant in CRF children. In our patients no effect of the MTHFR polymorphism on tHcy levels was seen This result, in addition to the limited number of patients, may partially be explained by the low prevalence of folate deficiency in our patients.

Comparison of first trimester, second trimester and integrated Down's syndrome screening results in unaffected pregnancies.

Our aim was to compare the results of first trimester combined test, second trimester triple test, and integrated test in the same pregnant population. We retrospectively studied 927 women, all giving birth to an unaffected baby except for two cases of Down's syndrome. The women underwent a nuchal translucency ultrasound measurement and a blood sampling for pregnancy-associated plasma protein A and free beta-hCG subunit (free total chorionic gonadotropin subunit) assay in the first trimester of pregnancy. A second trimester biochemical screening (alpha-fetoprotein, unconjugated oestriol and total hCG) was performed later. The correlations between each pair of markers and between each marker level and maternal age were calculated. No marker showed significant correlation with any other or with maternal age, with the obvious exception of free beta-hCG subunit and total hCG. The false-positive rate (cut-off level: 1 in 350 at term) was 1.5% for the first trimester test, 3.6% for the second trimester test and 0.54% for the integrated test. In 10/14 pregnancies, the increased risk in the first trimester was not confirmed neither in the second trimester nor by the integrated test. In 29/33 women with an increased risk in the second trimester, the first trimester and the integrated test results were discordant. The absence of correlation among different marker levels suggests that the information supplied by the first and second trimester tests is different. Integrating first and second trimester markers in a single test could pose the ethical problem of withholding first trimester results and thus denying the possible advantages of an earlier pregnancy termination.