Jean R. Goodman

Etiological heterogeneity of familial periventricular heterotopia and hydrocephalus.

Periventricular heterotopia (PH) represents a neuronal migration disorder that results in gray matter nodules along the lateral ventricles beneath an otherwise normal appearing cortex. While prior reports have shown that mutations in the filamin A (FLNA) gene can cause X-linked dominant PH, an increasing number of studies suggest the existence of additional PH syndromes. Further classification of these cortical malformation syndromes associated with PH allows for determination of the causal genes. Here we report three familial cases of PH with hydrocephalus. One pedigree has a known FLNA mutation with hydrocephalus occurring in the setting of valproic acid exposure. Another pedigree demonstrated possible linkage to the Xq28 locus including FLNA, although uncharacteristically a male was affected and sequencing of the FLNA gene in this individual revealed no mutation. However, in the third family with an autosomal mode of inheritance, microsatellite analysis ruled out linkage with the FLNA gene. Routine karyotyping and fluorescent in situ hybridization using BAC probes localized to FLNA also showed no evidence of genomic rearrangement. Western blot analysis of one of the affected individuals demonstrated normal expression of the FLNA protein. Lastly, sequencing of greater than 95% of the FLNA gene in an affected member failed to demonstrate a mutation. In conclusion, these findings demonstrate the etiological heterogeneity of PH with hydrocephalus. Furthermore, there likely exists an autosomal PH gene, distinct from the previously described X-linked and autosomal recessive forms. Affected individuals have severe developmental delay and may have radiographic findings of hydrocephalus.

Is Bisphenol-A Exposure During Pregnancy Associated with Blood Glucose Levels or Diagnosis of Gestational Diabetes?

Recent epidemiological studies indicate bisphenol A (BPA), an estrogenic chemical used in production of epoxy, polycarbonate, and plastic may increase risk of insulin resistance and type 2 diabetes. Exposure to BPA during pregnancy may contribute to development of gestational diabetes mellitus (GDM), a precursor to type 2 diabetes in women. This pilot study examined the association between BPA exposure, fasting blood glucose levels (FBG), and GDM diagnosis during pregnancy. Banked urine samples from 22 cases of GDM and 72 controls were analyzed for total (free BPA + conjugates) urinary BPA concentrations (μg/L). FBG levels (mg/dl) were obtained from 1-h 50-g glucose tolerance tests (GTT) that women underwent for routine GDM screening (mean gestational age = 26.6 weeks, SD = 3.8). Those with an initial screening value ≥135 mg/dl underwent 3-h 100 g oral GTT. GDM diagnoses were made when the initial screening value was ≥200 mg/dl or when values at ≥2 time points exceeded 3-h oral GTT thresholds. Among controls, median FBG levels (mg/dL) did not differ across exposure tertiles, defined according to the distribution of total specific-gravity-adjusted urinary BPA concentrations. Logistic regression models controlling for race/ethnicity did not provide evidence of association between BPA exposure and case status across increasing tertiles of BPA exposure (number of GDM cases/controls in tertile1: 13/24; in tertile 2: 6/24; in tertile 3: 3/24). Findings do not support a relationship between total urinary BPA concentrations and altered glucose metabolism during pregnancy. However, due to study limitations, findings need to be interpreted with caution.

Longitudinal Study of Group B Streptococcus Carriage in Pregnancy

Objective: This prospective study was designed to 1) determine the prevalence of group B streptococcus (GBS) in our obstetric population and 2) evaluate the predictive value of lower vaginal/ perianal GBS cultures obtained in each trimester of pregnancy relative to GBS culture status at delivery. Methods: Lower vaginal/perianal GBS cultures were obtained in the first trimester, at 26-28 weeks, at 37 weeks, and on admission for delivery. The investigators were blinded to the results of all cultures except those obtained at 37 weeks. The sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) of each group of cultures with respect to culture status at delivery were determined, and the pattern of GBS carriage in our patients was delineated. Results: Nine hundred seventy-three patients participated in this longitudinal study. The prevalence of GBS carriage was 14.0% in the first trimester, 13.9% at 26-28 weeks, 12.4% at 37 weeks, and 12.1% at delivery. GBS carriage was continuous (all 4 cultures positive) in 3.8% and identified on a single culture only in 7.8%. Sensitivity (S1), specificity (

Immediate compared with delayed cord clamping in the preterm neonate: a randomized controlled trial.

2), PPV, and NPV for each set of antepartum cultures with respect to culture status at delivery were as tabled: Delivery GBS status (%)

A randomized controlled trial of intramuscular versus vaginal progesterone for the prevention of recurrent preterm birth

OBJECTIVE: The comparative risks and benefits of early compared with delayed cord clamping in the preterm neonate remain unclear. Our objective was to evaluate the short-term effects of delayed clamping of the umbilical cord in preterm neonates. METHODS: We conducted a randomized controlled trial comparing immediate with delayed cord clamping among preterm neonates born between 24 and 34 weeks of gestation. The primary study outcome was the need for blood transfusion. To detect a 33% reduction in this outcome (from 65 to 43.5%) with a two-tailed &agr; of 0.5 and &bgr; of 0.8 required 178 patients equally divided into two groups. RESULTS: A total of 200 women were randomized, 99 to the delayed and 101 to the immediate clamp group. The groups were similar with respect to baseline characteristics. The mean gestational age at delivery was 30.8±3.1 weeks in the delayed compared with 30.7±2.8 weeks in the immediate clamp group (P=.64). There was no statistically significant difference between groups with regard to the need for blood transfusion: 25 of 99 (25.3%) in the delayed cord clamp group received one or more blood transfusion compared with 24 of 101 (23.7%) in the immediate clamp group (P=.8). The rates of various neonatal outcomes including respiratory distress syndrome, periventricular leukomalacia, necrotizing enterocolitis, anemia of prematurity, and neonatal morality did not differ significantly between the groups. However, the mean initial hemoglobin (17.4±2.5 compared with 16.3±2.3 g/dL, P=.001) and hematocrit (51.3±7.3 compared with 47.4±7.3, P=.001) was significantly higher in the delayed group. In the delayed clamp group, 11.1% (11/99) of neonates had intraventricular hemorrhage compared with 19.8% (20/101) in the immediate clamp group (P=.09). CONCLUSION: Delayed cord clamping for 30 seconds did not decrease the need for blood transfusion among preterm neonates. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00579839. LEVEL OF EVIDENCE: I

Urinary phthalate metabolite concentrations and blood glucose levels during pregnancy.

To compare the efficacy of intramuscular hydroxyprogesterone caproate with that of vaginal progesterone for prevention of recurrent preterm birth.

Pneumococcal meningitis during pregnancy: A case report and review of literature

PURPOSE To examine associations between phthalate metabolite urinary concentrations during early pregnancy and blood glucose levels obtained at the time of screening for gestational diabetes mellitus (GDM). METHODS Upon initiation of prenatal care, women with a mean gestational age of 12.8 weeks were recruited for a study of environmental chemical exposures (n = 110) and provided a spot urinary specimen. Blood glucose concentrations (mg/dl) were obtained from the electronic medical record for those patients who did not experience a pregnancy loss and did not transfer care to another facility prior to glucose screening (n = 72). Urinary concentrations of nine phthalate metabolites and creatinine were measured at the US Centers for Disease Control and Prevention. Associations between tertiles of phthalate metabolites concentrations and blood glucose levels were estimated using linear regression. RESULTS Compared to pregnant women in the lowest concentration tertile, women with the highest urinary concentrations (≥ 3 rd tertile) of mono-iso-butyl phthalate (tertile: ≥ 15.3 μg/l, β = -18.3, 95% CI: -35.4, -1.2) and monobenzyl phthalate (tertile: ≥ 30.3 μg/l, β = -17.3, 95% CI: -34.1, -0.4) had lower blood glucose levels at the time of GDM screening after adjustment for urinary creatinine and demographic covariates. CONCLUSION Because maternal glucose levels increase during pregnancy to provide adequate nutrition for fetal growth and development, these findings may have implications for fetal health. However, given the limitations of our study, findings should be interpreted cautiously.

Prenatal Identification of a Novel R937P L1CAM Missense Mutation

Background. Bacterial meningitis is a medical emergency for which prompt diagnosis and treatment are imperative to reducing the rate of death and long-term neurologic compromise. Few cases of meningitis have been reported during pregnancy, many of which had devastating outcomes for mother, neonate, or both. Case. A 38-year-old multigravida at 35 weeks of gestation presented with mental status changes, fever, and preterm contractions. Lumbar puncture revealed gram positive cocci consistent with S. pneumoniae. Patient was intubated and admitted to ICU where she was given antibiotics and adjunctive therapy with dexamethasone. Continuous fetal monitoring was utilized throughout her course of her hospitalization. Patient was discharged home after ten days in the hospital and had an uncomplicated vaginal birth after caesarean section (VBAC) at 38 weeks. Both she and the infant are doing well with no permanent neurologic sequelae. Conclusion. A review of literature indicates only isolated cases of pneumococcal meningitis being described during pregnancy. An extended period of time between onset of maternal illness and delivery appears to reduce the risk of neonatal transmission and improve both maternal and fetal outcomes.

Quantitation of the five forms of plasma high molecular weight angiotensinogen in women with pregnancy-induced hypertension.

The L1 cell adhesion molecule (L1CAM) is a protein encoded by a gene that has been localized to Xq28, is a member of the immunoglobulin superfamily of neuronal cell adhesion molecules, and plays a role in CNS development and maturation. L1CAM is expressed in neurons and Schwann cells, where it is active in neurite overgrowth, adhesion fasciculation, migration, myelination, and axon guidance. Mutations within the gene have been associated with phenotypic changes that include hydrocephalus due to aqueductal stenosis, agenesis or hypoplasia of the corpus callosum and corticospinal tracts, mental retardation, spastic paraplegia, and adducted thumbs. Here, we present a 19-year-old primigravida Caucasian woman who was referred to us in the 27th week of the pregnancy because of fetal polyhydramnios and ventriculomegaly. Our evaluation identified a male fetus with hydrocephalus, ventriculomegaly, aqueductal stenosis, and polyhydramnios. An amniocentesis was performed, and isolated fetal DNA revealed a hemizygous G > C mutation in codon 2809 of exon 21 of the L1CAM gene. The patient was later tested and identified to be a carrier of the same mutation. The fetus was delivered during the 38th week. Neonatal physical examination revealed marked frontal bossing, contractures of the feet with rocker bottom appearance, and hyperactive reflexes with ankle and knee clonus. He died at 4 months of life.

The role of fetal inflammatory response syndrome and fetal anemia in nonpreventable term neonatal encephalopathy

In the human pregnant state a high molecular weight form of angiotensinogen (HMrA) is present in significant quantities in addition to the usual low molecular weight angiotensinogen (LMrA). In a previous study involving a small number of white women, it was found that women who had developed pregnancy-induced hypertension (PIH) had significantly higher levels of plasma HMrA. It has been determined that there are five isoforms of HMrA. The objectives of this study were to expand the previous study with the inclusion of black women and to determine which isoform(s) of plasma HMrA are elevated in PIH. Plasma LMrA and HMrA were quantitated in 24 normotensive pregnant women and 65 women with PIH. The PIH group had higher levels of HMrA and somewhat lower levels of LMrA than the normotensive group. The HMrA/LMrA ratio was elevated in 47% of the PIH group. The five isoforms of HMrA were quantitated in plasma from 10 white women with PIH, 10 black women with PIH, and 6 normotensive pregnant white women. Half of both the white and black women with PIH had an elevated HMrA/LMrA ratio. The relative proportion of the HMrA isomers was similar in all groups. These studies show that half the women with PIH have a distinct abnormality in their renin angiotensin system. Both white and black women show this abnormality. In those women who have an elevated total HMrA, all five isoforms of HMrA are equally elevated.