Analytical approaches to detect maternal/fetal genotype incompatibilities that increase risk of pre-eclampsia

<p>Abstract</p> <p>Background</p> <p>In utero interactions between incompatible maternal and fetal genotypes are a potential mechanism for the onset or progression of pregnancy related diseases such as pre-eclampsia (PE). However, the optimal analytical approach and study design for evaluating incompatible maternal/offspring genotype combinations is unclear.</p> <p>Methods</p> <p>Using simulation, we estimated the type I error and power of incompatible maternal/offspring genotype models for two analytical approaches: logistic regression used with case-control mother/offspring pairs and the log-linear regression used with case-parent triads. We evaluated a real dataset consisting of maternal/offspring pairs with and without PE for incompatibility effects using the optimal analysis based on the results of the simulation study.</p> <p>Results</p> <p>We identified a single coding scheme for the incompatibility effect that was equally or more powerful than all of the alternative analysis models evaluated, regardless of the true underlying model for the incompatibility effect. In addition, the log-linear regression was more powerful than the logistic regression when the heritability was low, and more robust to adjustment for maternal or fetal effects. For the PE data, this analysis revealed three genes, lymphotoxin alpha (<it>LTA</it>), von Willebrand factor (<it>VWF</it>), and alpha 2 chain of type IV collagen (<it>COL4A2</it>) with possible incompatibility effects.</p> <p>Conclusion</p> <p>The incompatibility model should be evaluated for complications of pregnancy, such as PE, where the genotypes of two individuals may contribute to the presence of disease.</p

A new approach to fetal echocardiography: digital casts of the fetal cardiac chambers and great vessels for detection of congenital heart disease

OBJECTIVE: The purpose of this study was to describe a method of 4-dimensional (4D) reconstruction of the cardiac chambers and outflow tracts using a combination of spatiotemporal image correlation, "inversion mode," and "B-flow" imaging. METHODS: Spatiotemporal image correlation and the inversion mode were used in the examination of the volume data sets of 23 fetuses with congenital heart anomalies. A subset was also examined with B-flow imaging using the gradient light algorithm. Digital reconstructions from abnormal hearts were compared with a library obtained from fetuses without abnormalities. RESULTS: Rendered images of the 4-chamber view using the inversion mode were characterized by: (1) echogenic chambers; (2) sharp delineation of chamber contours when compared with 2-dimensional (2D) images; and (3) distinct display of the myocardium, interventricular septum, interatrial septum, and mitral and tricuspid valves as anechoic structures. Ventricular septal defects, abnormal differential insertion of the atrioventricular valves, and valve atresia were well visualized with the inversion mode. The application of inversion mode or B-flow imaging to 4D rendering of the outflow tracts resulted in "digital casts" displaying the spatial relationships between the outflow tracts as well as the connections between the great arteries and ventricular chambers. The spatial relationships and communications among cardiac structures cannot be visualized with conventional 2D ultrasonography. CONCLUSIONS: The application of spatiotemporal image correlation, inversion mode, and B-flow imaging generates information about the anatomy and pathologic characteristics of the fetal heart (digital casts) that cannot be obtained with 2D fetal echocardiography. We propose that these modalities enhance the information provided by ultrasonographic interrogation of the fetal heart and will improve prenatal diagnosis

CÁNCER DE COLON Y EMBARAZO: REPORTE DE CASO Y REVISIÓN DE LA LITERATURA

El cáncer colorrectal asociado al embarazo es una patología extremadamente infrecuente. Se presenta el caso de una paciente de 38 años con antecedentes familiares de cáncer de colon, cursando un embarazo de 35 semanas en la que se diagnosticó un cáncer de colon derecho. Se efectúa una revisión de la literatura en relación al diagnóstico y manejo de esta rara entida

National and regional estimates of term and preterm babies born small for gestational age in 138 low-income and middle-income countries in 2010.

BACKGROUND: National estimates for the numbers of babies born small for gestational age and the comorbidity with preterm birth are unavailable. We aimed to estimate the prevalence of term and preterm babies born small for gestational age (term-SGA and preterm-SGA), and the relation to low birthweight (<2500 g), in 138 countries of low and middle income in 2010. METHODS: Small for gestational age was defined as lower than the 10th centile for fetal growth from the 1991 US national reference population. Data from 22 birth cohort studies (14 low-income and middle-income countries) and from the WHO Global Survey on Maternal and Perinatal Health (23 countries) were used to model the prevalence of term-SGA births. Prevalence of preterm-SGA infants was calculated from meta-analyses. FINDINGS: In 2010, an estimated 32·4 million infants were born small for gestational age in low-income and middle-income countries (27% of livebirths), of whom 10·6 million infants were born at term and low birthweight. The prevalence of term-SGA babies ranged from 5·3% of livebirths in east Asia to 41·5% in south Asia, and the prevalence of preterm-SGA infants ranged from 1·2% in north Africa to 3·0% in southeast Asia. Of 18 million low-birthweight babies, 59% were term-SGA and 41% were preterm-SGA. Two-thirds of small-for-gestational-age infants were born in Asia (17·4 million in south Asia). Preterm-SGA babies totalled 2·8 million births in low-income and middle-income countries. Most small-for-gestational-age infants were born in India, Pakistan, Nigeria, and Bangladesh. INTERPRETATION: The burden of small-for-gestational-age births is very high in countries of low and middle income and is concentrated in south Asia. Implementation of effective interventions for babies born too small or too soon is an urgent priority to increase survival and reduce disability, stunting, and non-communicable diseases. FUNDING: Bill & Melinda Gates Foundation by a grant to the US Fund for UNICEF to support the activities of the Child Health Epidemiology Reference Group (CHERG)

Estimates of Burden and Consequences of Infants Born Small for Gestational Age in Low and Middle Income Countries with INTERGROWTH-21(st) Standard: Analysis of CHERG Datasets.

Objectives To estimate small for gestational age birth prevalence and attributable neonatal mortality in low and middle income countries with the INTERGROWTH-21st birth weight standard. Design Secondary analysis of data from the Child Health Epidemiology Reference Group (CHERG), including 14 birth cohorts with gestational age, birth weight, and neonatal follow-up. Small for gestational age was defined as infants weighing less than the 10th centile birth weight for gestational age and sex with the multiethnic, INTERGROWTH-21st birth weight standard. Prevalence of small for gestational age and neonatal mortality risk ratios were calculated and pooled among these datasets at the regional level. With available national level data, prevalence of small for gestational age and population attributable fractions of neonatal mortality attributable to small for gestational age were estimated. Setting CHERG birth cohorts from 14 population based sites in low and middle income countries. Main outcome measures In low and middle income countries in the year 2012, the number and proportion of infants born small for gestational age; number and proportion of neonatal deaths attributable to small for gestational age; the number and proportion of neonatal deaths that could be prevented by reducing the prevalence of small for gestational age to 10%. Results In 2012, an estimated 23.3 million infants (uncertainty range 17.6 to 31.9; 19.3% of live births) were born small for gestational age in low and middle income countries. Among these, 11.2 million (0.8 to 15.8) were term and not low birth weight (≥2500 g), 10.7 million (7.6 to 15.0) were term and low birth weight (\u3c2500 g) and 1.5 million (0.9 to 2.6) were preterm. In low and middle income countries, an estimated 606 500 (495 000 to 773 000) neonatal deaths were attributable to infants born small for gestational age, 21.9% of all neonatal deaths. The largest burden was in South Asia, where the prevalence was the highest (34%); about 26% of neonatal deaths were attributable to infants born small for gestational age. Reduction of the prevalence of small for gestational age from 19.3% to 10.0% in these countries could reduce neonatal deaths by 9.2% (254 600 neonatal deaths; 164 800 to 449 700). Conclusions In low and middle income countries, about one in five infants are born small for gestational age, and one in four neonatal deaths are among such infants. Increased efforts are required to improve the quality of care for and survival of these high risk infants in low and middle income countrie

Segmental demyelination induced by cerebrospinal fluid of progressive spastic paraparesis: Correlation with altered proteolytic parameters

Progressive spastic paraparesis (PSP) is a demyelinating disease of the central nervous system. We studied the ability of the cerebrospinal fluid (CSF) of patients to induce alterations in rat peroneal nerves, and to modify the proteolytic activity of trypsin in vitro. Subperineurial injection of native or heated CSF of patients induced segmental demyelination and other cytological alterations 5-7 days later, in the infiltrated zone, while proximal and distal regions were normal. The CSF of normal subjects did not induce demyelination, but upon heating, it did so. Trypsin was strongly inhibited by the normal CSF but upon heating, its inhibitory activity was replaced by a strong potentiation. In contrast, native and heated CSF of patients potentiated trypsin. Our findings indicate that (1) the normal CSF contains a thermostable factor that potentiates trypsin whose function is overruled by thermolabile protease inhibitors; (2) the CSF of PSP patients has a reduced inhibitory activity a

The calcium binding protein, S100B, is increased in the amniotic fluid of women with intra-amniotic infection/inflammation and preterm labor with intact or ruptured membranes

Objective: S100B is produced by glia of the central and peripheral nervous systems and is considered a marker of neurologic injury in the perinatal period. Indeed, increased neonatal urine S100B concentration is associated with adverse neurological outcomes including intraventricular hemorrhage and hypoxic-ischemic encephalopathy, while elevated adult serum concentrations are associated with infectious diseases/sepsis. The objective of this study was to determine whether amniotic fluid (AF) S100B concentrations change with advancing gestational age and intra-amniotic infection (IAI). // Study design: S100B concentration was measured in the AF of women in midtrimester, at term, and in pregnancies with preterm labor and intact membranes (PTL) or preterm premature rupture of membranes (PPROM), with and without IAI. Placental pathology was performed and neonatal outcomes were analyzed. // Results: (1) AF S100B concentration did not change during gestation; (2) patients with IAI had significantly higher AF S100B concentration than those without IAI following an episode of PTL or PPROM and; (3) neonates who had morbidity/mortality had had an elevated AF S100B concentration; however, this could be explained by the association with intra-amniotic infection/inflammation. Thus, AF S100B concentration was not an independent predictor of neonatal morbidity or fetal/neonatal death. // Conclusions: An elevated concentration of AF S100B may reflect intra-amniotic infection/inflammation and not necessarily fetal neurologic damage.Peer Reviewe

Normal pregnancy is characterized by systemic activation of the complement system

BACKGROUND: The complement system, a major component of innate immunity, has recently been implicated in the mechanisms of fetal loss and placental inflammation in the anti-phospholipid antibody syndrome. Inhibition of complement has been proposed as an absolute requirement for normal pregnancy. Yet, pregnancy is characterized by a generalized activation of the innate immune system. This study was conducted to determine whether or not normal pregnancy is associated with complement activation in the maternal circulation. METHODS: Anaphylatoxins (C3a, C4a and C5a) were determined in the plasma of normal pregnant (20-42 wks; n=134) and non-pregnant women (n=40). These complement split products (C3a, C4a and C5a) were measured using specific immunoassays. Non-parametric statistics were used for analysis. RESULTS: 1) The median plasma concentrations of C3a, C4a and C5a were significantly higher in normal pregnant women than in non-pregnant women (all p0.05); and 3) the median plasma concentration of C3a had a positive correlation with the plasma C4a and C5a concentrations (r=0.36, p<0.001 and r=0.35, p<0.001, respectively). CONCLUSION: 1) Normal human pregnancy is associated with evidence of complement activation, as determined by higher concentrations of the anaphylatoxins C3a, C4a and C5a in the maternal circulation; and 2) we propose that physiologic activation of the complement system during pregnancy is a compensatory mechanism aimed at protecting the host against infection