Ambient exposure to fine particulate matter with oxidative potential affects oxidative stress biomarkers in pregnancy.

Prenatal exposures to ambient particulate matter (PM2.5) from traffic may generate oxidative stress, and thus contribute to adverse birth outcomes. We investigated whether PM2.5 constituents from brake and tire wear affect levels of oxidative stress biomarkers (malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG)) using urine samples collected up to three times during pregnancy in 156 women recruited from antenatal clinics at the University of California Los Angeles. Land use regression models with co-kriging were employed to estimate average residential outdoor concentrations of black carbon (BC), PM2.5 mass, PM2.5 metal components, and three PM2.5 oxidative potential metrics during the 4-weeks prior to urine sample collection. 8-OHdG concentrations in mid-pregnancy increased by 24.8% (95% CI: 9.0, 42.8) and 14.3% (95% CI: 0.4%, 30.0%) per interquartile range (IQR) increase in PM2.5 mass and BC, respectively. The brake wear marker (barium) and the oxidative potential metrics were associated with increased MDA concentration in the 1st sample collected (10-17 gestational week), but 95% CIs included the null. Traffic-related air pollution contributed in early to mid-pregnancy to oxidative stress generation previously linked to adverse birth outcomes.

Gut Microbes and Circulating Cytokines in Preterm Infants with Growth Failure.

BACKGROUND: Growth failure (GF) is a multifactorial problem in preterm infants. The intestinal microbiome and inflammation may contribute to GF. OBJECTIVES: This study's objective was to compare the gut microbiome and plasma cytokines in preterm infants with and without GF. METHODS: This was a prospective cohort study of infants with birth weights of <1750 g. Infants with a weight or length z-score change from birth to discharge or death that was less than or equal to -0.8 (GF group) were compared with infants without GF [control (CON) group]. The primary outcome was the gut microbiome (at weeks 1-4 of age), assessed by 16S rRNA gene sequencing using Deseq2. Secondary outcomes included inferred metagenomic function and plasma cytokines. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States determined metagenomic function, which was compared using ANOVA. Cytokines were measured by 2-multiplexed immunometric assays and compared using Wilcoxon tests and linear mixed models. RESULTS: GF (n = 14) and CON group (n = 13) had similar median (IQR) birth weight (1380 [780-1578] g vs. 1275 [1013-1580] g) and gestational age (29 [25-31] weeks vs. 30 [29-32] weeks). Compared with the CON group, the GF group had a greater abundance of Escherichia/Shigella in weeks 2 and 3, Staphylococcus in week 4, and Veillonella in weeks 3 and 4 (P-adjusted < 0.001 for all). Plasma cytokine concentrations did not differ significantly between the cohorts. When all time points are combined, fewer microbes were involved in TCA cycle activity in the GF group compared with the CON group (P = 0.023). CONCLUSIONS: In this study, when compared with CON infants, GF infants had a distinct microbial signature with increased Escherichia/Shigella and Firmicutes and fewer microbes associated with energy production at later weeks of hospitalization. These findings may suggest a mechanism for aberrant growth.

Evaluation of Spatial Attentive Deep Learning for Automatic Placental Segmentation on Longitudinal MRI.

BACKGROUND: Automated segmentation of the placenta by MRI in early pregnancy may help predict normal and aberrant placenta function, which could improve the efficiency of placental assessment and the prediction of pregnancy outcomes. An automated segmentation method that works at one gestational age may not transfer effectively to other gestational ages. PURPOSE: To evaluate a spatial attentive deep learning method (SADL) for automated placental segmentation on longitudinal placental MRI scans. STUDY TYPE: Prospective, single-center. SUBJECTS: A total of 154 pregnant women who underwent MRI scans at both 14-18 weeks of gestation and at 19-24 weeks of gestation, divided into training (N = 108), validation (N = 15), and independent testing datasets (N = 31). FIELD STRENGTH/SEQUENCE: A 3 T, T2-weighted half Fourier single-shot turbo spin-echo (T2-HASTE) sequence. ASSESSMENT: The reference standard of placental segmentation was manual delineation on T2-HASTE by a third-year neonatology clinical fellow (B.L.) under the supervision of an experienced maternal-fetal medicine specialist (C.J. with 20 years of experience) and an MRI scientist (K.S. with 19 years of experience). STATISTICAL TESTS: The three-dimensional Dice similarity coefficient (DSC) was used to measure the automated segmentation performance compared to the manual placental segmentation. A paired t-test was used to compare the DSCs between SADL and U-Net methods. A Bland-Altman plot was used to analyze the agreement between manual and automated placental volume measurements. A P value < 0.05 was considered statistically significant. RESULTS: In the testing dataset, SADL achieved average DSCs of 0.83 ± 0.06 and 0.84 ± 0.05 in the first and second MRI, which were significantly higher than those achieved by U-Net (0.77 ± 0.08 and 0.76 ± 0.10, respectively). A total of 6 out of 62 MRI scans (9.6%) had volume measurement differences between the SADL-based automated and manual volume measurements that were out of 95% limits of agreement. DATA CONCLUSIONS: SADL can automatically detect and segment the placenta with high performance in MRI at two different gestational ages. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

A Description of the Imaging Innovations for Placental Assessment in Response to Environmental Pollution Study.

OBJECTIVE: The aim of Placental Assessment in Response to Environmental Pollution Study (PARENTs) was to determine whether imaging of the placenta by novel multiparametric magnetic resonance imaging (MRI) techniques in early pregnancy could help predict adverse pregnancy outcomes (APOs) due to ischemic placental disease (IPD). Additionally, we sought to determine maternal characteristics and environmental risk factors that contribute to IPD and secondary APOs. STUDY DESIGN: Potential patients in their first trimester of pregnancy, who agreed to MRI of the placenta and measures of assessment of environmental pollution, were recruited into PARENTs, a prospective population-based cohort study. Participants were seen at three study visits during pregnancy and again at their delivery from 2015 to 2019. We collected data from interviews, chart abstractions, and imaging. Maternal biospecimens (serum, plasma, and urine) at antepartum study visits and delivery specimens (placenta, cord, and maternal blood) were collected, processed, and stored. The primary outcome was a composite of IPD, which included any of the following: placental abruption, hypertensive disease of pregnancy, fetal growth restriction, or a newborn of small for gestational age. RESULTS: In this pilot cohort, of the 190 patients who completed pregnancy to viable delivery, 50 (26%) developed IPD. Among demographic characteristics, having a history of prior IPD in multiparous women was associated with the development of IPD. In the multiple novel perfusion measurements taken of the in vivo placenta using MRI, decreased high placental blood flow (mL/100 g/min) in early pregnancy (between 14 and 16 weeks) was found to be significantly associated with the later development of IPD. CONCLUSION: Successful recruitment of the PARENTs prospective cohort demonstrated the feasibility and acceptability of the use of MRI in human pregnancy to study the placenta in vivo and at the same time collect environmental exposure data. Analysis is ongoing and we hope these methods will assist researchers in the design of prospective imaging studies of pregnancy. KEY POINTS: · MRI was acceptable and feasible for the study of the human placenta in vivo.. · Functional imaging of the placenta by MRI showed a significant decrease in high placental blood flow.. · Measures of environmental exposures are further being analyzed to predict IPD..

Developing Brain Glucose Transporters, Serotonin, Serotonin Transporter, and Oxytocin Receptor Expression in Response to Early-Life Hypocaloric and Hypercaloric Dietary, and Air Pollutant Exposures.

Perturbed maternal diet and prenatal exposure to air pollution (AP) affect the fetal brain, predisposing to postnatal neurobehavioral disorders. Glucose transporters (GLUTs) are key in fueling neurotransmission; deficiency of the neuronal isoform GLUT3 culminates in autism spectrum disorders. Along with the different neurotransmitters, serotonin (5-HT) and oxytocin (OXT) are critical for the development of neural connectivity. Serotonin transporter (SERT) modulates synaptic 5-HT levels, while the OXT receptor (OXTR) mediates OXT action. We hypothesized that perturbed brain GLUT1/GLUT3 regulated 5-HT-SERT imbalance, which serves as a contributing factor to postnatal neuropsychiatric phenotypes, with OXT/OXTR providing a counterbalance. Employing maternal diet restriction (intrauterine growth restriction [IUGR]), high-fat (HF) dietary modifications, and prenatal exposure to simulated AP, fetal (E19) murine brain 5-HT was assessed by ELISA with SERT and OXTR being localized by immunohistochemistry and measured by quantitative Western blot analysis. IUGR with lower head weights led to a 48% reduction in male and female fetal brain GLUT3 with no change in GLUT1, when compared to age- and sex-matched controls, with no significant change in OXTR. In addition, a ∼50% (p = 0.005) decrease in 5-HT and SERT concentrations was displayed in fetal IUGR brains. In contrast, despite emergence of microcephaly, exposure to a maternal HF diet or AP caused no significant changes. We conclude that in the IUGR during fetal brain development, reduced GLUT3 is associated with an imbalanced 5-HT-SERT axis. We speculate that these early changes may set the stage for altering the 5HT-SERT neural axis with postnatal emergence of associated neurodevelopmental disorders.

Murine maternal dietary restriction affects neural Humanin expression and cellular profile.

To understand the cellular basis for the neurodevelopmental effects of intrauterine growth restriction (IUGR), we examined the global and regional expression of various cell types within murine (Mus musculus) fetal brain. Our model employed maternal calorie restriction to 50% daily food intake from gestation day 10-19, producing IUGR offspring. Offspring had smaller head sizes with larger head:body ratios indicating a head sparing IUGR effect. IUGR fetuses at embryonic day 19 (E19) had reduced nestin (progenitors), ß-III tubulin (immature neurons), Glial fibrillary acidic protein (astrocytes), and O4 (oligodendrocytes) cell lineages via immunofluorescence quantification and a 30% reduction in cortical thickness. No difference was found in Bcl-2 or Bax (apoptosis) between controls and IUGR, though qualitatively, immunoreactivity of doublecortin (migration) and Ki67 (proliferation) was decreased. In the interest of examining a potential therapeutic peptide, we next investigated a novel pro-survival peptide, mouse Humanin (mHN). Ontogeny examination revealed highest mHN expression at E19, diminishing by postnatal day 15 (P15), and nearly absent in adult (3 months). Subanalysis by sex at E19 yielded higher mHN expression among males during fetal life, without significant difference between sexes postnatally. Furthermore, female IUGR mice at E19 had a greater increase in cortical mHN versus the male fetus over their respective controls. We conclude that maternal dietary restriction-associated IUGR interferes with neural progenitors differentiating into the various cellular components populating the cerebral cortex, and reduces cerebral cortical size. mHN expression is developmental stage and sex specific, with IUGR, particularly in the females, adaptively increasing its expression toward mediating a pro-survival approach against nutritional adversity.

MicroRNA 122 Reflects Liver Injury in Children with Intestinal Failure-Associated Liver Disease Treated with Intravenous Fish Oil.

BACKGROUND: There is evidence that microRNA (MIR) 122 is a biomarker for various liver diseases in adults and children. To date, MIR122 has not been explored in children with intestinal failure-associated liver disease (IFALD, or hyperbilirubinemia associated with prolonged parenteral nutrition). OBJECTIVES: This study's purpose was to investigate changes in plasma miR-122, correlate miR-122 with serum liver function tests and enzymes, and investigate changes in whole blood transcripts including miR-122 targets in a group of children with IFALD who received pure intravenous fish oil (FO) as a treatment for cholestasis. METHODS: This was a prospective, observational study that enrolled children with IFALD who received intravenous FO (1 g/kg/d) and whose cholestasis resolved with FO. Plasma miR-122 was measured using reverse transcription-quantitative real-time PCR, and whole blood miR-122 targets were quantified using RNA sequencing. RESULTS: Fourteen subjects with median age 6 mo (IQR: 3-65 mo) were enrolled. RNA sequence data were available for 4 subjects. When compared with the start of FO, median miR-122 concentrations at 6 mo of FO therapy decreased [1.0 (IQR: 1.0-1.0) compared with 0.04 (IQR: 0.01-0.6), P = 0.009]. At the start of FO, miR-122 correlated with conjugated bilirubin (r = 0.56; P = 0.038). At ∼3 mo of FO, miR-122 correlated with conjugated bilirubin (r = 0.56; P = 0.045). Reactive oxygen species, heme metabolism, coagulation, adipogenesis, IL-6-Janus kinase-signal transducer and activator of transcription (JAK-STAT) 3, IL-2-STAT5, transforming growth factor-ß, TNF-α, inflammatory response, mammalian target of rapamycin gene families (normalized enrichment scores < -1.4), and miR-122 target genes were significantly downregulated with FO. CONCLUSIONS: In this small cohort of young children with IFALD, miR-122 decreased with FO therapy and correlated with conjugated bilirubin. Key pathways involving oxidation, inflammation, cellular differentiation, and nutrient regulation were downregulated. Data from this study provide information about IFALD and FO. This trial was registered at www.clinicaltrials.gov as NCT00969332.

Human Placenta Blood Flow During Early Gestation With Pseudocontinuous Arterial Spin Labeling MRI.

BACKGROUND: Noninvasive measurement of placental blood flow is the major technical challenge for predicting ischemic placenta (IPD). Pseudocontinuous arterial spin labeling (pCASL) MRI was recently shown to be promising, but the potential value in predicting the subsequence development of IPD is not known. PURPOSE: To derive global and regional placental blood flow parameters from longitudinal measurements of pCASL MRI and to assess the associations between perfusion-related parameters and IPD. STUDY TYPE: Prospective. POPULATION: Eighty-four women completed two pCASL MRI scans (first; 14-18 weeks and second; 19-24 weeks) from prospectively recruited 118 subjects. A total of 69 subjects were included for the analysis, of which 15 subjects developed IPD. FIELD STRENGTH/SEQUENCE: 3T/T2 -weighted half-Fourier single-shot turbo spin-echo (HASTE) and pCASL. ASSESSMENT: Four perfusion-related parameters in the placenta were derived: placenta volume, placental blood flow (PBF), high PBF (hPBF), and relative hPBF. The longitudinal changes of the parameters and their association with IPD were tested after being normalizing to the 16th and 20th weeks of gestation. STATISTICAL TESTS: Comparisons between two gestational ages within subjects were performed using the paired Wilcoxon tests, and comparisons between normal and IPD groups were performed using the unpaired Wilcoxon tests. RESULTS: The difference between the first and second MRI scans was statistically significant for volume (156.6 cm3 vs. 269.7 cm3 , P < 0.001) and PBF (104.9 ml/100g/min vs. 111.3 ml/100g/min, P = 0.02) for normal subjects, indicating an increase in pregnancy with advancing gestation. Of the parameters tested, the difference between the normal and IPD subjects was most pronounced in hPBF (278.1 ml/100g/min vs. 180.7 ml/100g/min, P < 0.001) and relative hPBF (259.1% vs. 183.2%, P < 0.001) at 16 weeks. DATA CONCLUSION: The high perfusion-related image parameters for IPD were significantly decreased from normal pregnancy at 14-18 weeks of gestation. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1 J. Magn. Reson. Imaging 2020;51:1247-1257.

Neural Deletion of Glucose Transporter Isoform 3 Creates Distinct Postnatal and Adult Neurobehavioral Phenotypes.

We created a neural-specific conditional murine glut3 (Slc2A3) deletion (glut3flox/flox/nestin-Cre+) to examine the effect of a lack of Glut3 on neurodevelopment. Compared with age-matched glut3flox/flox = WT and heterozygotes (glut3flox/+/nestin-Cre+), we found that a >90% reduction in male and female brain Glut3 occurred by postnatal day 15 (PN15) in glut3flox/flox/nestin-Cre+ This genetic manipulation caused a diminution in brain weight and cortical thickness at PN15, a reduced number of dendritic spines, and fewer ultrasonic vocalizations. Patch-clamp recordings of cortical pyramidal neurons revealed increased frequency of bicuculline-induced paroxysmal discharges as well as reduced latency, attesting to a functional synaptic and cortical hyperexcitability. Concomitant stunting with lower glucose concentrations despite increased milk intake shortened the lifespan, failing rescue by a ketogenic diet. This led to creating glut3flox/flox/CaMK2α-Cre+ mice lacking Glut3 in the adult male limbic system. These mice had normal lifespan, displayed reduced IPSCs in cortical pyramidal neurons, less anxiety/fear, and lowered spatial memory and motor abilities but heightened exploratory and social responses. These distinct postnatal and adult phenotypes, based upon whether glut3 gene is globally or restrictively absent, have implications for humans who carry copy number variations and present with neurodevelopmental disorders.SIGNIFICANCE STATEMENT Lack of the key brain-specific glucose transporter 3 gene found in neurons during early postnatal life results in significant stunting, a reduction in dendritic spines found on neuronal processes and brain size, heightened neuronal excitability, along with a shortened lifespan. When occurring in the adult and limited to the limbic system alone, lack of this gene in neurons reduces the fear of spatial exploration and socialization but does not affect the lifespan. These features are distinct heralding differences between postnatal and adult phenotypes based upon whether the same gene is globally or restrictively lacking. These findings have implications for humans who carry copy number variations pertinent to this gene and have been described to present with neurodevelopmental disorders.

Circulating blood cellular glucose transporters - Surrogate biomarkers for neonatal hypoxic-ischemic encephalopathy assessed by novel scoring systems.

OBJECTIVE: We examined Red Blood Cell (RBC) Glucose Transporter isoform 1 (GLUT1) and White Blood Cell (WBC) Glucose Transporter isoform 3 (GLUT3) protein concentrations to assess their potential as surrogate biomarkers for the presence of hypoxic-ischemic encephalopathy (HIE) and response to therapeutic hypothermia (TH), with respect to the neurodevelopmental prognosis. STUDY DESIGN: A prospective feasibility study of 10 infants with HIE and 8 age-matched control subjects was undertaken. Following parental consent, blood samples were obtained at baseline before institution of TH (<6 h of life), during TH, at rewarming and post-TH in the HIE group with a baseline sample from the control group. GLUT1 and GLUT3 were measured by Enzyme-linked immunosorbent assay (ELISA) with brain biomarkers, Neuron-Specific Enolase (NSE) and Glial Fibrillary Acidic Protein (GFAP). Novel "HIE-high risk" and "Neurological" scores were developed to help identify HIE and to assess severity and prognosis, respectively. RESULTS: RBC GLUT1 concentrations were increased at the baseline pre-TH time point in HIE versus control subjects (p = .006), normalizing after TH (p = .05). An association between GLUT1 and NSE concentrations (which was reflective of the HIE-high risk and the Neuro-scores) in controls and HIE pre-TH was seen (R2 = 0.36, p = .008), with GLUT1 demonstrating 90% sensitivity and 88% specificity for presence of HIE identified by Sarnat Staging. WBC GLUT3 concentrations were low and no different in HIE versus control, and GFAP concentrations trended higher during re-warming (p = .11) and post-TH (p = .16). We demonstrated a significant difference between HIE and controls for both the "HIE-high risk" and the "Neurological" Scores. The latter score revealing the severity of clinical neurological illness correlated with the corresponding RBC GLUT1 (R2 value = 0.39; p = .006). CONCLUSION: Circulating RBC GLUT1 concentrations with NSE demonstrate a significant potential in reflecting the severity of HIE pre-TH and gauging effectiveness of TH. In contrast, the low neonatal WBC GLUT3 concentrations make discerning differences between degrees of HIE as well as assessing effectiveness of TH difficult. The HIE-high risk and Neurological scores may extend the "Sarnat staging" towards assessing severity and neuro-developmental prognosis of HIE.

3D R2* mapping of the placenta during early gestation using free-breathing multiecho stack-of-radial MRI at 3T.

BACKGROUND: Multiecho gradient-echo Cartesian MRI characterizes placental oxygenation by quantifying R2* . Previous research was performed at 1.5T using breath-held 2D imaging during later gestational age (GA). PURPOSE: To evaluate the accuracy and repeatability of a free-breathing (FB) 3D multiecho gradient-echo stack-of-radial technique (radial) for placental R2* mapping at 3T and report placental R2* during early GA. STUDY TYPE: Prospective. POPULATION: Thirty subjects with normal pregnancies and three subjects with ischemic placental disease (IPD) were scanned twice: between 14-18 and 19-23 weeks GA. FIELD STRENGTH: 3T. SEQUENCE: FB radial. ASSESSMENT: Linear correlation (concordance coefficient, ρc ) and Bland-Altman analyses (mean difference, MD) were performed to evaluate radial R2* mapping accuracy compared to Cartesian in a phantom. Radial R2* mapping repeatability was characterized using the coefficient of repeatability (CR) between back-to-back scans. The mean and spatial coefficient of variation (CV) of R2* was determined for all subjects, and separately for anterior and posterior placentas, at each GA range. STATISTICAL TESTS: ρc was tested for significance. Differences in mean R2* and CV were tested using Wilcoxon Signed-Rank and Rank-Sum tests. P < 0.05 was considered significant. Z-scores for the IPD subjects were determined. RESULTS: FB radial demonstrated accurate (ρc ≥0.996; P < 0.001; |MD|<0.2s-1 ) and repeatable (CR<4s-1 ) R2* mapping in a phantom, and repeatable (CR≤4.6s-1 ) R2* mapping in normal subjects. At 3T, placental R2* mean ± standard deviation was 12.9s-1 ± 2.7s-1 for 14-18 and 13.2s-1 ± 1.9s-1 for 19-23 weeks GA. The CV was significantly greater (P = 0.043) at 14-18 (0.63 ± 0.12) than 19-23 (0.58 ± 0.13) weeks GA. At 19-23 weeks, the CV was significantly lower (P < 0.001) for anterior (0.49 ± 0.08) than posterior (0.67 ± 0.11) placentas. One IPD subject had a lower mean R2* than normal subjects at both GA ranges (Z<-2). DATA CONCLUSION: FB radial provides accurate and repeatable 3D R2* mapping for the entire placenta at 3T during early GA. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:291-303.

Measuring human placental blood flow with multidelay 3D GRASE pseudocontinuous arterial spin labeling at 3T.

BACKGROUND: Placenta influences the health of both a woman and her fetus during pregnancy. Maternal blood supply to placenta can be measured noninvasively using arterial spin labeling (ASL). PURPOSE: To present a multidelay pseudocontinuous arterial spin labeling (pCASL) combined with a fast 3D inner-volume gradient- and spin-echo (GRASE) imaging technique to simultaneously measure placental blood flow (PBF) and arterial transit time (ATT), and to study PBF and ATT evolution with gestational age during the second trimester. The PBF values were compared with uterine arterial Doppler ultrasound to assess its potential clinical utility. STUDY TYPE: This was a prospective study. SUBJECTS: Thirty-four pregnant women. FIELD STRENGTH/SEQUENCE: Multidelay 3D inner-volume GRASE pCASL sequence on 3T MR scanners. ASSESSMENT: Subjects underwent two longitudinal MRI scans within the second trimester, conducted between 14-16 and 19-22 weeks of gestational age, respectively. Placental perfusion was measured using the free-breathing pCASL sequence at three postlabeling delays (PLDs), followed by offline motion correction and model fitting for estimation of PBF and ATT. STATISTICAL TESTS: A paired t-test was conducted to evaluate the significance of PBF/ATT variations with placental development. A two-sample t-test was conducted to evaluate the significance of PBF difference in subjects with and without early diastolic notch. RESULTS: The mean PBF and ATT for the second trimester were 111.4 ± 26.7 ml/100g/min and 1387.5 ± 88.0 msec, respectively. The average PBF increased by 10.4% (P < 0.05), while no significant change in ATT (P = 0.72) was found along gestational ages during the second trimester. PBF decreased 20.3% (P < 0.01) in subjects with early diastolic notches in ultrasound flow waveform patterns. DATA CONCLUSION: Multidelay pCASL with inner-volume 3D GRASE is promising for noninvasive assessment of PBF during pregnancy. Its clinical use for the detection of aberrations in placental function and prediction of fetal developmental disorders awaits evaluation. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1667-1676.

Intrauterine Growth Restriction: Hungry for an Answer.

Intrauterine growth restriction (IUGR) has been defined in several ways, but in general describes a condition in which the fetus exhibits poor growth in utero. This complication of pregnancy poses a significant public health burden as well as increased morbidity and mortality for the offspring. In human IUGR, alteration in fetal glucose and insulin homeostasis occurs in an effort to conserve energy and survive at the expense of fetal growth in an environment of inadequate nutrient provision. Several animal models of IUGR have been utilized to study the effects of IUGR on fetal glucose handling, as well as the postnatal reprogramming of energy metabolite handling, which may be unmasked in adulthood as a maladaptive propensity for cardiometabolic disease. This developmental programming may be mediated in part by epigenetic modification of essential regulators of glucose homeostasis. Several pharmacological therapies and nonpharmacological lifestyle modifications have shown early promise in mitigating the risk for or severity of adult metabolic phenotypes but still require further study of unanticipated and/or untoward side effects.