Joaquin Santolaya

Candidate-Gene Association Study of Mothers with Pre-Eclampsia, and Their Infants, Analyzing 775 SNPs in 190 Genes

Pre-eclampsia (PE) affects 5–7% of pregnancies in the US, and is a leading cause of maternal death and perinatal morbidity and mortality worldwide. To identify genes with a role in PE, we conducted a large-scale association study evaluating 775 SNPs in 190 candidate genes selected for a potential role in obstetrical complications. SNP discovery was performed by DNA sequencing, and genotyping was carried out in a high-throughput facility using the MassARRAYTM System. Women with PE (n = 394) and their offspring (n = 324) were compared with control women (n = 602) and their offspring (n = 631) from the same hospital-based population. Haplotypes were estimated for each gene using the EM algorithm, and empirical p values were obtained for a logistic regression-based score test, adjusted for significant covariates. An interaction model between maternal and offspring genotypes was also evaluated. The most significant findings for association with PE were COL1A1 (p = 0.0011) and IL1A (p = 0.0014) for the maternal genotype, and PLAUR (p = 0.0008) for the offspring genotype. Common candidate genes for PE, including MTHFR and NOS3, were not significantly associated with PE. For the interaction model, SNPs within IGF1 (p = 0.0035) and IL4R (p = 0.0036) gave the most significant results. This study is one of the most comprehensive genetic association studies of PE to date, including an evaluation of offspring genotypes that have rarely been considered in previous studies. Although we did not identify statistically significant evidence of association for any of the candidate loci evaluated here after adjusting for multiple testing using the false discovery rate, additional compelling evidence exists, including multiple SNPs with nominally significant p values in COL1A1 and the IL1A region, and previous reports of association for IL1A, to support continued interest in these genes as candidates for PE. Identification of the genetic regulators of PE may have broader implications, since women with PE are at increased risk of death from cardiovascular diseases later in life.

Resistin: a hormone which induces insulin resistance is increased in normal pregnancy.

Abstract Aims: Resistin, a newly discovered adipokine, is thought to play a key role in the regulation of insulin resistance. The objectives of this study were to develop a nomogram of maternal plasma concentrations of resistin from 11 weeks of gestation to term and to determine whether resistin concentrations differ between normal and overweight pregnant women. Methods: In this cross-sectional study, plasma concentrations of resistin were determined in normal pregnant women of normal body mass index (BMI 18.5–24.9; n=261), overweight pregnant women (BMI ≥25; n=140), and non-pregnant women of normal BMI (n=40). Blood samples were collected once from each woman between the first trimester and term. Percentiles for resistin concentration were determined for five pre-specified windows of gestational age. Plasma resistin concentration was determined by immunoassay. Non-parametric statistics were used for analysis. Results: The median maternal plasma concentration of resistin between 11 to 14 weeks of gestation in women of normal weight was significantly higher than non-pregnant women; the plasma concentration of resistin increased with gestational age. Conclusions: Normal pregnant women have a higher median plasma concentration of resistin than non-pregnant women and the concentration of this adipokine increases with advancing gestation. Alterations in the maternal plasma concentration of resistin during pregnancy could contribute to metabolic changes of pregnancy.

Maternal-fetal glucose gradient in normal pregnancies and in pregnancies complicated by alloimmunization and fetal growth retardation

Maternal and fetal glucose concentrations were measured simultaneously in 54 pregnancies in which fetal blood sampling was conducted between 18 and 34 weeks gestation. Twenty-five pregnancies were normal (group 1), 13 were complicated by fetomaternal alloimmunization (group 2), and 16 by intrauterine growth retardation (group 3). The maternal glucose concentration was similar in the three groups. The fetal glucose level was significantly lower in growth-retarded (mean = 2.7 mmol/L) than in normal pregnancies (mean = 3.5 mmol/L). There was a statistically significant gradient between maternal and fetal glucose concentrations in groups 1 and 3, but no gradient was found in group 2. Maternal and fetal glucose concentrations were significantly correlated in all groups, but the correlations were distinct. For a given maternal glucose concentration, fetal glucose was higher in patients with alloimmunization and lower in patients with intrauterine growth retardation than in normal pregnancies. In patients with intrauterine growth retardation, fetal PO2 correlated positively with fetal glucose and inversely with maternal fetal glucose gradient.

Changes in fetal acid base status during intravascular transfusion

Umbilical venous pH, PCO2, PO2, and base excess was measured immediately before and after 72 intravascular transfusions in 34 fetuses with erythroblastosis fetalis. In 67 uncomplicated transfusions, infused adult blood led to a mean (95% confidence intervals) fall in pH (0.037, CI 0.029 to 0.044) and base excess (2.03, CI 1.61 to 2.45) and a mean rise in PCO2 (0.24 kPa, CI 0.13 to 0.35). These changes correlated significantly with the increase in fetal haemoglobin and packed cell volume. Five transfusions were associated with complications within six hours: intrauterine death in two, fetal-distress necessitating delivery in two, and preterm labour in one. Two had pre-existing acidosis, whereas two of the three with normal blood gas and acid base measurements before transfusion had acute changes that were outside the normal ranges that had been established in uncomplicated transfusions.

Cervical varix as a cause of vaginal bleeding during pregnancy: Prenatal diagnosis by color Doppler ultrasonography

Vaginal bleeding during pregnancy is a risk factor for adverse pregnancy outcome. Beyond 20 weeks of gestation, the most frequent causes of bleeding associated with maternal and perinatal morbidity and mortality are placenta previa and placental abruption. Cervical varix during pregnancy is a rare condition. To our knowledge, only six cases have been reported in the literature. Most of these cases were associated with preterm birth and high maternal morbidity. The optimal management and mode of delivery remain undetermined. We report a case of cervical varix diagnosed by transvaginal ultrasound at 21 weeks of gestation. The pregnancy was complicated by several episodes of vaginal bleeding and the patient delivered at 32 weeks. Color and power Doppler examination of the cervix played a key role in establishing the diagnosis.

Term and Preterm Parturition

Parturition is the act of giving birth.1 It is a complex process that includes the anatomical, physiological, biochemical and immunological events taking place in the mother, placenta and fetus. These events are responsible for: (1) the preparation of the uterus for labor; (2) labor per se, leading to the delivery of the fetus and placenta; and (3) post-partum uterine involution, breast feeding and adaptation of maternal behavior.

OC20.03: Middle cerebral artery peak systolic velocity—a new Doppler parameter in the evaluation of SGA fetuses with an abnormal umbilical artery

ultrasound units. Thanks to this venous flows in the fetus can be reproducibly measured. Different methodologies are a source of systematic errors, but they do not impair their possible diagnostic usage within centers. Errors due to diameter of the vessel and angle of interrogation of the Doppler beam are in fact limited by the quality of digital imaging. A third source of errors remains the difference between the ideal flow model as perfect parabolic flow and the real flow along any specific fetal vessels. However, while technological researches are ongoing, diagnostic application of volume flow are within reach. Umbilical venous flow can be measured and significant reductions in growth restricted fetuses can be diagnosed and followed. This is the base to understand the redistribution of flow at the liver cross roads. In normal pregnancies the blood shunted by the ductus venosus progressively decreases down to a 20% of the umbilical flow, in severe IUGR fetuses this percentage is dramatically inverted, and mirrored by a parallel ductal a-wave reduction. This inversion can become so sever as to draw blood from the portal sinus into the ductus venosus. Severe liver underperfusion and organ damage is the net result of this changes in flow redistribution. Umbilical and liver venous volume flow qualifies today for a powerful instrument to monitor growth restricted fetuses Similar changes in flow redistribution can be measured at the level of the heart and brain even though arterial flow volume measurements in such small vessels are probably limited by the higher expertise required.

P10.07: Inferior vena cava and ductus venosus Doppler in preterm IUGR fetuses

Objective: Adding NO donors to the antihypertensive treatment in gestational hypertensive patients complicated by fetal growth restriction. Methods: Fifty moderate to severe gestational hypertensive patients (27–30 weeks of gestation) with fetal abdominal circumference < 10th percentile for gestational age and normal fetal Doppler parameters, were submitted to maternal echocardiographic exam before and 14 days after treatment was started. Patients were randomised in two treatment groups: (1) 25 patients underwent Calcium antagonists and Bed Rest; (2) 25 patients underwent Calcium antagonists and Bed Rest + Transdermal glyceryl trinitrate (5–10 mg released in 24 hours administrated for 12–14 hours) + intravenous fluid infusion with 2000 mL over 24 hours. Results: Are shown in the table. Conclusions: Nitrates and fluid therapy added to standard antihypertensive treatment improve maternal hemodinamics and fetal growth more than standard antihypertensive treatment alone.