Ludmila N. Bakhireva

Accuracy of the Diagnosis of Physical Features of Fetal Alcohol Syndrome by Pediatricians After Specialized Training

OBJECTIVES. Accurate and early diagnosis of the fetal alcohol syndrome is important for secondary prevention, intervention, and treatment, yet many pediatricians lack expertise in recognition of the characteristic features of this disorder. After a structured training program for pediatricians, we examined the ability to accurately diagnose fetal alcohol syndrome. METHODS. Two dysmorphologists conducted a 2-day training program in the diagnosis of the physical features of fetal alcohol syndrome for 4 pediatricians in Moscow. Dysmorphologists and pediatricians worked in teams to examine children, demonstrate techniques, and validate that pediatricians could identify physical features of this disorder under direct observation. Subsequently, pediatricians independently evaluated children in 41 boarding schools and orphanages. Those children diagnosed with fetal alcohol syndrome or deferred (possible fetal alcohol syndrome) by the pediatricians were then evaluated by the dysmorphologists. Accuracy of the diagnosis of fetal alcohol syndrome or deferred was assessed, as well as the interrater agreement for specific selected features of the disorder. RESULTS. A total of 110 children were examined by both the pediatricians and the dysmorphologists. Of these, 79 were identified with fetal alcohol syndrome by the pediatricians; in 66 (83.5%) of these children, the diagnosis was confirmed by the dysmorphologists. Among 31 children who were classified as deferred by the pediatricians, 21 (67.7%) were confirmed with either fetal alcohol syndrome or deferred by the dysmorphologists. With respect to selected structural features characteristic of fetal alcohol syndrome, good interrater agreement was noted for height and head circumference ≤10th centile, whereas moderate-to-fair agreement was noted for smooth philtrum, long philtrum, presence of “hockey-stick” palmar crease, and palpebral fissure length ≤10th centile. Poor agreement was noted for thin upper lip. CONCLUSIONS. After a relatively short training session, pediatricians were reasonably accurate in diagnosing fetal alcohol syndrome on the basis of physical features and in recognizing most of the selected specific features associated with the disorder.

Asthma control during pregnancy and the risk of preterm delivery or impaired fetal growth.

BACKGROUND Concerns regarding potential harmful effect of medications on fetuses often result in inadequate treatment of asthma in pregnancy, whereas risks posed by poorly controlled maternal asthma are often underestimated. OBJECTIVE To evaluate the effect of maternal asthma on preterm delivery and fetal growth. METHODS Study participants were individuals enrolled in the Organization of Teratology Information Specialists Asthma Medications in Pregnancy Study between February 1, 1998, and December 31, 2003. Pregnant women with physician-diagnosed asthma (n = 719) evaluated their asthma control repeatedly during pregnancy based on symptom frequency and interference with daily activities and sleep and reported hospitalizations and unscheduled clinic visits for asthma exacerbations. The incidence of preterm delivery, the incidence of intrauterine growth restriction, and mean birth weight were evaluated relative to asthma symptom control and exacerbation measures. RESULTS The incidence of preterm delivery was significantly higher among patients with inadequate asthma symptom control during the first part of pregnancy (11.4%) compared with patients with adequate asthma control (6.3%; P = .02). Similarly, patients who were hospitalized for asthma during pregnancy had a higher incidence of preterm delivery (16.4%) compared with asthmatic women without a history of hospitalization (7.6%; P = .02). The effect seemed independent from use of systemic corticosteroids and other covariates. Neither the incidence of intrauterine growth restriction nor mean birth weight varied by any measures of asthma symptom control or exacerbations. CONCLUSIONS This study demonstrates a substantial risk for preterm delivery posed by poorly controlled maternal asthma and provides additional evidence regarding the importance of adequate treatment of asthma in pregnancy to maintain optimal asthma control.

The Validity of Phosphatidylethanol in Dried Blood Spots of Newborns for the Identification of Prenatal Alcohol Exposure

BACKGROUND Accurate identification of prenatal alcohol exposure (PAE) in the newborn period offers an opportunity for early identification of children at risk of future neurocognitive problems and the implementation of interventional approaches earlier in life. PAE newborn screening by measuring phosphatidylethanol in dried blood spot (PEth-DBS) cards is feasible, logistically easier, and more cost-efficient compared with other biomarkers. However, the sensitivity and specificity of this method have yet to be established. METHODS This prospective cohort study examined validity of PEth-DBS among 28 infants with PAE and 32 controls relative to maternal self-report and other biomarkers. Pregnant women were recruited from a University of New Mexico clinic and followed to early postpartum period. The composite index, which was based on self-reported measures of alcohol use and allowed to classify subjects into PAE and control groups, was the criterion measure used to estimate sensitivity and specificity of PEth-DBS. RESULTS The study included large proportions of patients representing ethnic minorities (7.4% American Indian, 81.7% Hispanic/Latina), low education (54.2% <high school), and unplanned pregnancy (90.0%). No differences in sociodemographic characteristics, smoking or illicit drug use were observed among the study groups. The sensitivity of maternal biomarkers (gamma glutamyltranspeptidase [GGT], % carbohydrate-deficient transferrin [%CDT], urine ethyl glucuronide [UEtG], urine ethyl sulfate [UEtS]) was low (<15%) reflecting a moderate chronic or intermittent binge pattern of drinking in this cohort. PEth-DBS demonstrated 100% specificity and the highest sensitivity (32.1%) compared with other biomarkers. A battery consisting of maternal direct ethanol metabolites (UEtG, UEtS, PEth) and newborn PEth-DBS increased sensitivity to 50% without a substantial drop in specificity (93.8%). CONCLUSIONS Newborn PEth-DBS is a highly specific biomarker and can facilitate accurate detection of PAE in conjunction with other biomarkers. Minimal invasiveness, ease of storage and transportation of DBS cards, absence of postcollection synthesis, cost savings, and potential integration with routine newborn screening are all unique advantages of this method.

Differences in association of bone mineral density with coronary artery calcification in men and women: the Rancho Bernardo Study.

Objective:Whether osteoporosis and calcification of atherosclerotic plaque are two independent, age-related processes or linked by similar mechanisms of bone mineralization and plaque calcification is unknown. This study examines the sex-specific association between bone mineral density (BMD) and coronary artery calcification with a particular focus on hormone therapy (HT). Design:Participants were 180 men (aged 47-86 years) and 186 women (aged 58-81 years) without a history of heart disease who had hip and spine BMD assessed by dual-energy x-ray absorptiometry and coronary artery calcium score (CACS) measured by electron-beam computed tomography. Calcium scores were categorized into none/minimal (≤10), mild (11-100), moderate (101-399), and severe (≥400). Ordinal and binary logistic regressions examined the associations between site-specific BMD and CACS. Results:In men and women not using HT, there was no age-independent association between BMD at any site and CACS. In contrast, among current HT users an inverse association of BMD with coronary artery calcification was observed at the total hip (odds ratio [OR] = 0.56, 95% CI, 0.33-0.95), trochanter (OR = 0.55, 95% CI, 0.32-0.93), and intertrochanter area (OR = 0.60, 95% CI, 0.41-0.86) after adjustment for age and other risk factors. Other skeletal sites showed similar, but not statistically significant, associations (P < 0.1). Conclusion:Lack of association between BMD and CACS in men and women not using HT and the inverse association in women on HT suggest that the association between coronary and bone calcium might be mediated by estrogen.

Can prenatal ultrasound detect the effects of in‐utero alcohol exposure? A pilot study

The aim of this pilot study was to explore possible ultrasound parameters for the early detection of alcohol‐mediated fetal somatic and central nervous system (CNS) maldevelopment. Maternal alcohol ingestion during pregnancy may lead to fetal alcohol spectrum disorders (FASD), which encompass a broad range of structural abnormalities including growth impairment, specific craniofacial features and CNS abnormalities. Early detection of fetuses at risk of FASD would support earlier interventions.

Effect of Maternal Asthma and Gestational Asthma Therapy on Fetal Growth

Asthma is a common chronic condition that might seriously complicate pregnancy and fetal development. This article provides a comprehensive review of the existing literature regarding the effect on fetal growth of maternal asthma and common asthma medications used during pregnancy, including short-and long-acting β 2-agonists, inhaled and oral corticosteroids, chromones, leukotriene receptor agonists, and theophylline. Evaluated outcomes of fetal growth include low birth weight, mean birth weight, small for gestational age, birth length and head circumference, and measures of asymmetrical growth retardation. Methodological and practical considerations related to safety of asthma medications in pregnancy and management of gestational asthma are discussed.

Fetal sex and maternal asthma control in pregnancy

Asthma is a prevalent chronic disorder that might substantially complicate pregnancy. Some recent reports suggest that the presence of a female fetus might be associated with worse maternal asthma symptoms during pregnancy. We tested this hypothesis using the sample of 719 pregnant women with asthma prospectively enrolled in the OTIS study. The presence of a female fetus was associated with a higher incidence of hospitalizations for asthma during pregnancy (OR = 1.84; 95% CI: 1.05; 3.21) independent of maternal age, BMI, ethnicity, smoking, and socioeconomic status. The current study suggests that pregnant asthmatic women carrying a girl might be more susceptible to asthma exacerbations.

Synergistic effect of statins and postmenopausal hormone therapy in the prevention of skeletal fractures in elderly women.

Study Objective. To examine the role of concurrent 3–hydroxy‐3–methylglutaryl coenzyme A reductase inhibitor (statin) use and postmenopausal hormone therapy on osteoporosis‐related fractures.

Implementation of a shared data repository and common data dictionary for fetal alcohol spectrum disorders research.

Many previous attempts by fetal alcohol spectrum disorders researchers to compare data across multiple prospective and retrospective human studies have failed because of both structural differences in the collected data and difficulty in coming to agreement on the precise meaning of the terminology used to describe the collected data. Although some groups of researchers have an established track record of successfully integrating data, attempts to integrate data more broadly among different groups of researchers have generally faltered. Lack of tools to help researchers share and integrate data has also hampered data analysis. This situation has delayed improving diagnosis, intervention, and treatment before and after birth. We worked with various researchers and research programs in the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CI-FASD) to develop a set of common data dictionaries to describe the data to be collected, including definitions of terms and specification of allowable values. The resulting data dictionaries were the basis for creating a central data repository (CI-FASD Central Repository) and software tools to input and query data. Data entry restrictions ensure that only data that conform to the data dictionaries reach the CI-FASD Central Repository. The result is an effective system for centralized and unified management of the data collected and analyzed by the initiative, including a secure, long-term data repository. CI-FASD researchers are able to integrate and analyze data of different types, using multiple methods, and collected from multiple populations, and data are retained for future reuse in a secure, robust repository.

Alcohol Use During Pregnancy is Associated with Specific Alterations in MicroRNA Levels in Maternal Serum

Background Given the challenges of confirming prenatal alcohol exposure (PAE) during pregnancy using currently established biomarkers of alcohol consumption, we examined whether serum microRNAs (miRNAs) may serve as stable biomarkers for PAE. Alterations in the levels of specific circulating miRNAs have been associated with various disease states and in animal models of fetal alcohol spectrum disorder. Methods Pregnant women in this prospective study were recruited from substance abuse and general maternity clinics affiliated with the University of New Mexico. Serum was collected at the time of admission for delivery from 14 subjects who reported ≥1 binge‐drinking episode or ≥3 drinks/wk during pregnancy and 16 subjects who reported abstinence during pregnancy and tested negative for 5 ethanol biomarkers. Total RNA was isolated from serum and used for microarray analysis. Results False discovery rate‐corrected analyses of covariance revealed that 55 miRNAs were significantly altered between the 2 groups. Hierarchical clustering using only the significantly altered miRNAs grouped samples into alcohol‐consuming and non‐alcohol‐consuming individuals. Discriminant analysis then identified miRs‐122*, ‐126, ‐216b, ‐221*, ‐3119, ‐3942‐5p, ‐4704‐3p, ‐4743, ‐514‐5p, and ‐602 as the top 10 discriminators between the 2 groups. Ingenuity Pathway Analysis of putative miRNA targets illustrated that miRNAs identified in this study are involved in biological pathways that mediate the effects of alcohol, such as brain‐derived neurotrophic factor, ERK1/2, and PI3K/AKT signaling. Conclusions This is the first report of alterations in serum miRNA expression that are associated with alcohol use during human pregnancy. These results suggest that serum miRNAs could be useful as biomarkers of alcohol exposure.