Search

The hippocampus is a vital brain structure deep in the medial temporal lobe that mediates a range of functions encompassing emotional regulation, learning, memory, and cognition. Hippocampal development is exquisitely sensitive to perturbations and adverse conditions during pregnancy and at birth, including preterm birth, fetal growth restriction (FGR), acute hypoxic-ischaemic encephalopathy (HIE), and intrauterine inflammation. Disruptions to hippocampal development due to these conditions can have long-lasting functional impacts. Here, we discuss a range of preclinical models of prematurity and FGR and conditions that induce hypoxia and inflammation, which have been critical in elucidating the underlying mechanisms and cellular and subcellular structures implicated in hippocampal dysfunction. Finally, we discuss potential therapeutic targets to reduce the burden of these perinatal insults on the developing hippocampus. IMPACT: The review explores the preclinical literature examining the association between pregnancy and birth complications, and hippocampal form and function. The developmental processes and cellular mechanisms that are disrupted within the hippocampus following perinatal compromise are described, and potential therapeutic targets are discussed., (© 2024. The Author(s).)

The hippocampus is a neuron-rich specialised brain structure that plays a central role in the regulation of emotions, learning and memory, cognition, spatial navigation, and motivational processes. In human fetal development, hippocampal neurogenesis is principally complete by mid-gestation, with subsequent maturation comprising dendritogenesis and synaptogenesis in the third trimester of pregnancy and infancy. Dendritogenesis and synaptogenesis underpin connectivity. Hippocampal development is exquisitely sensitive to perturbations during pregnancy and at birth. Clinical investigations demonstrate that preterm birth, fetal growth restriction (FGR), and acute hypoxic-ischaemic encephalopathy (HIE) are common perinatal complications that alter hippocampal development. In turn, deficits in hippocampal development and structure mediate a range of neurodevelopmental disorders, including cognitive and learning problems, autism, and Attention-Deficit/Hyperactivity Disorder (ADHD). In this review, we summarise the developmental profile of the hippocampus during fetal and neonatal life and examine the hippocampal deficits observed following common human pregnancy complications. IMPACT: The review provides a comprehensive summary of the developmental profile of the hippocampus in normal fetal and neonatal life. We address a significant knowledge gap in paediatric research by providing a comprehensive summary of the relationship between pregnancy complications and subsequent hippocampal damage, shedding new light on this critical aspect of early neurodevelopment., (© 2024. The Author(s).)

Background: Intrauterine growth restriction (IUGR) leads to cardiac dysfunction and adverse remodeling of the fetal heart, as well as a higher risk of postnatal cardiovascular diseases. The rat model of IUGR, via uterine artery ligation, is a popular model but its cardiac sequelae is not well investigated. Here, we performed an echocardiographic evaluation of its cardiac function to determine how well it can represent the disease in humans., Methods: Unilateral uterine artery ligation was performed at embryonic day 17 (E17) and echocardiography was performed at E19 and E20., Results: Growth-restricted fetuses were significantly smaller and lighter, and had an higher placenta-to-fetus weight ratio. Growth-restricted fetal hearts had reduced wall thickness-to-diameter ratio, indicating left ventricular (LV) dilatation, and they had elevated trans-mitral and trans-tricuspid E/A ratios and reduced left and right ventricular fractional shortening (FS), suggesting systolic and diastolic dysfunction. These were similar to human IUGR fetuses. However, growth-restricted rat fetuses did not demonstrate head-sparing effect, displayed a lower LV myocardial performance index, and ventricular outflow velocities were not significantly reduced, which were dissimilar to human IUGR fetuses., Conclusions: Despite the differences, our results suggest that this IUGR model has significant cardiac dysfunction, and could be a suitable model for studying IUGR cardiovascular physiology., Impact: Animal models of IUGR are useful, but their fetal cardiac function is not well studied, and it is unclear if they can represent human IUGR fetuses. We performed an echocardiographic assessment of the heart function of a fetal rat model of IUGR, created via maternal uterine artery ligation. Similar to humans, the model displayed LV dilatation, elevated E/A ratios, and reduced FS. Different from humans, the model displayed reduced MPI, and no significant outflow velocity reduction. Despite differences with humans, this rat model still displayed cardiac dysfunction and is suitable for studying IUGR cardiovascular physiology., (© 2021. The Author(s).)

Fetal growth restriction is a strong risk factor for perinatal morbidity and mortality. Reliable standards are indispensable, both to assess fetal growth and to evaluate birthweight and early postnatal growth in infants born preterm. The aim of this study was to create updated Swedish reference ranges for estimated fetal weight (EFW) from gestational week 12-42. This prospective longitudinal multicentre study included 583 women without known conditions causing aberrant fetal growth. Each woman was assigned a randomly selected protocol of five ultrasound scans from gestational week 12 + 3 to 41 + 6. Hadlock's 3rd formula was used to estimate fetal weight. A two-level hierarchical regression model was employed to calculate the expected median and variance, expressed in standard deviations and percentiles, for EFW. EFW was higher for males than females. The reference ranges were compared with the presently used Swedish, and international reference ranges. Our reference ranges had higher EFW than the presently used Swedish reference ranges from gestational week 33, and higher median, 2.5th and 97.5th percentiles from gestational week 24 compared with INTERGROWTH-21st. The new reference ranges can be used both for assessment of intrauterine fetal weight and growth, and early postnatal growth in children born preterm.

In Poland the issue of microsomic body structure (micro-SBS) and macrosomic body structure (macro-SBS) has so far been overlooked. Up until now only a small amount of data have been published, most often as an overview of the problem. The current study was designed to investigate the co-occurrence of microsomic/macrosomic body structure (micro/macro-SBS) and congenital nervous system disorders or neurological syndromes with symptoms visible from infancy, based on essential data acquired during admission procedures at a neurological rehabilitation ward for children and adolescents. The study applied a retrospective analysis of data collected during hospitalization of 327 children and adolescents, aged 4-18 years who had been affected since infancy by congenital disorders of the nervous system and/or neurological syndromes associated with a minimum of one neurodysfunction. To identify subjects with microsomic or macrosomic body structure in the group of children and adolescents, the adopted criteria took into account z-score values for body height (z-score Ht), body weight (z-score Wt), head circumference (z-score HC), BMI (z-score BMI) and head circumference index (z-score HCI). The rates of micro/macro-SBS in the study group amounted to 7.3% and 0.6%, respectively. The findings show a more frequent co-occurrence of, as well as statistically significant correlations between, micro/macro-SBS and type of spasticity (cerebral palsy) (p = 0.024) as well as hydrocephalus not treated surgically (p < 0.001). Macro-SBS was found to more frequently co-occur with hemiplegia and hydrocephalus not treated surgically.

Animal studies have demonstrated the therapeutic potential of polyphenol-rich pomegranate juice. We recently reported altered white matter microstructure and functional connectivity in the infant brain following in utero pomegranate juice exposure in pregnancies with intrauterine growth restriction (IUGR). This double-blind exploratory randomized controlled trial further investigates the impact of maternal pomegranate juice intake on brain structure and injury in a second cohort of IUGR pregnancies diagnosed at 24-34 weeks' gestation. Ninety-nine mothers and their eligible fetuses (n = 103) were recruited from Brigham and Women's Hospital and randomly assigned to 8 oz pomegranate (n = 56) or placebo (n = 47) juice to be consumed daily from enrollment to delivery. A subset of participants underwent fetal echocardiogram after 2 weeks on juice with no evidence of ductal constriction. 57 infants (n = 26 pomegranate, n = 31 placebo) underwent term-equivalent MRI for assessment of brain injury, volumes and white matter diffusion. No significant group differences were found in brain volumes or white matter microstructure; however, infants whose mothers consumed pomegranate juice demonstrated lower risk for brain injury, including any white or cortical grey matter injury compared to placebo. These preliminary findings suggest pomegranate juice may be a safe in utero neuroprotectant in pregnancies with known IUGR warranting continued investigation.Clinical trial registration: NCT04394910, https://clinicaltrials.gov/ct2/show/NCT04394910 , Registered May 20, 2020, initial participant enrollment January 16, 2016.

Individuals born extremely preterm are at significant risk for impaired neurodevelopment. After discharge from the neonatal intensive care, associations between the child's well-being and factors in the home and social environment become increasingly apparent. Mothers' prenatal health and socioeconomic status are associated with neurodevelopmental outcomes, and emotional and behavioral problems. Research on early life risk factors and on mechanisms underlying inter-individual differences in neurodevelopment later in life can inform the design of personalized approaches to prevention. Here, we review early life predictors of inter-individual differences in later life neurodevelopment among those born extremely preterm. Among biological mechanisms that mediate relationships between early life predictors and later neurodevelopmental outcomes, we highlight evidence for disrupted placental processes and regulated at least in part via epigenetic mechanisms, as well as perinatal inflammation. In relation to these mechanisms, we focus on four prenatal antecedents of impaired neurodevelopment, namely, (1) fetal growth restriction, (2) maternal obesity, (3) placental microorganisms, and (4) socioeconomic adversity. In the future, this knowledge may inform efforts to detect and prevent adverse outcomes in infants born extremely preterm. IMPACT: This review highlights early life risk factors and mechanisms underlying inter-individual differences in neurodevelopment later in life. The review emphasizes research on early life risk factors (fetal growth restriction, maternal obesity, placental microorganisms, and socioeconomic adversity) and on mechanisms (disrupted placental processes and perinatal inflammation) underlying inter-individual differences in neurodevelopment later in life. The findings highlighted here may inform efforts to detect and prevent adverse outcomes in infants born extremely preterm.

Intrauterine growth restriction (IUGR) and low birth weigth (LBW) are risk factors for neonatal chronic lung disease. However, maternal and fetal genetic factors and the molecular mechanisms remain unclear. We investigated the relationship between LBW and lung function with Mendelian randomisation analyses and studied angiogenesis in a low protein diet rat model of IUGR. Our data indicate a possible association between LBW and reduced FEV1 (p = 5.69E-18, MR-PRESSO) and FVC (6.02E-22, MR-PRESSO). Complimentary, we demonstrated two-phased perinatal programming after IUGR. The intrauterine phase (embryonic day 21) is earmarked by a reduction of endothelial cell markers (e.g. CD31) as well as mRNA expression of angiogenic factors (e.g., Vegfa, Flt1, Klf4). Protein analysis identified an activation of anti-angiogenic mTOR effectors. In the postnatal phase, lung capillaries (< 20 µm) were significantly reduced, expression of CD31 and VE-Cadherin were unaffected, whereas SMAD1/5/8 signaling and Klf4 protein were increased (p < 0.01). Moreover, elevated proteolytic activity of MMP2 and MMP9 was linked to a 50% reduction of lung elastic fibres. In conclusion, we show a possible link of LBW in humans and reduced lung function in adulthood. Experimental IUGR identifies an intrauterine phase with inhibition of angiogenic signaling, and a postnatal phase with proteolytic activity and reduced elastic fibres.

Abnormal maternal serum biomarkers (AMSB), identified through the aneuploidy screening programme, are frequent incidental findings in pregnancy. They are associated with fetal growth restriction (FGR), but previous studies have not examined whether this association is with early-onset (< 34 weeks) or late-onset (> 34 weeks) FGR; as a result there is no consensus on management. The aims of this study were to determine the prevalence and phenotype of FGR in women with AMSB and test the predictive value of placental sonographic screening to predict early-onset FGR. 1196 pregnant women with AMSB underwent a 21-24 week "placental screen" comprising fetal and placental size, and uterine artery Doppler. Multivariable regression was used to calculate a predictive model for early-onset FGR (birthweight centile < 3rd/< 10th with absent umbilical end-diastolic flow, < 34 weeks). FGR prevalence was high (10.3%), however early-onset FGR was uncommon (2.3%). Placental screening effectively identified early-onset (area under the curve (AUC) 0.93, 95% confidence interval (CI) 0.87-1.00), but not late-onset FGR (AUC 0.70, 95% CI 0.64-0.75). Internal validation demonstrated robust performance for detection/exclusion of early-onset FGR. In this cohort, utilisation of our proposed algorithm with targeted fetal growth and Doppler surveillance, compared with universal comprehensive surveillance would have avoided 1044 scans, potentiating significant cost-saving for maternity services.

Alpha-1-microglobulin (A1M) is an antioxidant previously shown to be elevated in maternal blood during pregnancies complicated by preeclampsia and suggested to be important in the endogenous defense against oxidative stress. A knockout mouse model of A1M (A1Mko) was used in the present study to assess the importance of A1M during pregnancy in relation to the kidney, heart and placenta function. Systolic blood pressure (SBP) and heart rate (HR) were determined before and throughout gestation. The morphology of the organs was assessed by both light and electron microscopy. Gene expression profiles relating to vascular tone and oxidative stress were analyzed using RT-qPCR with validation of selected gene expression relating to vascular tone and oxidative stress response. Pregnant age-matched wild type mice were used as controls. In the A1Mko mice there was a significantly higher SBP before pregnancy that during pregnancy was significantly reduced compared to the control. In addition, the HR was higher both before and during pregnancy compared to the controls. Renal morphological abnormalities were more frequent in the A1Mko mice, and the gene expression profiles in the kidney and the heart showed downregulation of transcripts associated with vasodilation. Simultaneously, an upregulation of vasoconstrictors, blood pressure regulators, and genes for osmotic stress response, ion transport and reactive oxygen species (ROS) metabolism occurred. Fetal weight was lower in the A1Mko mice at E17.5. The vessels in the labyrinth zone of the placentas and the endoplasmic reticulum in the spongiotrophoblasts were collapsed. The gene profiles in the placenta showed downregulation of antioxidants, ROS metabolism and oxidative stress response genes. In conclusion, intact A1M expression is necessary for the maintenance of normal kidney, heart as well as placental structure and function for a normal pregnancy adaptation.

Our main objective was to study respiratory evolution and pulmonary and cardiac function in adolescents born preterm in the post-surfactant era. Observational cross-sectional study, comparing very preterm (< 32 weeks) and moderately-late preterm adolescents (≥ 32 weeks) (74 each group). We recorded respiratory symptoms, spirometry and functional echocardiogram. Very preterm adolescents required more respiratory admissions (45.9% vs. 28.4%) (p = 0.03, OR 2.1, CI95% 1.1-4.2) and had more current asthma (21.6% vs. 9.5%, p = 0.04, OR 2.3, CI95% 1.1-5.2). Preterm subjects with intrauterine growth restriction (IUGR) presented lower FEV 1 (88.7 ± 13.9 vs. 95.9 ± 13.3, p = 0.027) and lower FVC (88.2 ± 13.6 vs. 95.5 ± 13.3, p = 0.025). When assessing right ventricle, very preterm showed a greater E/E' ratio (p = 0.02) and longer myocardial performance index (MPI) (p = 0.001). Adolescents with IUGR showed less shortening fraction (p = 0.016), worse E/E' ratio (p = 0.029) and longer MPI (p = 0.06). Regarding left ventricle, very preterm showed less E' wave velocity (p = 0.03), greater E/E' ratio (p = 0.005) and longer MPI (p < 0.001). Gestational age < 32 weeks is independently associated with current asthma in adolescence. Children 13-14 years old born very preterm required more respiratory admissions and had poorer diastolic and global function of both ventricles. IUGR is a risk factor for poorer lung function in preterm adolescents, regardless gestational age.

Low birthweight and decreased postnatal weight gain are known predictors of worse retinopathy of prematurity (ROP) but the role of prenatal growth patterns in ROP remains inconclusive. To distinguish small for gestational age (SGA) from intrauterine growth restriction (IUGR) as independent predictors of ROP, we performed a retrospective cohort study of patients who received ROP screening examinations at a level IV neonatal intensive care unit over a 7-year period. Data on IUGR and SGA status, worst stage of and need for treatment for ROP, and postnatal growth was obtained. 343 infants were included for analysis (mean gestational age = 28.6 weeks and birth weight = 1138.2 g). IUGR infants were more likely to have a worse stage of ROP and treatment-requiring ROP (both p < 0.0001) compared to non-IUGR infants. IUGR infants were more likely to be older at worst stage of ROP (p < 0.0001) and to develop postnatal growth failure (p = 0.01) than non-IUGR infants. Independent of postnatal growth failure status, IUGR infants had a 4-5 × increased risk of needing ROP treatment (p < 0.001) compared to non-IUGR infants. SGA versus appropriate for gestational age infants did not demonstrate differences in retinopathy outcomes, age at worst ROP stage, or postnatal growth failure. These findings emphasize the importance of prenatal growth on ROP development.

Background: Delayed brain function development in small-gestational-age (SGA) infants has been reported. We aimed to quantify rates of immature neonatal EEG patterns and their association with neurodevelopment in SGA full-term neonates., Methods: Using a cohort design, 50 SGA (birthweight <10th percentile) and 44 appropriate-gestational-age (AGA) term neonates underwent continuous video-EEG recordings lasting >3 h. Seventy-three of them were assessed at 2-years-old using Bayley-III-Scales. For EEG analysis, several segments of discontinuous/alternating EEG tracings were selected., Main Outcomes Measured: (1) Visual analysis (patterns of EEG maturity); (2) Power spectrum in δ, θ, α and β frequency bands; and (3) scores in motor, cognitive and language development., Results: (1) SGA infants, compared to AGA, showed: (a) higher percentages of discontinuous EEG, both asynchrony and interhemispheric asymmetry, and bursts with delta-brushes, longer interburst-interval duration and more transients/hour; (b) lower relative power spectrum in δ and higher in α; and (c) lower scores on motor, language and cognitive neurodevelopment. (2) Asymmetry >5%, interburst-interval >5 s, discontinuity >11%, and bursts with delta-brushes >11% were associated with lower scores on Bayley-III., Conclusions: In this prospective study, SGA full-term neonates showed high rates of immature EEG patterns. Low-birthweight and immaturity EEG were both correlated with low development scores.

Intrauterine growth restriction (IUGR) is a clinical definition applied to neonates born with clinical features of malnutrition and in-utero growth retardation irrespective of their birth weight percentile. This study was aimed to determine the frequency of pulmonary hypertension (PH) in neonates with IUGR. In this descriptive cross-sectional study, we followed 96 neonates with IUGR (≤28 days) and 38 neonates without IUGR born in the department of the neonatal intensive care unit children hospital complex Multan, Pakistan. We analyzed certain factors such as gender, gestational age (GA) (weeks), birth weight (BW in kg), weight percentile (WP) for GA, meconium aspiration syndrome (MAS), birth asphyxia (BA) and respiratory distress syndrome (RDS) for pulmonary hypertension (PH) in IUGR and non-IUGR group. GA was measured by the Ballard scoring system. Echocardiography was performed for all patients by the pediatric cardiologist to measure pulmonary arterial (PA) pressure using Bernoulli's equation. Out of total 96 IUGR neonates, 33.3% (n = 32) suffered from PH, of which 65.3% (n = 18) were male and 43.7% (n = 14) were female. The percentages of IUGR neonates with BA, MAS and RDS were 34.4%, 18.8% and 22.9% respectively. The data were analyzed using the SPSS-16 software to test the statistical significance of the results. A p-value less than 0.05 was considered significant. When the chi-square test was applied, it depicted that MAS was significantly associated with PH in IUGR neonates (p = 0.0001) compared to non-IUGR neonates. Our findings suggested an increased chance of PH in IUGR neonates and MAS may be a strong factor.

Background: Intrauterine growth restriction (IUGR) is a pregnancy condition where fetal growth is reduced, and offspring from IUGR pregnancies are at increased risk for type II diabetes as adults. The liver is susceptible to fetal undernutrition experienced by IUGR infants and animal models of growth restriction. This study aimed to examine hepatic expression changes in a maternal nutrient restriction (MNR) mouse model of IUGR to understand fetal adaptations that influence adult metabolism., Methods: Liver samples of male offspring from MNR (70% of ad libitum starting at E6.5) or control pregnancies were obtained at E18.5 and differential expression was assessed by RNAseq and western blots., Results: Forty-nine differentially expressed (FDR < 0.1) transcripts were enriched in hypoxia-inducible pathways including Fkbp5 (1.6-fold change), Ccng2 (1.5-fold change), Pfkfb3 (1.5-fold change), Kdm3a (1.2-fold change), Btg2 (1.6-fold change), Vhl (1.3-fold change), and Hif-3a (1.3-fold change) (FDR < 0.1). Fkbp5, Pfkfb3, Kdm3a, and Hif-3a were confirmed by qPCR, but only HIF-2a (2.2-fold change, p = 0.002) and HIF-3a (1.3 p = 0.03) protein were significantly increased., Conclusion: Although a moderate impact, these data support evidence of fetal adaptation to reduced nutrients by increased hypoxia signaling in the liver.

1 in 5 women report cannabis use during pregnancy, with nausea cited as their primary motivation. Studies show that (-)-△9-tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in cannabis, causes fetal growth restriction, though the mechanisms are not well understood. Given the critical role of the placenta to transfer oxygen and nutrients from mother, to the fetus, any compromise in the development of fetal-placental circulation significantly affects maternal-fetal exchange and thereby, fetal growth. The goal of this study was to examine, in rats, the impact of maternal Δ9-THC exposure on fetal development, neonatal outcomes, and placental development. Dams received a daily intraperitoneal injection (i.p.) of vehicle control or Δ9-THC (3 mg/kg) from embryonic (E)6.5 through 22. Dams were allowed to deliver normally to measure pregnancy and neonatal outcomes, with a subset sacrificed at E19.5 for placenta assessment via immunohistochemistry and qPCR. Gestational Δ9-THC exposure resulted in pups born with symmetrical fetal growth restriction, with catch up growth by post-natal day (PND)21. During pregnancy there were no changes to maternal food intake, maternal weight gain, litter size, or gestational length. E19.5 placentas from Δ9-THC-exposed pregnancies exhibited a phenotype characterized by increased labyrinth area, reduced Epcam expression (marker of labyrinth trophoblast progenitors), altered maternal blood space, decreased fetal capillary area and an increased recruitment of pericytes with greater collagen deposition, when compared to vehicle controls. Further, at E19.5 labyrinth trophoblast had reduced glucose transporter 1 (GLUT1) and glucocorticoid receptor (GR) expression in response to Δ9-THC exposure. In conclusion, maternal exposure to Δ9-THC effectively compromised fetal growth, which may be a result of the adversely affected labyrinth zone development. These findings implicate GLUT1 as a Δ9-THC target and provide a potential mechanism for the fetal growth restriction observed in women who use cannabis during pregnancy.

Background: Although prenatal and postnatal programming of metabolic diseases in adulthood is well established, the mechanisms underpinning metabolic programming are not. Dlk1, a key regulator of fetal development, inhibits adipocyte differentiation and restricts fetal growth., Methods: Assess DLk1 expression in a Wistar rat model of catch-up growth following intrauterine restriction. Dams fed ad libitum delivered control pups (C) and dams on a 50% calorie-restricted diet delivered pups with low birth weight (R). Restricted offspring fed a standard rat chow showed catch-up growth (R/C) but those kept on a calorie-restricted diet did not (R/R)., Results: Decreased Dlk1 expression was observed in adipose tissue and skeletal muscle of R/C pups along with excessive visceral fat accumulation, decreased circulating adiponectin, increased triglycerides and HOMA-IR (from p < 0.05 to p < 0.0001). Moreover, in R/C pups the reduced Dlk1 expression in adipose tissue and skeletal muscle correlated with visceral fat (r = -0.820, p < 00001) and HOMA-IR (r = -0.745, p = 0.002)., Conclusions: Decreased Dlk1 expression relates to visceral fat expansion and insulin resistance in a rat model of catch-up growth following prenatal growth restriction. Modulation of Dlk1 expression could be among the targets for the early prevention of fetal programming of adult metabolic disorders.

Fetal growth restriction (FGR) affects 5-10% of pregnancies, leading to clinically significant fetal morbidity and mortality. FGR placentae frequently exhibit poor vascular branching, but the mechanisms driving this are poorly understood. We hypothesize that vascular structural malformation at the organ level alters microvascular shear stress, impairing angiogenesis. A computational model of placental vasculature predicted elevated placental micro-vascular shear stress in FGR placentae (0.2 Pa in severe FGR vs 0.05 Pa in normal placentae). Endothelial cells cultured under predicted FGR shear stresses migrated significantly slower and with greater persistence than in shear stresses predicted in normal placentae. These cell behaviors suggest a dominance of vessel elongation over branching. Taken together, these results suggest (1) poor vascular development increases vessel shear stress, (2) increased shear stress induces cell behaviors that impair capillary branching angiogenesis, and (3) impaired branching angiogenesis continues to drive elevated shear stress, jeopardizing further vascular formation. Inadequate vascular branching early in gestation could kick off this cyclic loop and continue to negatively impact placental angiogenesis throughout gestation.

Background: Efficacy of surfactant therapy in fetal growth restricted (FGR) preterm neonates is unknown., Methods: Twin-bearing ewes underwent surgery at 105 days gestation to induce FGR in one twin by single umbilical artery ligation. At 123-127 days, catheters and flow probes were implanted in pulmonary and carotid arteries to measure flow and pressure. Lambs were delivered, intubated and mechanically ventilated. At 10 min, surfactant (100 mg kg -1 ) was administered. Ventilation, oxygenation, and hemodynamic responses were recorded for 1 h before euthanasia at 120 min. Lung tissue and bronchoalveolar lavage fluid was collected for analysis of surfactant protein mRNA and phosphatidylcholines (PCs)., Results: FGR preterm lambs were 26% lighter than appropriate for gestational age (AGA) lambs and had baseline differences in lung mechanics and pulmonary blood flows. Surfactant therapy reduced ventilator and oxygen requirements and improved lung mechanics in both groups, although a more rapid improvement in compliance and tidal volume was observed in AGA lambs. Surfactant administration was associated with decreased mean pulmonary and carotid blood flow in FGR but not AGA lambs. No major differences in surfactant protein mRNA or PC levels were noted., Conclusions: Surfactant therapy was associated with an altered pulmonary and cerebral hemodynamic response in preterm FGR lambs.

Hypertension is an important modifiable risk factor for cardiovascular diseases. Its high prevalence, combined with the significant morbidity and mortality associated with secondary complications, make it a major public health concern. Despite decades of research, over 95% of all cases of hypertension remain of unknown etiology, necessitating that treatments target the established symptoms and not the cause. One of the important recent advances in hypertension research is an understanding that hypertension often may have a developmental origin. A substantial body of evidence indicates that exposure to an adverse intrauterine environment during critical periods of development may predispose an individual to develop hypertension later in life. A causative mechanism has yet to be identified, but may include epigenetic modifications, and/or alterations in renal, vascular or autonomic cardiovascular functions. This review will present evidence regarding changes in autonomic activity as a possible causative pathophysiological mechanism underlying the development of programmed hypertension. In man, low birth weight is the best-known risk factor for hypertension of developmental origins, although this is a broad surrogate measure for intrauterine adversity. This review will include clinical studies across the lifespan that have investigated autonomic function in individuals with fetal growth restriction and those born preterm. A determination of whether altered autonomic function is seen in these individuals in early life is imperative, as hypertensive disorders that have their origins in utero, and that can be identified early, will open the door to risk stratification, and the development of new strategies that prevent or specifically target these mechanisms.

Fetal growth restriction (FGR) affects about 5-10% pregnancies and is associated with poorer outcomes in the perinatal period. Additionally, long standing epidemiological data support its association with chronic diseases such as hypertension and diabetes. Cardiac and vascular adaptations in response to chronic hypoxemia due to utero-placental insufficiency are hallmarks of fetal adaptations. Investigators have attempted to identify these changes in the placenta at the microscopic and molecular level. The ex vivo dual perfusion model of the placenta enables the study of placental haemodynamics in growth-restricted pregnancies. Persistent arterial abnormalities (thickness and stiffness) noted on vascular ultrasound during fetal life through to the young-adult age group for those affected by FGR, seem to be a plausible link between in utero events and chronic circulatory diseases. Using these, this review reflects current thought on vascular maladaptive changes in the FGR cohorts and the role in investigating current and future therapeutics.

Placental sexual dimorphism is of special interest in prenatal programming. Various postnatal diseases with gender dependent incidence, especially neuropsychiatric disorders like schizophrenia and autism spectrum disorders, have prenatal risk factors established. However, the functional relevance of placental microarchitecture in prenatal programming is poorly investigated, mainly due to a lack of statistically efficient methods. We hypothesized that the recently established 3D microscopic analysis of villous trees would be able to identify microscopic structural correlates of human placental sexual dimorphism. We analyzed the density of cell nuclei of villous trophoblast, i.e. the materno-fetal exchange barrier, in placentas from term pregnancies. The cell nuclei were grouped into proliferative and non-proliferative nuclei by detection of a proliferation marker (PCNA). Normal female placentas showed a higher density of non-proliferating nuclei (PCNA-negative) in villous trophoblast than normal male placentas. The density of PCNA-negative cell nuclei was higher in placentas of pregnancies with intrauterine growth retardation (IUGR) than in control placentas. The data of the present study shows that the density of non-proliferative cell nuclei in the syncytial layer of villous trophoblast is influenced by fetal sex and by IUGR, while proliferation remains unchanged. A novel concept of post-fusion regulation of syncytial structure and function is proposed.

Background: We determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts cell death in the brain with implications for neurodevelopmental adversity., Methods: Guinea pigs were fed ad libitum (Control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Fetuses were necropsied near term and brain tissues processed for necrosis (H&E), apoptosis (TUNEL), and pro- (Bax) and anti- (Bcl-2 and Grp78) apoptotic protein immunoreactivity., Results: FGR-MNR fetal and brain weights were decreased 38% and 12%, respectively, indicating brain sparing but with brains still smaller. While necrosis remained unchanged, apoptosis was increased in the white matter and hippocampus in the FGR brains, and control and FGR-related apoptosis were increased in males for most brain areas. Bax was increased in the CA4 and Bcl-2 was decreased in the dentate gyrus in the FGR brains supporting a role in the increased apoptosis, while Grp78 was increased in the FGR females, possibly contributing to the sex-related differences., Conclusions: MNR-induced FGR results in increased brain apoptosis with regional and sex-related differences that may contribute to the reduction in brain area size reported clinically and increased risk in FGR males for later neurodevelopmental adversity.

Intrauterine growth restriction (IUGR) is a pregnancy complication due to placental dysfunction that prevents the fetus from obtaining enough oxygen and nutrients, leading to serious mortality and morbidity risks. There is no treatment for IUGR despite having a prevalence of 3% in developed countries, giving rise to an urgency to improve our understanding of the disease. Applying biomechanics investigation on IUGR placental tissues can give important new insights. We performed pressure-diameter mechanical testing of placental chorionic arteries and found that in severe IUGR cases (RI > 90 th centile) but not in IUGR cases (RI < 90 th centile), vascular distensibility was significantly increased from normal. Constitutive modeling demonstrated that a simplified Fung-type hyperelastic model was able to describe the mechanical properties well, and histology showed that severe IUGR had the lowest collagen to elastin ratio. To demonstrate that the increased distensibility in the severe IUGR group was related to their elevated umbilical resistance and pulsatility indices, we modelled the placental circulation using a Windkessel model, and demonstrated that vascular compliance (and not just vascular resistance) directly affected blood flow pulsatility, suggesting that it is an important parameter for the disease. Our study showed that biomechanics study on placenta could extend our understanding on placenta physiology.

Background: Maternal nutrient restriction (MNR) is a widespread cause of fetal growth restriction (FGR), an independent predictor of heart disease and cardiovascular mortality. Our objective was to examine the developmental and long-term impact of MNR-induced FGR on cardiac structure in a model that closely mimics human development., Methods: A reduction in total caloric intake spanning pregestation through to lactation in guinea pig sows was used to induce FGR. Proliferation, differentiation, and apoptosis of cardiomyocytes were assessed in late-gestation fetal, neonatal, and adult guinea pig hearts. Proteomic analysis and pathway enrichment were performed on fetal hearts., Results: Cardiomyocyte proliferation and the number of mononucleated cells were enhanced in the MNR-FGR fetal and neonatal heart, suggesting a delay in cardiomyocyte differentiation. In fetal hearts of MNR-FGR animals, apoptosis was markedly elevated and the total number of cardiomyocytes reduced, the latter remaining so throughout neonatal and into adult life. A reduction in total cardiomyocyte number in adult MNR-FGR hearts was accompanied by exaggerated hypertrophy and a disorganized architecture. Pathway analysis identified genes related to cell proliferation, differentiation, and survival., Conclusions: FGR influences cardiomyocyte development during critical windows of development, leading to a permanent deficiency in cardiomyocyte number and compensatory hypertrophy in a rodent model that recapitulates human development.

Individuals born after intrauterine growth restriction (IUGR) are more impulsive towards palatable foods, but it is not clear 1) if IUGR-related impulsivity is specific for foods and solely based on response inhibition and 2) if the development of impulsivity is due to being born IUGR per se or to growing up fast in the first few years of life (catch up growth). Children were classified in the IUGR group if the birth weight ratio was below 0.85. Delta z score for BMI was used as a measure of catch up growth. In MAVAN (N = 274), impulsivity was measured by the Information Sampling Task from the Cambridge Neuropsychological Test Automated Battery (IST - CANTAB), and in GUSTO using the Sticker Delay Task (N = 327). There is a significant effect of interaction between being born IUGR and the magnitude of catch up growth on the reflection impulsivity from IST-CANTAB at 60 months, in which greater catch up growth associates with greater impulsivity in the IST fixed condition in IUGR children. The finding was reproduced in children from the GUSTO cohort using the Sticker Delay Task. We confirmed that catch up growth interacts with IUGR, having a major role in the development of impulsivity in the first years of life and influencing inhibitory control and decision making processes.

Fetal growth may be impaired by poor placental function or maternal conditions, each of which can influence the transfer of nutrients and oxygen from the mother to the developing fetus. Large-scale studies of metabolites (metabolomics) are key to understand cellular metabolism and pathophysiology of human conditions. Herein, maternal and cord blood plasma samples were used for NMR-based metabolic fingerprinting and profiling, including analysis of the enrichment of circulating lipid classes and subclasses, as well as the number of sub-fraction particles and their size. Changes in phosphatidylcholines and glycoproteins were prominent in growth-restricted fetuses indicating significant alterations in their abundance and biophysical properties. Lipoprotein profiles showed significantly lower plasma concentrations of cholesterol-intermediate density lipoprotein (IDL), triglycerides-IDL and high-density lipoprotein (HDL) in mothers of growth-restricted fetuses compared to controls (p < 0.05). In contrast, growth-restricted fetuses had significantly higher plasma concentrations of cholesterol and triglycerides transporting lipoproteins [LDL, IDL, and VLDL, (p < 0.005; all)], as well as increased VLDL particle types (large, medium and small). Significant changes in plasma concentrations of formate, histidine, isoleucine and citrate in growth-restricted fetuses were also observed. Comprehensive metabolic profiling reveals that both, mother and fetuses of pregnancies complicated with fetal growth restriction have a substantial disruption in lipid metabolism.

Endocrine disrupting chemicals are long suspected to impair reproductive health. Bisphenol A (BPA) has estrogenic activity and therefore the capacity of interfering with endocrine pathways. No studies dissected its short-term effects on pregnancy and possible underlying mechanisms. Here, we studied how BPA exposure around implantation affects pregnancy, particularly concentrating on placentation and uterine remodeling. We exposed pregnant female mice to 50 µg/kg BPA/day or 0.1% ethanol by oral gavage from day 1 to 7 of gestation. High frequency ultrasound was employed to document the presence and size of implantations, placentas and fetuses throughout pregnancy. Blood velocity in the arteria uterina was analyzed by Doppler measurements. The progeny of mothers exposed to BPA was growth-restricted compared to the controls; this was evident in vivo as early as at day 12 as analyzed by ultrasound and confirmed by diminished fetal and placenta weights observed after sacrificing the animals at day 14 of gestation. The remodeling of uterine spiral arteries (SAs) was considerably impaired. We show that short-term exposure to a so-called "safe" BPA dose around implantation has severe consequences. The intrauterine growth restriction observed in more than half of the fetuses from BPA-treated mothers may owe to the direct negative effect of BPA on the remodeling of uterine SAs that limits the blood supply to the fetus. Our work reveals unsuspected short-term effects of BPA on pregnancy and urges to more studies dissecting the mechanisms behind the negative actions of BPA during early pregnancy.

Intra-Uterine Growth Restriction (IUGR) is a major cause of fetal and neonatal mortality. Understanding the impact of IUGR on utero-placental gene expression is key to developing effective therapy. In this report we elucidated the impact of IUGR on NOSTRIN and its downstream effector gene expression in the utero-placental compartments. We showed here that induction of IUGR by maternal dexamethasone administration in rats led to up-regulation of NOSTRIN transcript and protein in the mesometrial triangle of the uterus (MG) and not in other utero-placental compartments as compared to control. This was associated with down-regulation of twelve genes and four cytokines that were known to be regulated by NOSTRIN and also required for maintenance of pregnancy. Interestingly, there was remarkable decrease in phosphorylation of RelA transcription factor in the MG during IUGR in line with the fact that the down regulated genes harbour RelA transcription activation domain in their promoters. Furthermore, HIF-1α level was reciprocal to NOSTRIN expression pattern in the mesometrial compartment during IUGR and also in CoCl 2 treated endothelial cells. Over-expression of HIF-1α led to a decrease in NOSTRIN levels suggesting inhibition of Nostrin transcription by HIF-1α. Our findings highlight the importance of NOSTRIN in uterine pathophysiology during IUGR.

Fetal growth may be a precursory factor in observed association between birthweight and atopic dermatitis (AD), however, recent studies utilizing fetal ultrasound-based data have reported contradictory results. This study aims to clarify previous findings through comprehensive investigation of association between several trimester-specific ultrasound-based anthropometric measures with AD diagnosis by age 3 years. Measurements of 386 newborns in the Ulm SPATZ Health Study were converted into adjusted z-scores categorized as "low" (≤1 SD below mean), "normal," or "high" (≥1 SD above mean). AD cases were defined using parent- or pediatrician-report of physician-diagnosis or clinical diagnosis. Adjusted risk ratios (RR) with 95% confidence intervals (95% CI) were calculated using modified Poisson regression. Compared to normal, both low and high 2 nd trimester abdominal circumference [RR 1.51, (95% CI 1.01; 2.24) and 1.83 (1.21; 2.76)], high 2 nd trimester head- abdominal circumference ratio [1.69 (1.16; 2.48)], and faltering 2 nd to 3 rd trimester [1.59 (1.04; 2.43)] head circumference were associated with greater AD risk. High 3 rd trimester femur length [0.54 (0.31; 0.94)] was associated with lower risk. Using more inclusive exposure cut-points (0.8 SD), lower 1 st trimester crown-rump length was also associated with greater AD risk. Our data suggest several different patterns of fetal growth may be differentially associated with AD.

Aberrant fetal growth is associated with morbidities and mortality during childhood and adult life. Although genetic and environmental factors are known to influence in utero growth, their relative contributions over pregnancy is unknown. We estimated, across gestation, the genetic heritability, contribution of shared environment, and genetic correlations of fetal growth measures (abdominal circumference (AC), humerus length (HL), femur length (FL), and estimated fetal weight (EFW)) in a prospective cohort of dichorionic twin gestations recruited through the NICHD Fetal Growth Studies. Structural equation models were fit at the end of first trimester, during mid-gestation, late second trimester, and third trimester of pregnancy. The contribution of fetal genetics on fetal size increased with gestational age, peaking in late second trimester (AC = 53%, HL = 57%, FL = 72%, EFW = 71%; p < 0.05). In contrast, shared environment explained most of phenotypic variations in fetal growth in the first trimester (AC = 50%, HL = 54%, FL = 47%, EFW = 54%; p < 0.05), suggesting that the first trimester presents an intervention opportunity for a more optimal early fetal growth. Genetic correlations between growth traits (range 0.34-1.00; p < 0.05) were strongest at the end of first trimester and declined with gestation, suggesting that different fetal growth measures are more likely to be influenced by the same genes in early pregnancy.

Fetal growth restriction increases the risk of poor childhood growth and development and chronic disease in adulthood. Yet, little is known about biological pathways that mediate the long-lasting effects of suboptimal intrauterine growth. We explored the plasma proteome in a cohort of 500 Nepalese children 6-8 years of age to identify plasma proteins associated with multiple anthropometric size indicators at birth. Among 982 proteins analyzed, no proteins differed by birth weight, length, or weight-for-length indicators. However, 25 proteins were differentially abundant in children with a small vs normal head circumference at birth (<-2 vs. ≥-2 z-scores of the WHO growth standards). Angiopoietin-like 6 was 19.4% more abundant and the other 24 proteins were 7-21% less abundant in children with a small vs normal head circumference at birth, adjusted for potential confounders. The less abundant proteins included actins, actin filament organizing proteins (α-actinin, talin, filamin, cofilin, profilin, and vinculin), proteins involved in muscle contraction, and glycolytic enzymes, which were all positively correlated with each other. A novel cluster of childhood plasma proteins involved in angiogenesis and cytoskeleton dynamics was associated with a small head size at birth. The prognostic value of an altered proteomic phenotype remains to be investigated.

Indoleamine 2,3-dioxygenase-1 (IDO1) mediates the degradation of L-tryptophan (L-Trp) and is constitutively expressed in the chorionic vascular endothelium of the human placenta with highest levels in the microvasculature. Given that endothelial expression of IDO1 has been shown to regulate vascular tone and blood pressure in mice under the condition of systemic inflammation, we asked whether IDO1 is also involved in the regulation of placental blood flow and if yes, whether this function is potentially impaired in intrauterine growth restriction (IUGR) and pre-eclampsia (PE). In the large arteries of the chorionic plate L-Trp induced relaxation only after upregulation of IDO1 using interferon gamma and tumor necrosis factor alpha. However, ex vivo placental perfusion of pre-constricted cotyledonic vasculature with L-Trp decreases the vessel back pressure without prior IDO1 induction. Further to this finding, IDO1 protein expression and activity is reduced in IUGR and PE when compared to gestational age-matched control tissue. These data suggest that L-Trp catabolism plays a role in the regulation of placental vascular tone, a finding which is potentially linked to placental and fetal growth. In this context our data suggest that IDO1 deficiency is related to the pathogenesis of IUGR and PE.

Objective: To assess arterial morphology and mechanics in preterm infants with fetal growth restriction (FGR) compared with those appropriate for gestational age (AGA) in the early neonatal period., Study Design: This observational study involved 20 preterm FGR infants (28 to 32 weeks) of gestational age (GA) and birth weight (BW) <10th centile and 20 preterm AGA infants. Vascular ultrasound was performed to measure aortic properties., Results: GA and BW of FGR and AGA infants were 29.8±1.3 vs 30±0.9 weeks (P=0.78) and 923.4±168 vs 1403±237 g (P<0.001), respectively. At 10.5±1.3 (s.d.) days after birth, blood pressure (systolic 51±3 vs 46±4 mm Hg, P<0.001) and maximum aorta intima-media thickness (621±76 vs 479±54 μm; P<0.001) were significantly higher in FGR infants. Arterial wall stiffness and peripheral resistance were also increased in the FGR infants (2.36±0.24 vs 2.14±0.24, P=0.008 and 22.2±5 vs 13.7±2.3 mm Hg min ml -1 , P<0.001), respectively. Significant correlations between vascular mechanics and cardiac function were observed (resistance vs E/E', r=0.7 and Tei index, r=0.79)., Conclusion: Maladaptive arterial-ventricular coupling was noted. Early detection may aid in early therapeutic strategies such as afterload reduction.

Pregnancies in women of advanced maternal age (AMA) are susceptible to fetal growth restriction (FGR) and stillbirth. We hypothesised that maternal ageing is associated with utero-placental dysfunction, predisposing to adverse fetal outcomes. Women of AMA (≥35 years) and young controls (20-30 years) with uncomplicated pregnancies were studied. Placentas from AMA women exhibited increased syncytial nuclear aggregates and decreased proliferation, and had increased amino acid transporter activity. Chorionic plate and myometrial artery relaxation was increased compared to controls. AMA was associated with lower maternal serum PAPP-A and sFlt and a higher PlGF:sFlt ratio. AMA mice (38-41 weeks) at E17.5 had fewer pups, more late fetal deaths, reduced fetal weight, increased placental weight and reduced fetal:placental weight ratio compared to 8-12 week controls. Maternofetal clearance of 14 C-MeAIB and 3 H-taurine was reduced and uterine arteries showed increased relaxation. These studies identify reduced placental efficiency and altered placental function with AMA in women, with evidence of placental adaptations in normal pregnancies. The AMA mouse model complements the human studies, demonstrating high rates of adverse fetal outcomes and commonalities in placental phenotype. These findings highlight placental dysfunction as a potential mechanism for susceptibility to FGR and stillbirth with AMA.

BackgroundWe determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts markers for tissue hypoxia, implicating a mechanistic role for chronic hypoxia.MethodsGuinea pigs were fed ad libitum (Control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Near term, hypoxyprobe-1 (HP-1), a marker of tissue hypoxia, was injected into pregnant sows. Fetuses were then necropsied and liver, kidney, and placental tissues were processed for erythropoietin (EPO), EPO-receptor (EPOR), and vascular endothelial growth factor (VEGF) protein levels, and for HP-1 immunoreactivity (IR).ResultsFGR-MNR fetuses were 36% smaller with asymmetrical growth restriction compared to controls. EPO and VEGF protein levels were increased in the female FGR-MNR fetuses, providing support for hypoxic stimulus and linkage to increased erythropoiesis, but not in the male FGR-MNR fetuses, possibly reflecting a weaker link between oxygenation and erythropoiesis. HP-1 IR was increased in the liver and kidneys of both male and female FGR-MNR fetuses as an index of local tissue hypoxia, but with no changes in the placenta.ConclusionChronic hypoxia is likely to be an important signaling mechanism for the decreased fetal growth seen with maternal undernutrition and appears to be post-placental in nature.

Objective: A proper maternal cardiovascular adaptation to the pregnancy plays a key role for promoting an adequate uteroplacental perfusion, for ensuring normal fetal development and for preventing gestational hypertensive complications such as preeclampsia. This study aims to evaluate hemodynamic measurements obtained by noninvasive methods among preclamptic women with and without fetal growth restriction (FGR) and the relationship with plasma levels of natriuretic peptides., Study Design: The study compared 98 pregnant women (n=48 with preeclampsia; n=50 normotensive pregnant women) and 50 nonpregnant normotensive control subjects undergoing anultrasonic cardiac output monitor (USCOM) and plasma assessment of atrial N-terminal pro B-type natriuretic peptide (NT-proBNP). The statistical analysis was carried out by analysis of variance and correlation analysis., Results: Preeclampsia state is associated with increased vascular resistance (mean 1587±236 vs 978±153 dyn s cm -3 ) and lower cardiac output (mean 5.7±1.1 vs 6.78±0.8 l) and this hemodynamic state is associated with higher levels of NT-proBNP (mean 121.2±26.3 vs 42.5±11.4 pg ml -1 ); furthermore, we found an inverse correlation between maternal cardiac output and plasma levels of NT-proBNP only if preeclampsia is associated with FGR., Conclusion: The elevated NT-proBNP in preeclampsia may reflect ventricular stress and subclinical cardiac dysfunction worsening if FGR is present. This may have implications for the acute management of the preeclampsia and FGR women and for appropriately timed therapeutic interventions later in life.

Ischemic placental disease is a concept that links intrauterine growth retardation (IUGR) and preeclampsia (PE) back to insufficient remodeling of uterine spiral arteries. The rheological consequences of insufficient remodeling of uterine spiral arteries were hypothesized to mediate the considerably later manifestation of obstetric disease. However, the micro-rheology in the intervillous space (IVS) cannot be examined clinically and rheological animal models of the human IVS do not exist. Thus, an in silico approach was implemented to provide in vivo inaccessible data. The morphology of a spiral artery and the inflow region of the IVS were three-dimensionally reconstructed to provide a morphological stage for the simulations. Advanced high-end supercomputing resources were used to provide blood flow simulations at high spatial resolution. Our simulations revealed turbulent blood flow (high-velocity jets and vortices) combined with elevated blood pressure in the IVS and increased wall shear stress at the villous surface in conjunction with insufficient spiral artery remodeling only. Post-hoc histological analysis of uterine veins showed evidence of increased trophoblast shedding in an IUGR placenta. Our data support that rheological alteration in the IVS is a relevant mechanism linking ischemic placental disease to altered structural integrity and function of the placenta.

Inbred strains of mice are powerful models for understanding human pregnancy complications. For example, the exclusive mating of CBA/J females to DBA/2J males increases fetal resorption to 20-35% with an associated decline in placentation and maintenance of maternal Th1 immunity. More recently other complications of pregnancy, IUGR and preeclampsia, have been reported in this model. The aim of this study was to qualify whether the CBA/CaH substrain female can substitute for CBA/J to evoke a phenotype of embryonic/fetal mortality and IUGR. (CBA/CaH × DBA/2J) F1 had significantly higher embryonic/fetal mortality mortality (p = 0.0063), smaller fetuses (p < 0.0001), and greater prevalence of IUGR (<10 th percentile; 47% vs 10%) than (CBA/CaH × Balb/c) F1. Placentae from IUGR fetuses from all mating groups were significantly smaller (p < 0.0001) with evidence of thrombosis and fibrosis when compared to normal-weight fetuses ( > 10 th percentile). In addition, placentae of "normal-weight" (CBA/CaH × DBA/2J) F1 were significantly smaller (p < 0.0006) with a greater proportion of labyrinth (p = 0.0128) and an 11-fold increase in F4/80 + macrophage infiltration (p < 0.0001) when compared to placentae of (CBA/CaH × Balb/c) F1. In conclusion, the embryonic/fetal mortality and IUGR phenotype is not exclusive to CBA/J female mouse, and CBA/CaH females can be substituted to provide a model for the assessment of novel therapeutics.

Background: Cardiovascular dysfunction at birth may underlie poor outcomes after fetal growth restriction (FGR) in neonates. We compared the cardiovascular transition between FGR and appropriately grown (AG) preterm lambs and examined possible mechanisms underlying any cardiovascular dysfunction in FGR lambs., Methods: FGR was induced in ewes bearing twins at 0.7 gestation; the twin was used as an internal control (AG). At 0.8 gestation, lambs were delivered and either euthanized with their arteries isolated for in vitro wire myography, or ventilated for 2 h. At 60 min, inhaled nitric oxide (iNO) was administered in a subgroup for 30 min. Molecular assessment of the nitric oxide (NO) pathway within lung tissue was conducted., Results: FGR lambs had lower left ventricular output and cerebral blood flow (CBF) and higher systemic vascular resistance compared with AG lambs. INO administration to FGR lambs rapidly improved cardiovascular and systemic hemodynamics but resulted in decreased CBF in AG lambs. Isolated arteries from FGR lambs showed impaired sensitivity to NO donors, but enhanced vasodilation to Sildenafil and Sodium nitroprusside, and altered expression of components of the NO pathway., Conclusion: Cardiovascular dysfunction at birth may underlie the increased morbidity and mortality observed in preterm FGR newborns. Impaired NO signaling likely underlies the abnormal vascular reactivity.

Background: Intrauterine growth restriction (IUGR) predisposes to cardiovascular diseases in adulthood. The mechanisms of this phenomenon remain cryptic. We hypothesized that heart mitochondria in IUGR-born adult rats are more sensitive to acute hypoxia which translates into dysfunctional cardiac response to hypoxic stress., Methods: Adult IUGR-born male rats (the offspring of dams fed with calories-restricted diet during pregnancy) were exposed to acute hypoxic stress with echocardiographic assessment of cardiac function. In parallel, mitochondrial respiration in organelles isolated from left ventricle (LV) and right ventricle (RV) was tested in normoxic and anoxic conditions. The extent of post-anoxic inhibition of mitochondrial respiration and cardiac function was compared with controls, non-IUGR rats., Results: Compared with controls, in the IUGR rats hypoxia significantly reduced only RV contractility, evidenced by decreased fractional shortening, functional area of contraction, and tricuspid annular plane systolic excursion. In isolated mitochondria, anoxic challenge inhibited respiratory chain in both groups of rats. However, compared with controls, the extent of anoxic mitochondrial depression was significantly greater in IUGR-born rats, but only in the organelles isolated from RV., Conclusions: In adult IUGR-born rats, mitochondria from RV are hypersensitive to oxygen deprivation and this translates into maladaptive RV cardiac response to acute hypoxia.

Objective: To test the hypothesis that fetuses exposed to maternal preeclampsia or chronic hypertension have deranged development of cardiac time intervals., Study Design: Pregnancies were divided into three groups: Intrauterine Growth Restricted (IUGR), Hypertensive, and Normal. Each group's mean fetal cardiac time intervals (P, PR, QRS and RR) derived by magnetocardiography were calculated using an analysis of covariance model's regression-adjusted estimates for a gestational age of 35 weeks., Results: We reviewed 141 recordings from 21 IUGR, 46 Hypertensive and 74 Normal patients. The IUGR, Hypertensive and Normal groups, respectively, had adjusted mean intervals in milliseconds of 66.4, 66.8 and 76.2 for P (P=0.001), 95.9, 101.6 and 109.6 for PR (P=0.002), 77.2, 78.7 and 78.7 for QRS (P=0.81) and 429.8, 429.2 and 428.5 for RR (P=0.97)., Conclusion: P and PR intervals are abbreviated in normotrophic fetuses exposed to maternal hypertension, suggesting shortened atrioventricular conduction times.

Intrauterine growth restriction (IUGR) refers to the situation where a fetus does not grow according to its genetic growth potential. One of the main causes of IUGR is uteroplacental vascular insufficiency. Under these circumstances of chronic oxygen and nutrient deprivation, the growth-restricted fetus often displays typical circulatory changes, which in part represent adaptations to the suboptimal intrauterine environment. These fetal adaptations aim to preserve oxygen and nutrient supply to vital organs such as the brain, the heart, and the adrenals. These prenatal circulatory adaptations are thought to lead to an altered development of the cardiovascular system and "program" the fetus for life long cardiovascular morbidities. In this review, we discuss the alterations to cardiovascular structure, function, and control that have been observed in growth-restricted fetuses, neonates, and infants following uteroplacental vascular insufficiency. We also discuss the current knowledge on early life surveillance and interventions to prevent progression into chronic disease.

Background: The aim of this study was to establish the underlying mechanisms by which a post-weaning high-fat diet (HFD) accelerates the perinatal programming of kidney injury occurring in the offspring of diabetic mothers., Methods: Male mice, offspring of nondiabetic and diabetic dams were fed with normal diet (ND) or HFD from 4 to 20 wk of age. Rat renal proximal tubular cells were used in vitro., Results: On ND, the offspring of dams with severe maternal diabetes had an intrauterine growth restriction (IUGR) phenotype and developed mild hypertension and evidence of kidney injury in adulthood. Exposing the IUGR offspring to HFD resulted in rapid weight gain, catch-up growth, and later to profound kidney injury with activation of renal TGFβ1 and collagen type IV expression, increased oxidative stress, and enhanced renal lipid deposition, but not systemic hypertension. Given our data, we speculate that HFD or free fatty acids may accelerate the process of perinatal programming of kidney injury, via increased CD36 and fatty acid-binding protein 4 expression, which may target reactive oxygen species, nuclear factor-kappa B, and TGFβ1 signaling in vivo and in vitro., Conclusion: Early postnatal exposure to overnutrition with a HFD increases the risk of development of kidney injury, but not hypertension, in IUGR offspring of dams with maternal diabetes.

Background: Our aim was to determine the influence of breastfeeding and postnatal nutrition on cardiovascular remodeling induced by fetal growth restriction (FGR)., Methods: A cohort study including 81 children with birthweight <10th centile (FGR) and 121 with adequate fetal growth for gestational age (AGA) was conducted. Cardiovascular endpoints were left ventricular sphericity index (LVSI), carotid intima-media thickness (cIMT), and blood pressure (BP) at 4-5 y of age. The combined effect of FGR and postnatal variables-including breastfeeding, fat dietary intake, and BMI-on cardiovascular endpoints was assessed by linear and robust regressions., Results: FGR was the strongest predictor of cardiovascular remodeling in childhood, leading to lower LVSI and increased cIMT and BP as compared with AGA. Breastfeeding >6 mo (coefficient: 0.0982) and healthy-fat dietary intake (coefficient: -0.0128) showed an independent beneficial effect on LVSI and cIMT, respectively. Overweight/obesity induced an additional increment of 1 SD on cIMT in FGR children (interaction coefficient: 0.0307) when compared with its effect in AGA. BMI increased systolic BP (coefficient: 0.7830) while weight catch-up increased diastolic BP (coefficient: 4.8929)., Conclusions: Postnatal nutrition ameliorates cardiovascular remodeling induced by FGR. Breastfeeding and healthy-fat dietary intake improved while increased BMI worsened cardiovascular endpoints, which opens opportunities for targeted postnatal interventions from early life.

Background: Intrauterine growth restriction (IUGR) and postnatal nutrition are risk factors for cardiovascular and renal diseases in both humans and animals. The long-term renal effects of protein intake early in life remain unknown. The objective was to evaluate the effects of a neonatal feeding with high protein (HP) milk on renal functions and structure in IUGR male rats., Methods: Maternal gestational low protein diet was used to produce IUGR. At day 5, IUGR pups were gastrostomized in the "pup-in-the cup" model and received either normal protein (NP) milk or HP (+50% protein content) milk until day 21. After weaning, the animals were fed the same standard diet. Renal functions and structure were assessed at postnatal day 18 (D18) and in adult offspring., Results: During the preweaning period, the postnatal weight gain between the two groups was unaffected. On D18, kidneys from HP offspring were heavier with significant glomerular hypertrophy (+40%, P < 0.05). HP diet was associated with significant proteinuria and glomerulosclerosis (+49%, P < 0.05). Glomerular number was unaltered., Conclusion: Neonatal HP feeding following IUGR affects renal functions and structure at adulthood. These alterations may result from a single nephron glomerular hyperfiltration.

Background: Few studies have addressed the growing concerns of chronic kidney diseases in children with intrauterine growth restriction (IUGR). Therefore, the purpose of this study was to evaluate long-term kidney dysfunction and determine if urinary angiotensinogen (AGT) was suitable as a novel early biomarker for kidney dysfunction in IUGR offspring., Methods: Pregnant rats underwent bilateral uterine artery ligation, and as a control group, sham surgeries were performed., Results: The birth weight was reduced, the urinary AGT to creatinine ratio was significantly higher at week 20, and urinary protein levels were significantly higher at week 32 in IUGR rats than in control rats. On the other hand, the histological findings at week 32 revealed long-term kidney dysfunction, more severe glomerulosclerosis, and greater glomerular diameters in IUGR rats. Moreover, AGT mRNA expression and immunohistological staining were significantly increased in IUGR rats; this suggests that the intrarenal renin-angiotensin system (RAS) contributes to renal dysfunction of IUGR offspring., Conclusion: Urinary AGT elevation prior to urinary protein levels suggests that AGT is an early biomarker. At week 32, kidney dysfunction was severe in IUGR rats and intrarenal RAS appeared to be one of the causes.

We investigated the association between maternal zinc level during pregnancy and the risks of low birth weight (LBW) and small for gestational age (SGA) infants in a large population-based birth cohort study. In this study, 3187 pregnant women were recruited. For serum zinc level, 2940 pregnant women were sufficient (≥56 μg/dL) and 247 deficient (<56 μg/dL). Of interest, 7.3% newborns were with LBW among subjects with low zinc level (RR: 3.48; 95% CI: 2.03, 5.96; P < 0.001). Adjusted RR for LBW was 3.41 (95% CI: 1.97, 5.91; P < 0.001) among subjects with low zinc level. Moreover, 15.0% newborns were with SGA among subjects with low zinc level (RR: 1.98; 95% CI: 1.36, 2.88; P < 0.001). Adjusted RR for SGA was 1.93 (95% CI: 1.32, 2.82; P < 0.001) among subjects with low zinc level. A nested case-control study within above cohort showed that maternal serum zinc level was lower in SGA cases as compared with controls. By contrast, maternal serum C-reactive protein, TNF-α and IL-8 levels were significantly higher in SGA cases than that of controls. Moreover, nuclear NF-κB p65 was significantly up-regulated in placentas of SGA cases as compared with controls. Taken together, maternal zinc deficiency during pregnancy elevates the risks of LBW and SGA infants.

Background: Intrauterine growth restriction (IUGR) is a frequent complication of pregnancy defined as a restriction of fetal growth. The objective of this work was to improve the knowledge on the pathophysiology of IUGR using a genome-wide method of expression analysis., Methods: We analyzed differentially expressed genes in pooled placental tissues from vascular IUGR (four pools of three placentas) and normal pregnancies (four pools of three placentas) using a long nucleotide microarray platform (Nimblegen). We first did a global bioinformatics analysis based only on P value without any a priori. We secondly focused on "target" genes among the most modified ones. Finally, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed on an extended panel of tissue samples (n = 62) on selected "target"., Results: We identified 636 modified genes among which 206 were upregulated (1.5 and higher; P < 0.05). Groups of patients were classified unambiguously. Genes involved in mitochondrial function and oxidative phosphorylation were decreased affecting three out of five complexes of the respiratory chain of the mitochondria, and thus energy production and metabolism. Among the most induced genes, we identified LEP, IGFBP1, and RBP4., Conclusion: Complementary studies on the role and function of LEP, IGFBP1, and RBP4 in IUGR pathophysiology and also in fetal programming remain necessary.

Objective: To study the association between the cerebroplacental ratio (CPR) and the development of pre-eclampsia., Study Design: Three study groups were determined: Group 1-normal umbilical artery (UA; referent), Group 2-abnormal UA and normal CPR and Group 3-abnormal UA and an abnormal CPR. The primary outcome was the development of severe pre-eclampsia., Results: We included 270 women. Women in Group 3 had significantly elevated rates of severe pre-eclampsia versus those in Group 1 and Group 2, 52.5% versus 5.1% and 15.4%, respectively, (P<0.01), adjusted odds ratio 4.14 (95% confidence interval, 2.59 to 6.61). Kaplan-Meier analysis revealed earlier delivery in women with pre-eclampsia in Group 3 versus Group 1, Cox-Mantel hazard ratio 2.39 (1.17 to 4.88), log rank P=0.01., Conclusion: An abnormal CPR is associated with a higher rate severe pre-eclampsia with delivery at earlier gestational ages than with a normal UA or an abnormal UA, but normal CPR.