Fetal disseminated intravascular coagulopathy, hydrops and massive umbilical vein thrombosis consequence of a rare placental condition: multifocal chorangiomatosis.

Purpose: Villous capillary lesions are rare abnormal placental developmental conditions which include chorangiosis, chorangiomatosis, chorangioma and a rare variant of the latter called multiple chorangioma syndrome. The causes of villous capillary lesion are not completely clear but appear to involve excessive angiogenesis. MATERIALS AND METHODS: In this paper we start illustrating our experience of multifocal chorangiomatosis with the newborn affected by massive umbilical vein thrombosis, disseminated intravascular coagulopathy and hydrops, going to a literature review of cases available.Results: Two other similar cases have been previously published in literature. Comparing clinical characteristics and fetal outcomes, we confirm the association with unfavorable neonatal outcome mentioned in literature. Our case is the first characterized by severe hemolytic anemia, thrombocytopenia, heart congestion with the overlap of disseminated intravascular coagulopathy and massive umbilical vein thrombosis and congenital anomalies. CONCLUSIONS: Our clinical case and the review of literature highlight how multifocal chorangiomatosis, within the three subgroups identified, is the rarer form with distinct placental features and the worst outcomes for neonates. No cases of multifocal chorangiomatosis have never been described prenatally and, for further studies, could be reasonable investigate the involvement of some growth factors like vascular endothelial growth factor and placental growth factor that could lead to a detection of a subgroup of patient at higher risk to manifest placental vascular lesions and the follow fetal and maternal complications.

Lower maternal serum tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) levels in early preeclampsia. A retrospective study.

OBJECTIVE: To determine whether maternal serum concentrations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a cytokine with anti-inflammatory activity, also involved in cardiovascular morbidity, differ between women with early preeclampsia (<34 weeks) and those with uncomplicated pregnancies. STUDY DESIGN: This nested case control study included 40 women carrying a single fetus with an uncomplicated pregnancy and 20 women with early preeclampsia (<34 weeks). Data were matched 1:2 for gestational age at the time of venipuncture (28-34 weeks of gestation), converted into multiples of the median and adjusted for maternal weight. The maternal serum TRAIL concentrations were determined using an enzyme immunoassay. RESULTS: The TRAIL concentrations were lower in the patients with early preeclampsia when compared with those of the control group, being 29.64 ±â€¯8.83 pg/dL and 43.8 ±â€¯12.53 pg/dL (p-value < 0.001), respectively. The difference was also present after multiple of median conversion and maternal weight adjustment. The quoted multiple of median values were 1.00 ±â€¯0.27 and 0.82 ±â€¯0.23, respectively (p-value < 0.001). CONCLUSIONS: Serum TRAIL concentrations are significantly reduced in patients with early preeclampsia. This result is in line with the presence of an intravascular inflammation typical of preeclampsia. The lower levels of TRAIL detected in preeclampsia should be useful for a more proper selection of women with long-term cardiovascular risk later in life.

Prospective evaluation of ultrasound and biochemical-based multivariable models for the prediction of late pre-eclampsia.

OBJECTIVE: Prospective assignment at 11 + 0 to 13 + 6 weeks of risk for late pre-eclampsia (PE) using eight logistic regression-based statistical models. METHODS: Five hundred and fifty-four pregnancies. Uterine artery pulsatility index, parity, body mass index, mean arterial pressure, pregnancy-associated plasma protein-A, free ß-human chorionic gonadotrophin and maternal age, were combined to obtain 'a posteriori risk of PE'. RESULTS: We observed 39 cases (7%) of late PE. There were 12 cases of severe PE and 27 of mild PE. According to the models used, the estimated detection rate ranged from 38.5% to 84.6% with a false-positive rate of 10%. The median risk ratio (estimated median risk of PE in affected pregnancies divided by estimated risk of PE in unaffected pregnancies) ranged between 1.66 and 7.61. The most reproducible biochemical-based model was a mixed model encompassing maternal history and pregnancy-associated plasma protein-A. CONCLUSION: Some of the multivariable models drawn from the literature accurately predicted the late PE occurrence. The failure of some models may be because of the population in question not bearing several of the risk factors used to generate the models proposed. An effective combined screening at first trimester for late PE seems possible.

Uterine artery Doppler and biochemical markers (PAPP-A, PIGF, sFlt-1, P-selectin, NGAL) at 11 + 0 to 13 + 6 weeks in the prediction of late (> 34 weeks) pre-eclampsia.

OBJECTIVE: To determine the performance of screening for late pre-eclampsia (PE) by maternal characteristics, uterine artery Doppler and a set of biochemical markers at 11 + 0 to 13 + 6 weeks' gestation. METHODS: Prospectively enrolled women at 11 + 0 to 13 + 6 weeks. Maternal characteristics, highest UtA pulsatility index and serum placental biomarkers including pregnancy-associated plasma protein-A, placental growth factor, soluble fms-like tyrosine kinase 1, P-selectin and neutrophil gelatinase-associated lipocalin were recorded. RESULTS: The rate of PE was 2.5% (13/528). Four (0.8%) had severe PE. A combined screening model that included placental growth factor, soluble fms-like tyrosine kinase 1 and neutrophil gelatinase-associated lipocalin could detect 77% of PE at a 10% false-positive rate. Mean risk for mild PE was 8.8% ± 6.4, mean risk for severe PE was 38.6% ± 4.3. Mean risk for controls was 2% ± 4.1. CONCLUSION: This combination of maternal biochemical variables in the first trimester can detect a consistent number of late PE. Further studies on a new and independent series of data could confirm the presented results.

Gene expression in chorionic villous samples at 11 weeks of gestation in women who develop pre-eclampsia later in pregnancy: implications for screening.

OBJECTIVES: To determine the gene expression profile in chorionic villous samples (CVSs) of women destined to develop pre-eclampsia (PE). METHOD: Case-control study encompassing five women destined to develop PE [cases matched for gestational age with 30 controls]. We quantified mRNA expression on tissue samples from CVS of normal and PE patients. We then assessed mRNA expressions of cathepsin (CTSD), angiopoietin 2 (ANGPT2), interleukin 8, chemokine (C-X-C motif) ligand 10, neurokinin B (NKB), matrix metallopeptidase 9, major histocompatibility complex, class I, C (HLA-C)and human leukocyte antigen-G (HLA-G). Data were analyzed by nonparametric rank analysis. RESULTS: For all the mRNA species considered in this study, except CTSD and ANGPT2, all the mean observed ranks in the PE group were significantly altered compared with the rank expectation among controls. mRNA for NKB and HLA-C were the markers with the highest degree of aberration in PE, compared with those in controls. CONCLUSION: Our study has directly showed that gene expressions relating to trophoblastic cell invasion or utero-placental hemodynamic adaptation are altered in the first trimester trophoblasts that go on to develop PE later. These results posit the use of residual CVS as a possible screening method for PE.

Performance of messenger RNAs circulating in maternal blood in the prediction of preeclampsia at 10-14 weeks.

OBJECTIVE: The purpose of this study was to determine whether the combined distribution of a panel of cellular messenger RNA markers can detect preeclampsia long before onset. STUDY DESIGN: We compared blood at 10-14 weeks from 11 women who ultimately experienced preeclampsia with 88 matched control subjects. After multiples of the median conversion of all the markers, logistic regression was used to calculate the risk of the development of preeclampsia. RESULTS: Higher multiples of the median values than expected were found for endoglin, fms-related tyrosine kinase 1, and transforming growth factor-ß1. Lower multiples of the median values were found for placental growth factor and placental protein 13. Endoglin fms-related tyrosine kinase 1 and transforming growth factor-ß1 had the best discriminant power. Messenger RNA species provided independent contributions to the prediction of preeclampsia. In fact, 11 women with preeclampsia scored a median risk of 50% of experiencing preeclampsia. Control subjects scored a median risk of preeclampsia of 0.18%. The detection rate at a 5% false positive rate was 72.3%. CONCLUSION: The messenger RNA dosage in maternal blood would be a useful method for the calculation of the risk of the development of preeclampsia.

Gene expression in chorionic villous samples at 11 weeks of gestation in women who develop preeclampsia later in pregnancy: implications for screening.

OBJECTIVES: To determine the gene expression profile in chorionic villous samples (CVS) of women destined to develop preeclampsia. METHOD: cDNA microarray technology was employed. Ten singleton fetuses of women who subsequently developed preeclampsia where compared with a pool of 50 controls. The mRNA expression of some of the genes previously found to be up- or down-regulated were validated by RT-PCR in peripheral blood from 23 pregnant women at term affected with preeclampsia and 23 controls. RESULTS: Altered expression was found among several genes including those involved in invasion of human trophoblasts (Titin), in inflammatory stress (Lactotransferrin), endothelial aberration (Claudin 6), angiogenesis (Vasohibin 1), blood pressure control (Adducin 1). Also the peripheral blood from preeclampsia patients showed significant differences for all the genes studied. CONCLUSION: CVS show an aberrant gene profile prior to preeclampsia onset that may be predictive of the disease.

TGF alpha has low protein expression in nonsyndromic clefts.

Genetic studies have demonstrated that nonsyndromic cleft is composed of two separate entities: the cleft palate only and cleft of the lip, alveolus with or without cleft palate; both have a heterogeneous genetic background and environmental factors contribute to the onset of these malformations. The role of transforming growth factor alpha (TGF-A) was considered possible, but conflicting results have been reported. To detect if TGF-A is involved in the onset of cleft diseases, a series of patients with nonsyndromic clefts and control subjects were analyzed with regard to protein expression. Forty-three patients with nonsyndromic clefts and 21 unaffected subjects were enrolled in this study. Paraffin-embedded specimens were matched with TGF-A antibody and then scanned with a computerized image analyzer. TGF-A was scored as absent, moderately (from 10% to 30%), and highly expressed in epithelium, gland, and muscle. Data were statistically analyzed with a Kruskal-Wallis test. Comparison between control subjects and patients with clefts showed that only gland and epithelium reached a significant P value. A subsequent comparison between cleft of the lip, alveolus with or without cleft palate and cleft palate only groups demonstrated a statistically significant difference only for gland. TGF-A was decreasingly expressed in unaffected, cleft of the lip, alveolus with or without cleft palate, and patient with cleft palate only and thus further strength has been given to its role in the onset of the disease.

Quantitative distribution of a panel of circulating mRNA in preeclampsia versus controls.

OBJECTIVE: The aim of this study was to evaluate whether the quantitative distribution of a panel of circulating mRNAs from maternal whole blood of normal pregnancies is statistically different from those complicated with preeclampsia (PE) with or without intrauterine growth restriction (IUGR). METHODS: Maternal whole blood of six subjects with mild or severe PE with or without IUGR and 30 matched controls (1:5 match for gestational age) were retrospectively examined for circulating mRNA markers. Seven specific mRNA markers were identified and chosen based on previous microarray mRNA expressions performed on placental tissue from normal and PE patients. They were human placental lactogen (hPL), inhibin A, KISS-1, pregnancy-associated plasma protein-A (PAPP-A), plasminogen activator inhibitor type 1 (PAI-1), selectin-P and vascular endothelial growth factor receptor (VEGFR), which were therefore quantified for statistical purposes. RESULTS: Median gestational age was 229 (178-283) and 232 (194-262) days for controls and cases respectively. All mRNA markers but PAPP-A, showed statistically different median values. They were hPL, inhibin A, KISS-1, PAI-1, Selectin-P, and VEGFR. Inhibin A, Selectin-P and VEGFR showed higher values than expected for controls. Instead, hPL, KISS-1 and PAI-1 values of PE patients were lower than those of controls. Selectin-P was the marker with the most aberrant difference, followed by VEGFR and KISS-1. CONCLUSION: This preliminary analysis revealed that the median values of a panel of mRNAs from the maternal blood of PE patients were different from those of the same gestational age control group at the third trimester. If prospective studies at the second trimester could detect a related marker sufficiently able to discriminate between affected and unaffected patients and thus detect the disease before its clinical onset, then a screening project using a panel of mRNAs would be feasible.

Total activin A in maternal blood as a marker of preterm delivery in low-risk asymptomatic patients.

OBJECTIVES: To retrospectively evaluate whether increased serum levels of total activin A (t-activin A) are found in women who subsequently experience preterm delivery (PTD). METHODS: Data on maternal serum t-activin A concentrations were available from a total of 84 singleton pregnant women and included 14 PTD pregnancies, each matched for gestational age and length of freezer storage, with 5 control pregnancies having term delivery (TD). Analyte values were expressed as multiple(s) of the control median. RESULTS: The median t-activin A for controls and cases was 1.00 +/- 0.45 and 1.27 +/- 0.53 MoM, respectively. Univariate analysis of the MoM values was performed using the Kaplan-Meier algorithm. Differences in the rate of delivery using a t-activin A MoM cut-off of > or = 1 SD (equivalent to 1.26 MoM) were analysed using the log rank test. The cumulative rate of PTD (< 37 weeks) was significantly higher for women with t-activin A concentrations > or = 1.26 MoM than those with t-activin A concentrations below this cut-off (40% vs.. 10%, p-value = 0.0218 log rank test). CONCLUSIONS: T-activin A concentration is higher in women who will develop PTD in a low-risk population. T-activin A values are inversely proportional to the time elapsed from blood test to delivery. Prospective studies would determine the precise discriminability of this marker for PTD and the best week for performing the blood test, allowing for a proper calculation of the detection rate and a positive predictive value.

Evidence of genetic underexpression in chorionic villi samples of euploid fetuses with increased nuchal translucency at 10-11 weeks' gestation.

OBJECTIVE: To retrospectively investigate whether the genetic profile from chorionic villous sampling (CVS) found in euploid fetuses with increased NT differs from matched controls. STUDY DESIGN: We employed cDNA microarray technology to characterize and compare the gene expression profile of chorionic villous tissues (which encompass the trophoblast and inner mesenchymal core) belonging to four singleton male fetuses with increased NT at 10-11 weeks' gestation. A pool of four normal chorionic villous tissues belonging to four respective fetuses, matched for gestational age and gender, was used as controls. RESULTS: In euploid fetuses, we found several underexpressed genes, possibly involved in mechanisms associated with the abnormal NT thickness. All these genes are likely to belong to the mesenchymal core of the villus that originates from the extraembryonic mesoderm, and thus might be closely representative of the embryonic genetic profile. They include: (1) genes of embryonic development and differentiation such as Endothelin 3 (EDN3) and secreted frizzled-related protein 4 (SFRP4); (2) genes of the extracellular matrix (ECM) metabolism such as tissue inhibitor of metalloproteinase1 (TIMP1), and disintegrin-like and matrix metalloproteinase (MMP) (reprolysin type) with thrombospondin type 1 Motif or ADAMTS2, exostoses (multiple)-like 1 (EXTL1), heparan sulfate (HS) 6-O-sulfotransferase 1 or HS6ST1, fibronectin 1 (FN1) and Integrin Alpha 10 (ITGA10) involved in HS and proteoglycan bio-synthesis, ECM synthesis and cell-matrix adhesion; (3) genes involved in vessel formation and differentiation such as angiogenic factor (VG5Q), and in blood pressure control and muscle contraction, like Endothelin 3 or EDN3 and sarcolemma associated protein (SLMAP). Such lower expressions of the villous tissues might be related to an immature genetic profile of the embryo development as well as abnormal regulation of ECM bio-synthesis and/or improper vessel growth and blood pressure control. Also, the results partially support the theories proposed for NT enlargement such as altered composition of ECM and abnormal/delayed development of the circulatory system. CONCLUSIONS: Abnormal extraembryonic genetic expression is found at 10-11 weeks' gestation in euploid fetuses with increased NT. If both extra- and intraembryonic mesoderms express the same genetic alterations, then microarray analyses on CVS could be used to screen several mesoderm-derivate anomalies.

Delaire's cheilorhinoplasty: unilateral cleft aesthetic outcome scored according to the EUROCLEFT guidelines.

OBJECTIVE: The aim of our study is to evaluate, in accordance with EUROCLEFT guidelines, the aesthetics of nasolabial area in a sample of complete unilateral cleft of lip and palate patients (UCLP), after surgical correction with Delaire' technique. METHODS: Twenty-two UCLP patients (16 males and 6 females, 9 right and 13 left side clefts) were enrolled in this retrospective study. Patients were operated at 7 (mean value) months of age by a single surgeon. Frontal and sub-mental photos for each baby were recorded at 8.5 (mean value) years of age, and evaluated twice, by three independent maxillofacial surgeons. A five-point scale (EUROCLEFT guidelines) was used. Nonparametric analysis (Kruskal-Wallis test) was applied to detect differences in medians obtained in studied groups. RESULTS: Kruskal-Wallis test showed no statistical significant differences among evaluations of three surgeons and between the first and the second evaluation of the same surgeon. The global appearance of the upper lip and nose was scored with a mean value of 2 (i.e. good). The sample was then divided into two subgroups, according with patient' age; the aesthetics and the symmetry of the nose resulted better in elder patients (i.e. subgroup A, mean period of observation=10.2 years), whereas upper lip achieved better results in younger patients (i.e. subgroup B, mean period of observation=4.9 years). CONCLUSIONS: EUROCLEFT guidelines are a useful method to evaluate--aesthetically and over time--cleft lip and palate patients, treated with a single surgical procedure. We hypothesize that Delaire technique could progressively improve aesthetics and symmetry of the nose, throughout the growth of the patient.

Non-syndromic orofacial clefts in Southern Italy: pattern analysis according to gender, history of maternal smoking, folic acid intake and familial diabetes.

BACKGROUND: Genetic studies have demonstrated that non-syndromic clefts of the lip, alveolus and palate have an heterogeneous genetic background, and that environmental factors contribute to the onset of this malformation. Therefore studies on different and homogeneous populations can be useful in detecting potentially related environmental and genetic factors. PURPOSE: The aim of the present study was to evaluate whether gender, folic acid intake, family history of diabetes and/or smoking during pregnancy were associated with a specific type of cleft in a group of patients affected by non-syndromic clefts, collected from Southern Italy. MATERIAL AND METHODS: Data from one hundred and twenty-six patients were evaluated retrospectively. Each cleft was described as composed by separate antomical entities such as lip, alveolus, primary and secondary palate. None had an isolated alveolar cleft and this was used as internal control. Pattern analysis was used to detect differences in the frequencies of any possible combination of 7 types of clefting stratified according to the studied variables. Data were analysed by comparing observed proportions. RESULTS: Isolated cleft palate as well as right-sided clefts of lip, alveolus and palate were more frequent in females (p = 0.0014 and 0.0281, respectively), while left sided clefts were more frequent in males (p = 0.0359). A lack of consumption of folic acid was associated with an higher incidence of clefts of the left lip (p = 0.018), while familial diabetes was associated more often with isolated cleft palate (p = 0.0014). CONCLUSIONS: Gender-related results were comparable with those found in Northern Italy and other countries. Environmentally related results disclosed specific subclasses of clefting associated with lack of folic acid consumption and familial diabetes.