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The study aims to evaluate the risk factors as well as the postnatal outcomes associated with first-trimester fetal growth restriction. The results indicate that maternal physical characteristics and lifestyle habits were independently associated with early fetal growth and first-trimester fetal growth restriction was associated with an increased risk of adverse birth outcomes.

Prenatal ethanol exposure causes fetal alcohol spectrum disorders (FASD) in part by disrupting the neural cell adhesion molecule L1. L1 gene mutations cause neuropathological abnormalities similar to those of FASD. Ethanol and 1-butanol inhibit L1-mediated cell-cell adhesion (L1 adhesion), whereas 1-octanol antagonizes this action. To test the hypothesis that there are alcohol binding sites on L1, we used 3-azibutanol and 3-azioctanol, the photoactivatable analogs of 1-butanol and 1-octanol, to photolabel the purified Ig1-4 domain of human L1 (hL1 Ig1-4). 3-Azibutanol (11 mM), like ethanol, inhibited L1 adhesion in NIH/3T3 cells stably transfected with hL1, whereas subanesthetic concentrations of 3-azioctanol (14 [micro]M) antagonized ethanol inhibition of L1 adhesion. 3-Azibutanol (100-1,000 [micro]M) and 3-azioctanol (10-100 [micro]M) photoincorporated into Tyr-418 on Ig4 and into two adjacent regions in the N terminus, Glu-33 and Glu-24 to Glu-27. A homology model of hL1 Ig1-4 (residues 33-422), based on the structure of the Ig1-4 domains of axonin-1, suggests that Glu-33 and Tyr-418 hydrogen-bond at the interface of Igl and Ig4 to stabilize a horseshoe conformation of L1 that favors homophilic binding. Furthermore, this alcohol binding pocket lies within 7 [Angstrom] of Leu-120 and Gly-121, residues in which missense mutations cause neurological disorders similar to FASD. These data suggest that ethanol or selected mutations produce neuropathological abnormalities by disrupting the domain interface between Igl and Ig4. Characterization of alcohol agonist and antagonist binding sites on L1 will aid in understanding the molecular basis for FASD and might accelerate the development of ethanol antagonists. ethyl alcohol | fetal alcohol spectrum disorders | photolabel

Reduced uterine perfusion initiated in late gestation in the rat results in intrauterine growth restriction (IUGR) and development of hypertension by 4 wk of age. We hypothesize that the renin angiotensin system (RAS), a regulatory system important in the long-term control of blood pressure, may be programmed by placental insufficiency and may contribute to the etiology of IUGR hypertension. We previously reported that RAS blockade abolished hypertension in adult IUGR offspring; however, the mechanisms responsible for the early phase of hypertension are unresolved. Therefore, the purpose of this study was to examine RAS involvement in early programmed hypertension and to determine whether temporal changes in RAS expression are observed in IUGR offspring. Renal renin and angiotensinogen mRNA expression were significantly decreased at birth (80 and 60%, respectively); plasma and renal RAS did not differ in conjunction with hypertension (mean increase of 14 mmHg) in young IUGR offspring; however, hypertension (mean increase of 22 mmHg) in adult IUGR offspring was associated with marked increases in renal angiotensin-converting enzyme (ACE) activity (122%) and renal renin and angiotensinogen mRNA (7-fold and 7.4-fold, respectively), but no change in renal ANG II or angiotensin type 1 receptor. ACE inhibition (enalapril, 10 mg*[kg.sup.-1]*[day.sup.-1], administered from 2 to 4 wk of age) abolished hypertension in IUGR at 4 wk of age (decrease of 15 mmHg, respectively) with no significant depressor effect in control offspring. Therefore, temporal alterations in renal RAS are observed in IUGR offspring and may play a key role in the etiology of IUGR hypertension. intrauterine growth restriction; kidney; brain; angiotensin; rat

In cerebellum and other brain regions, neuronal cell death because of ethanol consumption by the mother is thought to be the leading cause of neurological deficits in the offspring. However, little is known about how surviving cells function. We studied cerebellar Purkinje cells in vivo and in vitro to determine whether function of these cells was altered after prenatal ethanol exposure. We observed that Purkinje cells that were prenatally exposed to ethanol presented decreased voltage-gated calcium currents because of a decreased expression of the 3,-isoform of protein kinase C. Long-term depression at the parallel fiber-Purkinje cell synapse in the cerebellum was converted into long-term potentiation. This likely explains the dramatic increase in Purkinje cell firing and the rapid oscillations of local field potential observed in alert fetal alcohol syndrome mice. Our data strongly suggest that reversal of long-term synaptic plasticity and increased firing rates of Purkinje cells in vivo are major contributors to the ataxia and motor learning deficits observed in fetal alcohol syndrome. Our results show that calcium-related neuronal dysfunction is central to the pathogenesis of the neurological manifestations of fetal alcohol syndrome and suggest new methods for treatment of this disorder. calcium | cerebellum | protein kinase | long-term depression | motor learning

Intrauterine growth restriction (IUGR) is associated with accelerated growth after birth. Together, IUGR and accelerated growth after birth predict reduced lean tissue mass and increased obesity in later life. Although placental insufficiency is a major cause of IUGR, whether it alters growth and adiposity in early postnatal life is not known. We hypothesized that placental restriction (PR) in the sheep would reduce size at birth and increase postnatal growth rate, fat mass, and feeding activity in the young lamb. PR reduced survival rate and size at birth, with soft tissues reduced to a greater extent than skeletal tissues and relative sparing of head width (P < 0.05 for all). PR did not alter absolute growth rates (i.e., the slope of the line of best fit for age vs. parameter size from birth to 45 days of age) but increased neonatal fractional growth rates (absolute growth rate relative to size at birth) for body weight (+24%), tibia (+15%) and metatarsal (+18%) lengths, hindlimb (+23%) and abdominal (+19%) circumferences, and fractional growth rates for current weight (P < 0.05) weekly throughout the first 45 days of life. PR and small size at birth reduced individual skeletal muscle weights and increased visceral adiposity in absolute and relative terms. PR also altered feeding activity, which increased with decreasing size at birth and was predictive of increased postnatal growth and adiposity. In conclusion, PR reduced size at birth and induced catch-up growth postnatally, normalizing weight and length but increasing adiposity in early postnatal life. Increased feeding activity may contribute to these alterations in growth and body composition following prenatal restraint and, if they persist, may lead to adverse metabolic and cardiovascular outcomes in later life. adiposity; fetal growth restriction; catch-up growth

OBJECTIVE. The 4-Digit Diagnostic Code for fetal alcohol spectrum disorders and the Hoyme fetal alcohol spectrum disorders diagnostic guidelines differ markedly. The performances of the 2 diagnostic systems were compared. METHODS. The fetal alcohol syndrome diagnostic criteria from the 4-Digit Code and Hoyme guidelines were applied to 952 patients who had received an interdisciplinary, fetal alcohol spectrum disorders, diagnostic evaluation at the University of Washington with the 4-Digit Diagnostic Code and 16 children with confirmed absence of prenatal alcohol exposure. RESULTS. The prevalence of fetal alcohol syndrome was 3.7% with the 4-Digit Code and 4.1% with the Hoyme guidelines. Although the prevalences were similar, the patients identified were not. Only 17 individuals met the fetal alcohol syndrome criteria for both systems. An extraordinary number of patients (35%) met the Hoyme criteria for the fetal alcohol syndrome facial phenotype, but only 39 of those 330 patients met the Hoyme criteria for fetal alcohol syndrome. Even some children with no alcohol exposure (25%) had the Hoyme fetal alcohol syndrome face. The specificities of the Hoyme fetal alcohol syndrome face for the Hoyme fetal alcohol syndrome diagnosis and prenatal alcohol exposure were low in these populations. CONCLUSIONS. Without a specific facial phenotype, a valid diagnosis of fetal alcohol syndrome cannot be rendered for patients with prenatal alcohol exposure, because a causal link between their outcomes and exposure cannot be established, and a valid diagnosis of fetal alcohol syndrome cannot be rendered for patients with unknown alcohol exposure, because the face cannot serve as a valid proxy measure for alcohol exposure. Diagnostic guidelines must confirm the specificity of their fetal alcohol syndrome facial criteria to validate their diagnostic criteria. Key Words diagnostic methods, fetal alcohol syndrome, fetal alcohol spectrum disorders, evaluation, guidelines Abbreviations FASD--fetal alcohol spectrum disorders FAS--fetal alcohol syndrome OFC--occipital frontal circumference PFL--palpebral fissure length IOM--Institute of Medicine CDC--Centers for Disease Control and Prevention ARND--alcohol-related neurodevelopmental disorder ARBD--alcohol-related birth defects CNS--central nervous system DPN--Diagnostic and Prevention Network CI--confidence interval, FETAL ALCOHOL SPECTRUM disorders (FASD) is a general term used to describe the full spectrum of adverse outcomes observed among individuals with prenatal alcohol exposure. Fetal alcohol syndrome (FAS) and [...]

OBJECTIVE. The purpose of this work was to study the stiffness of systemic arteries in appropriate and small for gestational age newborn infants. The distance between diametrically opposite points of the arterial lumen was measured with a phase locked loop echo tracking system coupled to a B-mode ultrasonic imager. PATIENTS AND METHODS. A cross-sectional study of 51 appropriate for gestation age infants including 22 preterm infants was done to obtain normal data. We also studied 47 small for gestational age infants, who were identified antenatally by an umbilical artery Doppler flow waveform pulsatility index >95th percentile. The stiffness index of the common carotid artery and abdominal aorta was calculated from the relationship between systemic blood pressure and arterial diameter during the cardiac cycle. RESULTS. In the appropriate for gestation age group, the systolic and diastolic diameters of the common carotid artery and abdominal aorta, as well as the stiffness index, increased with the gestational age at birth. In the small for gestational age group, the arterial diameters and blood pressure were also within the reference range. Using the arterial stiffness index values from the appropriate for gestation age group, the small for gestational age group was divided into 3 subgroups: 18 infants with normal stiffness index values for both arteries, 19 infants with a high stiffness index of the abdominal aorta, and 10 infants with a high stiffness index for both arteries. The clinical outcome was significantly worse in the latter 2 subgroups compared with the normal infants and was also worse in the infants with a high stiffness index for both arteries compared with the high abdominal aorta subgroup. CONCLUSION. The antenatal increase of afterload caused by a high placental vascular resistance was associated with a decrease of aortic distensibility in the compromised small for gestational age infants, suggesting that the structure of the aortic wall was altered. In the most profoundly compromised small for gestational age infants, the high stiffness index of both the common carotid artery and abdominal aorta may indicate more extensive arterial damage. Key Words umbilical placental insufficiency, newborn infant, stiffness, intrauterine growth restriction Abbreviations IUGR--intrauterine growth restriction SGA--small for gestational age CCA common carotid artery AA--abdominal aorta AGA appropriate for gestational age SI--stiffness index bpm beats per minute FHR fetal heart rate, THE TERM "PLACENTAL insufficiency" has long existed in obstetrics to indicate a state of inadequate blood flow through the placenta. It is associated with the fetal syndrome of intrauterine growth [...]

Fetal nutritional stress may result in intrauterine growth restriction and postnatal insulin resistance. To determine whether insulin resistance can begin in utero, we subjected late-gestation (130-135 days) ewes to 120 h of complete fasting and compared the results with our previous work in fed ewes (38). We determined the effect of insulin and/or recombinant human (rh)IGF-I infusion on ovine fetal phenylalanine kinetics, protein synthesis, and phenylalanine accretion. Experimental infusates were 1) saline, 2) rhIGF-I plus a replacement dose of insulin (40 nmol IGF-I/h + 16 mIU insulin/h), 3) insulin (890 mIU/h), and 4) IGF-I plus insulin (40 nmol IGF-I/h + 890 mIU insulin/h). During hormone infusion, both glucose and amino acid concentrations were clamped at basal concentrations. Amino acid infusion was required during infusion of either hormone to maintain plasma concentrations constant. However, the amount required during insulin infusion was less than during IGF-I infusion and 40% less than the amount required during identical studies in nonfasted animals. Phenylalanine used for protein synthesis and accretion was increased compared with control animals but again less so than in the nonfasted animals. In contrast to nonfasted animals, neither hormone increased the fractional synthetic rate of skeletal muscle protein nor that of plasma albumin. These results indicate that a short but severe nutritional stress can significantly alter the fetal anabolic response to insulin even when both glucose and amino acid substrate supplies are restored. Therefore, adaptive responses characterized by insulin resistance begin in utero when the fetus is subjected to sufficient nutritional stress. protein synthesis; skeletal muscle; phenylalanine kinetics; fetal programming

DOI: 10.1371/journal.pmed.0030147 The most common cause of nongenetic mental retardation in the Western world is fetal alcohol syndrome (FAS). About one in 1,000 United States children is born with FAS, [...]

ABSTRACT Background Exposure to alcohol during brain development may cause a neurological syndrome called fetal alcohol syndrome (FAS). Ethanol induces apoptotic neuronal death at specific developmental stages, particularly during the [...]

Results of a study to evaluate the risk factors and outcomes associated with first-trimester determination of growth restriction have revealed that maternal physical characteristics and lifestyle habits were independently associated with early fetal growth and first-trimester fetal growth restriction was associated with an increased risk of adverse birth outcomes. Combined ultrasonic and biochemical screening in early pregnancy can identify women at high risk of complications in late pregnancy.

OBJECTIVES. Prenatal exposure to alcohol interferes with fetal development and is the leading preventable cause of birth defects and developmental disabilities. The purpose of this study was to identify current knowledge, diagnosis, prevention, and intervention practices related to fetal alcohol syndrome and related conditions by members of the American Academy of Pediatrics. METHODS. This study was developed collaboratively by the American Academy of Pediatrics and the Centers for Disease Control and Prevention. Questionnaires were mailed to a 3% random sample (n = 1600) of American Academy of Pediatrics members in the United States. General pediatricians, pediatric subspecialists, and pediatric residents were included. RESULTS. Participation rate was 55% (n = 879). Respondents almost universally knew the teratology and clinical presentation of fetal alcohol spectrum disorders. However, they were less likely to report comfort with routine pediatric care of these children. Whereas 62% felt prepared to identify and 50% felt prepared to diagnose, only 34% felt prepared to manage and coordinate the treatment of children with fetal alcohol spectrum disorders. Even fewer (n = 114 [13%]) reported that they routinely counsel adolescent patients about the risks of drinking and pregnancy. CONCLUSIONS. The survey confirms that pediatricians are knowledgeable about fetal alcohol syndrome but do not feel adequately trained to integrate the management of this diagnosis or prevention efforts into everyday practice. Furthermore, the respondents were not active in routine anticipatory guidance with adolescents for prevention of alcohol-affected pregnancies. The development, dissemination, and implementation of best practice tools for prevention, diagnosis, and referral of fetal alcohol syndrome that are specific for general and sub-specialist pediatricians are recommended. KEY WORDS. fetal alcohol syndrome, developmental disabilities, medical home, alcohol., Sheila Gahagan, MD, MPH, Tanya Telfair Sharpe, PhD, Michael Brimacombe, PhD, Yvonne Fry-Johnson, MD, Robert Levine, MD, Mark Mengel, AID, MPH, Mary O'Connor, PhD, Blair Paley, PhD, Susan Adubato, PhD, [...]