Anatomy of a patient safety event: a pediatric patient safety taxonomy.

BACKGROUND: Idiosyncratic terminology and frameworks in the study of patient safety have been tolerated but are increasingly problematic. Agreement on standard language and frameworks is needed for optimal improvement and dissemination of knowledge about patient safety. METHODS: Patient safety events were assessed using critical incident analysis, a method used to classify risks that has been more recently applied to medicine. Clinician interviews and clinician reports to a web based reporting system were used for analysis of hospital based and ambulatory care events, respectively. Events were classified independently by three investigators. RESULTS: A pediatric patient safety taxonomy, relevant to both hospital based and ambulatory pediatric care, was developed from the analysis of 122 hospital based and 144 ambulatory care events. It is composed of four main categories: (1) problem type; (2) domain of medicine; (3) contributing factors in the patient (child-specific), environment (latent conditions) and care providers (human factors); and (4) outcome or result of the event and level of harm. A classification of preventive mechanisms was also developed. Inter-rater reliability of classifications ranged from 72% to 86% for sub-categories of the taxonomy. CONCLUSIONS: This patient safety taxonomy reflects the nature of events that occur in both pediatric hospital based and ambulatory care settings. It is flexible in its construction, permits analysis to begin at any point, and depicts the relationships and interactions of elements of an event.

Altered hepatic gene expression of enzymes involved in energy metabolism in the growth-retarded fetal rat.

Intrauterine growth retardation (IUGR) resulting from placental insufficiency is a common complication of pregnancy. Bilateral uterine artery ligation of the pregnant rat is a model which mimics intrauterine growth retardation in the human. IUGR rat fetuses have altered hepatic energy and redox states, with reduced fetal hepatic ATP/ADP ratio, increased cytosolic NAD+/NADH ratio, and decreased mitochondrial NAD+/NADH ratio. These critical changes in energy metabolism contribute to IUGR. The effects of these changes at the molecular level are largely unknown. To address these effects we compared hepatic mRNA populations of IUGR and normal fetuses and neonates using mRNA differential display, a polymerase chain reaction-based method for assaying transcriptional differences under various conditions. We isolated and sequenced 18 cDNA products whose mRNA levels were elevated in IUGR compared with normal fetal and neonatal liver. These analyses demonstrated that NADH-ubiquinone oxireductase subunit 4L mRNA (ND-4L) was significantly increased in liver of IUGR fetuses and neonates. This suggested that IUGR may be associated with altered expression of genes involved in the generation of ATP and NADH. Therefore, we measured mRNA levels of adenine-nucleotide translocator-2 (ANT-2), glucose-6-phosphate dehydrogenase (G6PD), mitochondrial malate dehydrogenase (MMD), ornithine transcarbamylase (OTC), and phosphofructokinase-2 (PFK-2) using a semiquantitative reverse transcriptase-polymerase chain reaction-based technique. In the IUGR fetus, ND-4L, ANT-2, G6PD, and MMD mRNA levels were significantly elevated; PFK-2 mRNA levels were unchanged, and OTC levels were decreased. In the IUGR newborn rat, mRNA levels of all 6 enzymes were increased suggesting that the metabolic state of the growth retarded newborn remains abnormal after birth. Uteroplacental insufficiency affects the immediate and long-term metabolic milieu of the growth retarded animal, and forces specific adjustments, including the expression of mRNA encoding enzymes involved with hepatic energy production.

Prenatal and perinatal influences on long-term psychomotor development in offspring of diabetic mothers.

OBJECTIVE: Our purpose was to assess to what extent disturbances in antepartum maternal metabolism and perinatal complications and morbidities contribute to poorer psychomotor development in offspring of diabetic mothers. STUDY DESIGN: One hundred ninety-six pregnant women and their singleton offspring participated in this prospective cohort-analytic study. Ninety-five women had pregestational diabetes mellitus, and 101 women had gestational diabetes mellitus. Serial estimates of circulating maternal fuels were obtained throughout each index pregnancy along with detailed records of the perinatal course and outcome. Offspring were administered the psychomotor development index of the Bayley Scales of Infant Development at age 2 years and the Bruininks-Oseretsky Test Of Motor Proficiency at ages 6, 8, and 9 years. Tests were performed blinded to the mother's antepartum metabolic status, and perinatal history, and the child's previous test scores. Partial correlations and analyses of covariance were used to control for other influences and confounds, such as family socioeconomic status, racial or ethnic origin, patient group (i.e., pregestational or gestational diabetes mellitus), and sex of child. RESULTS: Children's average score on the Bruininks-Oseretsky test at ages 6 to 9 years correlated significantly with maternal second (p < 0.02) and third trimester (p < 0.001) beta-hydroxybutyrate. There was also a borderline association between the children's scores on the psychomotor development index at age 2 years and maternal third-trimester beta-hydroxybutyrate levels (p = 0.06). No other correlations approached significance. CONCLUSIONS: Intrauterine metabolic experiences continue to influence the neurodevelopmental course in offspring of diabetic mothers. Prevailing practices in diabetes management and obstetric and neonatal care appear to effectively mitigate the potential long-term effects of most perinatal complications and morbidities. Management and obstetric and neonatal care appear to effectively miltigate the potential long-term effects of most perinatal complications and morbidities.

Chronic maternal hypoxia retards fetal growth and increases glucose utilization of select fetal tissues in the rat.

The development of intrauterine growth retardation (IUGR) is frequently associated with fetal hypoxia, hypoglycemia, and abnormal fetal glucose metabolism. To determine the effects of hypoxia (without concomitant hypoglycemia) on fetal glucose metabolism, we continuously exposed pregnant rats to 10% (10.1 kPa) ambient oxygen from day 15 through day 20 of gestation (term, 21.5 days) and used radiolabeled 2-deoxyglucose (2DG) to measure in vivo relative glucose utilization (rGU) of several fetal tissues on day 20 of gestation. Pair-fed rats in room-air oxygen were used as controls. Maternal hypoxia resulted in significant IUGR, fetal hypoxia and acidosis, and fetal lactate accumulation on day 20 of gestation. Following 5 days of hypoxia, rGU values for fetal lung, heart, and kidney were increased by 61%, 54%, and 47%, respectively (P < .05). rGU values for fetal brain, liver, muscle, and placenta were not significantly affected. Fetal plasma glucose concentrations were similar in hypoxic and control fetuses. We speculate that the increased rGU of hypoxic fetal tissues is due in part to anaerobic metabolism and increased glycolysis.

Perinatal complications and cognitive development in 2- to 5-year-old children of diabetic mothers.

OBJECTIVE: Our purpose was to assess whether perinatal complications contribute to lower intellectual attainment in offspring of diabetic mothers, independent of antepartum metabolic disregulation. STUDY DESIGN: Subjects were 223 pregnant women and their singleton offspring. Eighty-nine women had pregestational diabetes mellitus, 99 had gestational diabetes mellitus, and 35 had normal gestational glucose metabolism. Perinatal complications were prospectively recorded on an examination checklist. The intelligence quotient of the child was assessed with the Bayley Scales of Infant Development at age 2 years and the Stanford-Binet Intelligence Scale at age 3 to 5 years. RESULTS: No significant correlations emerged between either measure of child's intelligence quotient and any prevalent perinatal complication, after statistical correction for socioeconomic status, race or ethnic origin, patient group, and antepartum metabolic control. CONCLUSIONS: Given prevailing practices in diabetes management and obstetric and neonatal care, the effects of prevalent perinatal complications on the intellectual development of offspring of diabetic mothers appear minimal.

The effects of severe maternal diabetes on glucose transport in the fetal rat.

We mimicked the condition of severe maternal diabetes by administering high doses of streptozotocin (STZ) to the pregnant rat to determine the effects of increased glucose availability on fetal glucose transport and to assess whether a relationship might exist between glucose transport and altered fetal growth. Fetuses of STZ-treated pregnant rats were growth retarded (3.86 +/- 0.13 vs. 5.29 +/- 0.06 g), hyperglycemic (30.0 +/- 1.0 vs. 5.5 +/- 0.5 mM/liter), and hyperinsulinemic (1263.8 +/- 138.3 vs. 817.9 +/- 116.7 pM/liter). Glucose uptake, Glut 1 messenger RNA (mRNA), and Glut 1 protein were greater in STZ-treated fetal brain than in controls (50%, 83%, and 50%, respectively; P < 0.05). Glut 3 mRNA levels in STZ-treated and control fetal brain were equivalent and significantly less than levels of Glut 1. Glucose uptake in muscle of STZ fetuses was 70% greater than control values (P < 0.05). Glut 1 mRNA levels were increased by 93% in STZ fetal muscle (P < 0.05). Neither Glut 3 nor Glut 4 mRNA could be detected in STZ-treated and control fetal muscle. Glut 1 protein levels were increased by 70% in STZ-treated fetal muscle compared to control muscle (P < 0.05). These observations indicate that altered glucose transport per se does not directly contribute to fetal growth retardation with maternal STZ diabetes. Perturbations in other physiological and metabolic factors may contribute to the pathogenesis of fetal growth retardation in STZ-induced diabetes during pregnancy.

The effect of insulin and insulin-like growth factor-I on glucose transport in normal and small for gestational age fetal rats.

In a model of asymmetric small for gestational age (SGA) fetal growth retardation, we have previously found that glucose transport is decreased in lung (an organ whose growth is restricted) and unaffected in brain (growth is normal). The SGA model alters a number of physiological and metabolic factors that may decrease glucose transport, thereby causing growth retardation. Specifically, insulin and insulin-like growth factor-I (IGF-I) concentrations are diminished in SGA fetuses. We hypothesized that the specific modulation by these factors of gene expression of a glucose transporter, Glut-1, is impaired. We performed bilateral uterine arterial ligation in pregnant rats on day 19 of gestation (term = 21.5 days) and obtained fetal brain, lung, and skeletal muscle on day 20. Lung and muscle explants and monolayers of glial cells and type II pneumocytes were cultured in the presence or absence of insulin or IGF-I for 24 h. Glucose uptake and levels of Glut-1 protein and mRNA were similar in brains of SGA and control fetuses and were not affected by treatment with insulin or IGF-I. Treatment with insulin or IGF-I increased glucose uptake and levels of Glut-1 protein and mRNA in a dose-dependent manner in lung and muscle from control fetuses. However, the response in SGA lung was not as great as that in controls. SGA muscle demonstrated no significant response to either hormone. These findings suggest that changes in glucose transport modulation might contribute to the development of asymmetric growth retardation, and that maintenance of normal transporter function and expression in brain may play a role in sparing its growth.

Cost-benefit analysis of preconception care for women with established diabetes mellitus.

OBJECTIVE: To determine whether the additional costs of preconception care are balanced by the savings from averted complications. Several studies have demonstrated the efficacy of preconception care in reducing congenital anomalies in infants born of mothers with pre-existing diabetes mellitus. RESEARCH DESIGN AND METHODS: This study used literature review, consensus development among an expert panel of physicians, and surveys of medical care personnel to obtain information about the costs and consequences of preconception plus prenatal care compared with prenatal care only for women with established diabetes. Preconception care involves close interaction between the patient and an interdisciplinary health-care team as well as intensified evaluation, follow-up, testing, and monitoring. The outcome measures assessed in this study are the medical costs of preconception care versus prenatal care only and the benefit-cost ratio. RESULTS: The costs of preconception plus prenatal care are $17,519/delivery, whereas the costs of prenatal care only are $13,843/delivery. Taking into account maternal and neonatal adverse outcomes, the net savings of preconception care are $1720/enrollee over prenatal care only and the benefit-cost ratio is 1.86. The preconception care program remained cost saving across a wide range of assumptions regarding incidence of adverse outcomes and program cost components. CONCLUSIONS: Despite significantly higher per delivery costs for participants in a hypothetical preconception care program, intensive medical care before conception resulted in cost savings compared with prenatal care only. Third-party payers can expect to realize cost savings by reimbursing preconception care in this high-risk population.

Glucose regulates glut 1 function and expression in fetal rat lung and muscle in vitro.

The mechanisms that regulate cellular glucose transport (glucose uptake, Glut 1 protein, and mRNA) in the fetus are not known. We attempted to define the effects of glucose availability alone in vitro on glucose transport in fetal rat lung and muscle. On day 20 of gestation (term = 21.5 days), lung and muscle tissues were harvested from normal fetal rats, minced into explants, and cultured for 24 h in standard culture medium (lung, 28 mM; muscle, 5.5 mM glucose). Explant cultures were washed and cultured for an additional 1 or 24 h in medium containing one of four concentrations of glucose: 1) glucose free, 2) low glucose, 3) high glucose, and 4) standard. Twenty-four-hour, but not 1-h, treatment of fetal lung and muscle in vitro with low concentrations of glucose increased 2-deoxyglucose uptake and Glut 1 protein and mRNA levels (P < 0.05). Culture in high glucose medium for 24 h, but not 1 h, decreased 2-deoxyglucose uptake and Glut 1 protein and mRNA levels (P < 0.05). Culture in glucose-free medium for 24 h up-regulated glucose transport in lung and down-regulated glucose transport in muscle, indicating that regulation of fetal glucose transport may be tissue specific. These findings differ from our studies of in vivo models of altered fetal growth and abnormal glucose availability. Maternal bilateral uterine artery ligation limits glucose availability to the fetus, and glucose transport is down-regulated. Low glucose in vitro has the opposite effect. Maternal diabetes increases glucose availability to the fetus, and glucose transport is up-regulated. High glucose in vitro does the opposite. We conclude that while glucose alone in vitro affects its uptake by the cell, other factors that are altered in these in vivo conditions act in concert with glucose to regulate glucose transport in the fetus.

Circulating levels of insulin, insulin-like growth factor-I (IGF-I), IGF-II, and IGF-binding proteins in the small for gestational age fetal rat.

Insulin-like growth factors (IGFs) are important regulators of somatic growth in childhood and circulate in association with specific binding proteins (IGFBPs). Insulin is important for the regulation of IGFs and IGFBPs in postnatal life and is required for normal growth in utero. We asked whether alterations in the availability of IGFs and/or their BPs may contribute to impaired fetal growth 24 h after bilateral uterine artery ligation when circulating levels of insulin are low and fetuses are small for gestational age (SGA). Bilateral uterine arterial ligation or sham surgery was performed on maternal rats on day 19 of gestation (term = 21.5 days). One day after ligation, fetuses were SGA compared to shams (2.9 +/- 0.1 vs. 3.5 +/- 0.1 g/fetus, respectively; P < 0.001), and liver weight was reduced (242 +/- 9 vs. 300 +/- 6 mg/liver; P < 0.001). Serum levels of both insulin and IGF-I were reduced approximately 50% in SGA litters compared to those in shams (P < 0.001) and correlated with each other (P < 0.02). IGF-I levels also correlated with fetal body and liver weights (P < 0.005 for each) even after controlling for the effects of insulin. Insulin levels correlated with body and liver weights (P < 0.02 and P < 0.03, respectively), but these relationships were not significant after controlling for the effects of IGF-I. Serum levels of IGF-II were not significantly reduced in SGA and did not correlate with fetal weight or insulin or IGF-I levels. [125I]IGF-I binding assay demonstrated that the availability of IGFBPs was increased in SGA serum, and Western ligand blotting indicated that circulating levels of 32K IGFBPs were increased in SGA fetuses compared to shams. Densitometric analysis indicated that levels of 32K IGFBPs were 4-fold greater in SGA litters (P < 0.001 vs. shams), and the level of 32K IGFBPs correlated with fetal body and liver weights (P < 0.05 for each) and with levels of both insulin and IGF-I (P < 0.001 for each), but not with levels of IGF-II. Immunoblotting with newly developed antiserum against rat IGFBP-1 confirmed that levels of immunoreactive 32K IGFBP-1 are increased in SGA serum, and immunoprecipitation studies confirmed that IGFBP-1 accounted for the rise in 32K IGFBPs in SGA serum.(ABSTRACT TRUNCATED AT 400 WORDS)

Differential effects of short and long durations of insulin-induced maternal hypoglycemia upon fetal rat tissue growth and glucose utilization.

We studied the effects of short and long durations of insulin-induced maternal hypoglycemia upon in vivo glucose utilization of several fetal tissues in the rat. Osmotic minipumps filled with insulin were implanted in pregnant rats on d 15 or 18 of gestation (term 21.5 d), and radiolabeled 2-deoxyglucose was used to measure relative glucose utilization rates (rGU) of fetal liver, lung, muscle, kidney, heart, placenta, and brain on d 20 of gestation after 2 or 5 d of hypoglycemia. Maternal plasma glucose concentrations decreased within 24 h of pump placement and remained less than controls throughout gestation. Fetal plasma glucose and insulin concentrations on d 20 were equally reduced after 2 and 5 d of hypoglycemia. Both 2 and 5 d of hypoglycemia were associated with significant reductions in the rGU of fetal liver, lung, and muscle. Reductions in fetal kidney rGU also occurred after 2 and 5 d of hypoglycemia but to a smaller degree. rGU of fetal heart was reduced after 2 d of hypoglycemia, but was normal after 5 d of hypoglycemia. Both 2 and 5 d of hypoglycemia were associated with increased rGU of fetal brain. Five d, but not 2 d of hypoglycemia resulted in decreased fetal weight on d 20 of gestation. However, at term, newborn pups delivered of hypoglycemic mothers weighed significantly less than controls regardless of the timing of minipump placement. Liver, lung, and carcass of these growth-retarded pups weighed less than control tissues, whereas kidney, heart, and brain weights were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Financial implications of implementing standards of care for diabetes and pregnancy.

This article examines the financial implications of implementing standards of care for pregnancy among women with diabetes, including both the costs of enhanced treatment and the savings of avoided adverse outcomes. Numerous studies have demonstrated the harmful effects of poor blood glucose control for both mother and fetus. Standards set forth by the American Diabetes Association aim to reduce maternal complications and fetal adverse outcomes, such as congenital malformations. Because the precise configuration of resources required to meet these standards was not outlined in the American Diabetes Association statement, a panel of physicians (all specialists in pregnancy care for women with diabetes) was convened to develop a model program. Implementing such a program during the preconception and prenatal periods will represent an intensification of resource use in the outpatient setting. However, through these preventive measures, medical care costs for maternal and fetal complications can be avoided.

Intrauterine growth retardation: fetal glucose transport is diminished in lung but spared in brain.

"Uteroplacental insufficiency" often causes asymmetric fetal growth retardation. Glucose transporters control cell glucose utilization and thus may be critical in the control of fetal growth. We hypothesized that uteroplacental insufficiency might alter glucose transporter activity, protein, and gene expression and thereby affect discordant organ growth in small-for-gestational-age (SGA) fetuses. We performed bilateral uterine artery ligation in pregnant rats on d 19 of gestation (term-21.5 d) to cause uteroplacental insufficiency and obtained fetal brain and lung tissue on d 20. The brain mass of SGA fetuses did not differ from that of sham and normal fetuses, but lung mass was significantly diminished. Glucose transport, measured with [3H]2-deoxyglucose, was similar in glial cells and brain tissue of SGA, sham, and normal fetuses. In contrast, type II pneumocytes, lung fibroblasts, and lung tissue of SGA fetuses had significantly decreased glucose transport. The intrinsic activity of the glucose transporter (Km) was not altered in the brain or lung of SGA fetuses. Total glucose transporter protein measured by cytochalasin-B binding and glucose transporter 1 mRNA was diminished in SGA lung tissue and type II pneumocytes, but not in SGA brain tissue or glial cells. We could not detect glucose transporter 3 mRNA in significant quantity in any tissue. With uteroplacental insufficiency, glucose transport is differentially altered in lung and brain. Glucose transporter protein and gene expression are diminished in the lung and normal in the brain of SGA fetuses. These changes may contribute to fetal growth retardation and the phenomenon of "brain sparing."

Long-term prospective evaluation of offspring of diabetic mothers.

We have suggested that altered maternal metabolism may affect the subsequent anthropometric and neuropsychological development of children who were in utero during disturbances in maternal fuel economy. This study reports the physical growth through 8 yr of age and the neuropsychological development through 4 yr of age in offspring of diabetic mothers (ODM). At birth, 50% of infants had weights greater than 90th percentile for gestational age. By 12 mo, length and weight were similar to the general population. Height remained normal until 7 yr of age, when it became slightly greater than average. After 5 yr of age, relative weight increased dramatically, and by 8 yr of age, half of the ODM had weights greater than 90th percentile. This childhood obesity in ODM is correlated with maternal prepregnant weight and independently with amniotic fluid insulin at 32-38 wk gestation. The Brazelton Neonatal Behavioral Assessment Scale (BNBAS) was administered to 185 newborn ODM. Significant correlations were found between poorer second- and third-trimester glycemic regulation and lower scores in three of four newborn BNBAS dimensions. The Stanford-Binet Intelligence Scale was measured in 102 ODM at 4 yr of age. We found an inverse correlation between childhood IQ and second- and third-trimester maternal lipid metabolism (serum free fatty acids and beta-hydroxybutyrate). This correlation is not explained by adverse perinatal events, socioeconomic status, maternal IQ, ethnicity, or diabetes type. These long-range associations between altered maternal metabolism and childhood growth and development continue to support Freinkel's hypothesis of fuel-mediated teratogenesis.

Absence of hyperinsulinemia in isoimmunized fetuses treated with intravascular transfusion.

We serially sampled blood from fetuses of five severely isoimmunized pregnancies at the time of each intrauterine intravascular transfusion and at birth. We were unable to demonstrate either an elevation in the plasma insulin/glucose ratio or a relationship between the insulin/glucose ratio and hemoglobin concentration at any time period. Plasma total glutathione concentration, however, decreased dramatically from the initial to the second transfusion (323 +/- 114 to 43 +/- 9 ng/ml; t = -5.06, p less than 0.01). We speculate that intrauterine transfusion may modify or prevent the previously reported fetal pancreatic beta-cell hyperplasia and hyperinsulinemia associated with isoimmunization by decreasing red blood cell hemolysis and thereby circulating glutathione.

The infant of the diabetic mother: pregnancy as a "tissue culture experience".

Studies of the infant of the diabetic mother at the Diabetes in Pregnancy Center at Northwestern University have aimed to delineate the relationship between the transplacental metabolic fuel availability and fetal growth and development. Data are presented linking the altered metabolic fuel availability and the various problems, short- and long-range implications, of the infant of the diabetic mother.

A controlled trial of insulin infusion and parenteral nutrition in extremely low birth weight infants with glucose intolerance.

To determine whether a continuous insulin infusion improves glucose tolerance in extremely low birth weight infants, we conducted a prospective, randomized trial in 24 neonates 4 to 14 days old (mean birth weight 772.9 +/- 128 gm; mean gestational age 26.3 +/- 1.6 weeks). Infants who had glucose intolerance were randomly assigned to receive either intravenous glucose and total parenteral nutrition with insulin through a microliter-sensitive pump or standard intravenous therapy alone. One infant assigned to receive insulin never required it. The groups were similar in birth weight, gestational age, race, gender, medical condition, and energy intake before the study. The mean duration of therapy was 14.6 days (range 7 to 21 days). During the study, the 11 insulin-treated infants tolerated higher glucose infusion rates (20.1 +/- 2.5 vs 13.2 +/- 3.2 mg/kg/min (1.1 +/- 0.1 vs 0.7 +/- 0.2 mmol/L); p less than 0.01), had greater nonprotein energy intake (124.7 +/- 18 vs 86.0 +/- 6 kcal/kg/day; p less than 0.01), and had better weight gain (20.1 +/- 12.1 vs 7.8 +/- 5.1 gm/kg/day; p less than 0.01) than the 12 control infants. The incidence of hypoglycemia, electrolyte imbalance, chronic lung disease, and death did not differ between groups. We conclude that a controlled insulin infusion improves and sustains glucose tolerance, facilitates provision of calories, and enhances weight gain in glucose-intolerant premature infants.

Uterine artery ligation in the maternal rat alters fetal tissue glucose utilization.

We studied the effects of maternal uterine artery ligation on fetal rat tissue glucose utilization (GU). Unilateral uterine artery ligations were performed on the 19th d of gestation (term 21.5 d) and 2-[3H]deoxy-D-glucose was used to measure GU of placenta, liver, brain, muscle, kidney, and heart from fetuses in the ligated (IUGR) and nonligated (control) uterine horns 24 and 48 h after the procedure. At both periods, IUGR fetuses weighed significantly less and had lower fetal/maternal plasma glucose ratios than controls. Twenty-four h after ligation, placenta, liver, brain, and muscle from IUGR fetuses had lower relative GU rates than corresponding tissues from control fetuses (p less than 0.01-0.05). However, at 48 h, IUGR liver, muscle, kidney, and heart had higher relative GU rates than control tissues (p less than 0.01-0.05). The lower GU of IUGR fetal tissues observed at 24 h postligation was likely related to the acute decrease in fetal glucose availability. Other factors, such as hypoxemia and acidosis, that affect cellular metabolism may also have led to lower GU rates. The increase in GU by IUGR tissues at 48 h occurred despite a persistence of low fetal glucose concentrations and can be explained by either: 1) an attempt by IUGR fetal tissues to compensate for the persistently low plasma glucose; 2) an increased demand for metabolic fuel for repair processes; or 3) a less efficient use of glucose due to alterations in cellular respiration. We speculate that this increase in fetal tissue GU may be partially responsible for the supranormal glucose requirements seen in small-for-gestational-age newborns.

Amniotic fluid insulin concentration as a predictor of obesity.

Longitudinal correlations were obtained between amniotic fluid insulin concentration at 32 to 38 weeks' gestation and anthropometric characteristics at the age of 6 years in 56 children of diabetic mothers. The prospective studies indicated that at the age of 6 years, as at birth, the greatest increase in weight in relation to height (relative obesity) was seen in children who experienced the greatest exposures to insulin in the uterus (as judged by amniotic fluid insulin concentration). Significant correlations between amniotic fluid insulin and relative obesity at the age of 6 years were found after adjustment for maternal obesity and macrosomia at birth. The highest amniotic fluid insulin values are clustered in the subgroup of 14 children who were obviously obese by the age of 6 years. These findings are consistent with the hypothesis that there is an association between anthropometric development and intrauterine metabolism, and suggest that premature and excessive exposure to insulin during gestation may predispose to obesity in childhood. The amniotic fluid insulin concentration may predict this eventuality.

Circulating levels of insulin-like growth factor binding protein-1 (IGFBP-1) and hepatic mRNA are increased in the small for gestational age (SGA) fetal rat.

Insulin-like growth factors (IGFs) circulate in association with a family of specific binding proteins (BPs). Recently, we reported that circulating levels of IGFBP-1 and IGFBP-2 are increased in streptozotocin-diabetic adult rats and are differentially regulated in accordance with insulin and metabolic status. Since IGF BPs appear to be important modulators of IGF bioactivity in post-natal life, we asked whether serum levels of IGF BPs also might be altered in utero when the delivery of maternal nutrients is restricted and fetal growth is impaired. Bilateral uterine artery ligation or sham surgery was performed on maternal rats on d 19 of gestation (term 21.5 d). One day after ligation (d 20), fetuses were (SGA) compared to shams (3.1 +/- 1 vs 3.7 +/- 0.2 g, p less than .02) and serum levels of glucose (70 +/- 5 vs 96 +/- 6 mg/dL, p less than .01) and insulin (62 +/- 4 vs 138 +/- 14 microU/mL) also were reduced. In contrast, serum [125I]IGF-I binding activity was markedly increased in SGA litters compared to sham (65 +/- 5% maximum binding with 2.5 microL/mL SGA serum vs 14 +/- 3% for sham serum, p less than .001), and correlated with fetal weight (r = -0.539, p less than .05) and insulin (r = -0.622, p less than .05). Ligand blotting with [125I]IGF-I revealed that serum levels of IGFBP-1 (32 K) were greater in SGA than shams, while immunoblotting with specific antiserum demonstrated that levels of IGFBP-2 (34 K), the major fetal rat IGF BP, were similar in serum from SGA and shams litters. Affinity labeling and immunoprecipitation confirmed that IGF binding activity is increased in SGA, due largely to increased availability of IGFBP-1. In addition, Northern analysis of hepatic RNA revealed that the abundance of IGFBP-1 mRNA is increased in the SGA fetal rat, while hepatic mRNA for IGFBP-2 is similar in SGA and sham-operated litters. We conclude that circulating levels of IGFBP-1 and the abundance of hepatic mRNA are increased in the SGA fetal rat. IGFBP-1 may be an important modulator of IGF bioactivity and somatic growth in utero.